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Four-Component Synthesis of 1,2-Dihydropyridine Derivatives and their Evaluation as Anticancer Agents
Mohamed A. O. Abdelf-Fattah, Mahmoud A. M. El-Naggar, Rasha M. H. Rashied, Bernard D. Gary, Gary A. Piazza and Ashraf H. Abadi
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00001]


CoMFA and CoMSIA Studies of 1,2-Dihydropyridine Derivatives as Anticancer Agents
Ismail Salama, Mohamed A. O. Abdel-Fattah, Marwa S. Hany, Shaimaa A. El-Sharif, Mahmoud A. M. El-Naggar, Rasha M. H. Rashied, Gary A. Piazza and Ashraf H. Abadi
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00002]


First Study on Antimicriobial Activity And Synergy between Isothiocyanates And Antibiotics Against Selected Gram-Negative And Gram-Positive Pathogenic Bacteria From Clinical And Animal Source
Carla Dias, Alfredo Aires, Richard N. Bennett, Eduardo A. S. Rosa and Maria J. Saavedra
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00003]


In vitro Anti-glycation and Anti-oxidant Properties of Synthesized Schiff Bases
Sabina Jhaumeer-Laulloo, Minu Gupta Bhowon, Shabneez Mungur, Mohamad Fawzi Mahomoodally and Anwar Hussein Subratty
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00004]


Synthesis and Biological Evaluation Of The Salicylamide and Salicylic Acid Derivatives As Anti-Estrogen Agents
Yasemin Dündar, Yasemin Özatik, Orhan Özatik, Volkan Ergin, Tijen Önkol, Adnan Menevşe, Kevser Erol and M. Fethi Şahin
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00005]


Synthesis and Activity of [{Cis-PtCl(NH3)2}2µ{Trans-Pt(3-Hydroxypyridine)2(H2N(CH2)6NH2)2}]Cl4 in the Human Ovarian Tumour Models
Shahnaz AH Hamad, Philip Beale, Jun Qing Yu, Keith Fisher and Fazlul Huq
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00006]


Biological and Anti-inflammatory Evaluation of Two Thiazole Compounds in RAW Cell Line: Potential Cyclooxygenase-2 Specific Inhibitors
Eva Hamade, Aida Habib, Ali Hachem, Alaa H. Hussein, Malak Abbas, Taghreed Hirz, Mirvat Al Masri and Wissam H. Faour
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00007]


New Adamantane Derivatives with Sigma Affinity and Antiproliferative Activity
Stefanos Riganas, Ioannis Papanastasiou, George B. Foscolos, Andrew Tsotinis, Kostas Dimas, Vassilios N. Kourafalos, Andreas Eleutheriades, Vassilios I. Moutsos, Humaira Khan, Prassa Margarita, Stavroula Georgakopoulou, Angeliki Zaniou, Maria Theodoropoulou, Athanasios Mantelas, Stavroula Pondiki and Alexandre Vamvakides
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00008]


Synthesis of Novel 4-Aryl-1,2,3,4-tetrahydroisoquinolines as Probes for Dopamine Receptor Ligands
Gianfabio Giorgioni, Dario Ambrosini, Giovanni Filippo Palmieri, Barbara Costa, Antonio Di Stefano and Claudia Martini
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00009]


A Quantitative Structure-Activity Relationship Study on a Few Series of Anti-hepatitis C Virus Agents
Jonish Varshney, Anjana Sharma and Satya P. Gupta
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00010]


Synthesis and Antiglycation Activity of Kaempferol-3-O-rutinoside (Nicotiflorin)
Sajan Lal Shyaula, Ghulam Abbas, Hina Siddiqui, Samina A. Sattar, M. Iqbal Choudhary and Fatima Z. Basha
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00011]


Synthesis and β-Glucuronidase Inhibitory Potential of Benzimidazole Derivatives
Khalid Mohammed Khan, Momin Khan, Nida Ambreen, Fazal Rahim, Shagufta Naureen, Shahnaz Perveen, M. Iqbal Choudhary and Wolfgang Voelter
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00012]


Synthesis and Biological Evaluation of Some New N4-Aryl Substituted 5-Chloroisatin-3 thiosemicarbazones
Humayun Pervez, Muhammad Ramzan, Muhammad Yaqub, Faiz-Ul-Hassan Nasim and Khalid Mohammed Khan
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00013]


2,4,6-Trichlorophenylhydrazine Schiff Bases as DPPH Radical and Super Oxide Anion Scavengers
Khalid Mohammed Khan, Zarbad Shah, Viqar Uddin Ahmad, Momin Khan, Muhammad Taha, Fazal Rahim, Sajjad Ali, Nida Ambreen, Shahnaz Perveen, M. Iqbal Choudhary and Wolfgang Voelter
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00014]


Application of Artificial Neural Networks for the Prediction Of Antitumor Activity of A Series of Acridinone Derivatives
Marcin Koba
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00015]


Synthesis and Biological Evaluation of 3΄-C-Ethynyl and 3΄-C-(1,4-disubstituted-1,2,3-triazolo) Double-Headed Pyranonucleosides
Christos Kiritsis, Stella Manta, Ioannis Papasotiriou, Evdoxia Coutouli-Argyropoulou, Sakellarios Trakossas, Jan Balzarini  and Dimitri Komiotis
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00016]


Structure-Activity Relationships of Pyrrole Hydrazones as New Anti-Tuberculosis Agents
Iglika Lessigiarska, Ilza Pajeva, Penka Prodanova, Maya Georgieva and Atanas Bijev
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00017]


S-Ntrosylation and Attenuation of Excessive Calcium Flux by Pentacycloundecane Deriva Tives
Hendrik, J.R. Lemmer, Jacques Joubert, Sandra van Dyk, Francois, H. van der Westhuizen and Sarel, F. Malan
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00018]


Serum Specific Vasopressin-Degrading Activity is Related to Blood Total Cholesterol Levels in Men But not In Women
Ramírez-Expósito  María Jesús, Arrazola  Marcelina, Carrera- González María Pilar, Arias de Saavedra  José Manuel, Sánchez-Agesta  Rafael, Mayas María Dolores and Martínez-Martos José Manuel
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00019]


SAR Analysis of New Dual Targeting Fluoroquinolones. Implications of the Benzenesulfonyl Group
Marcelo J. Nieto, Adriana B. Pierini, Nidhi Singh, Christopher R. McCurdy, Ruben H. Manzo and María R. Mazzieri
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00020]


Prodrug Strategies in Ocular Drug Delivery
Megha Barot, Mahuya Bagui, Mitan R. Gokulgandhi and Ashim K. Mitra
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00021]


Synthesis and Biological Evaluation of Naloxone and Naltrexone-Derived Hybrid Opioids
Bahman E. Nassim and Ming-Lei Wang
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00022]


A QSAR Analysis of 2-phenoxy-N-substituted acetamide Analogues as Hypoxia-Inducible Factor-1(HIF-1) inhibitors: A Rational Approach to Anticancer Drug Design
Malleshappa N. Noolvi, Harun M. Patel and Sarita Kamboj
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00023]


Synthesis, In Vitro And In Silico Ns5b Polymerase Inhibitory Activity Of Benzimidazole Derivatives
Vaishali M. Patil, Gurukumar K. R., Maksim Chudayeu, Satya Prakash Gupta, Subeer Samanta, Neeraj Masand and Neerja Kaushik-Basu
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00024]


A new Class of Anticonvulsants Possessing 6 Hz Psychomotor Seizure Test Activity: 2-(1H-Benzotriazol-1-yl)-N'-[Substituted] Acetohydrazides
Praveen Kumar, Birendra Shrivastava, Surendra Nath Pandeya, Laxmi Tripathi  and James P. Stables
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00025]


Synthesis and Biological Evaluation of a Series of 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-2-substituted Tetrahydroisoquinoline Derivatives
Zhi-hong Zou, Xiao-bu Lan, Chun-lei Tang, Xiao-yun Zhu, Bao-min Liu, Hai Qian, Wen-long Huang and Yun-man Li
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00026]


Generation of Pharmacophore and Atom Based 3D-QSAR Model of Novel Isoquinolin-1-one and Quinazolin-4-one-type Inhibitors of TNFα
Pradeep Hanumanthappa, Mahesh K. Teli and Rajanikant G. Krishnamurthy
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00027]


A QSAR Study of Biphenyl Analogues of 2-Nitroimidazo-[2, 1-b] [1, 3] - oxazines as Antitubercular Agents using Genetic Function Approximation
Supratim Ray and Partha Pratim Roy
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00028]


Differences in Vanadocene Dichloride And Cisplatin Effect on MOLT-4 Leukemia and Human peripheral Blood Mononuclear Cells
Havelek Radim, Siman Pavel, Cmielova Jana, Stoklasova Alena, Vavrova Jirina, Vinklarek Jaromir, Knizek Jiri and Rezacova Martina
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00029]


In Vitro Synergy Testing of Anidulafungin with Fluconazole, Tioconazole,  5-Flucytosine and Amphotericin B  Against Some Candida spp
Antonio Rosato,  Monica Piarulli,  Brigida Immacolata Pia Schiavone,  Maria Teresa Montagna,  Giuseppina Caggiano,  Marilena Muraglia,  Addolorata Carone, Carlo Franchini and Filomena Corbo
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00030]


Structural Insight for Imidazopyridazines as Malarial Kinase PfPK7 Inhibitors Using QSAR Techniques
Nitendra K. Sahu and D. V. Kohli
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00031]


Substituted Urea Derivatives: A Potent Class of Antidepressant Agents
Shahnaz Perveen, Sana Mustafa, Muhammad A. Khan, Ahsana Dar Khalid M. Khan and Wolfgang Voelter
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00032]


A QSAR Study on Novel Series of Carbonic Anhydrase Inhibitors  hCA IX—Tumor-Associated (Hypoxia)
Shalini Singh
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00033]


Synthesis and ¹⁸⁸Re Radiolabelling of Dendrimer Polyamide Amine (PAMAM) Folic Acid Conjugate
Wei Cui, Yuanqing Zhang, Xiaoping Xu and Yu-Mei Shen
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00034]


Computational Approaches To Improve Aggrecanase-1 Inhibitory Activity Of (4-Keto) Phenoxy) Methyl biphenyl-4-Sulfonamide: Group Based QSAR and Docking Studie
Ponnurengam Malliappan Sivakumar, J. Mohanapriya, Naga Vignesh Selva Raj, G. Ramesh  and Mukesh Doble
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00035]


In vitro Antibacterial and Antifungal Activity of Salicylanilide Pyrazine-2-Carboxylates
Martin Krátký, Jarmila Vinšová and Vladimír Buchta
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00036]


Design, Synthesis and Multidrug Resistance Reversal Activity Evaluation of 8-Oxocoptisine Derivatives
Jian Bo Wu, Fan Lei, Xiang Juan Cui, Yun He, Li Hai, Juan Zhang and Yong Wu
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00037]


Design, Synthesis and Antiproliferative Studies Of 2-Acetylamino-Thiazole-5-Carboxamide Derivatives
Wukun Liu, Jinpei Zhou, Yu Zheng, Fan Qi, Huibin Zhang, Hai Qian, Jing Wang, Yanhua Chen and Ronald Gust
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00038]


Synthesis of 3-(2, 8, 9-Trioxa-5-Aza-1-Germatricyclo [3.3.3.0] Undecane-1-Yl)-3-(4-Hydroxyl-3- Methoxyphenyl)-Propionic Acid and its Inhibitory Effect on the Cervical Tumor U14 In Vitro and In Vivo
Lianbao Ye, Xiaomin Ou, Xuedong Peng and Yan Luo
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00039]


A QSAR Study on a Series of Pyrrole Derivatives Acting as Lymphocyte-Specific Kinase (Lck) Inhibitors
Zaihra Anwe and Satya P. Gupta
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00040]


Acylhydrazide Schiff Bases: DPPH Radical and Superoxide Anion Scavengers
Khalid Mohammed Khan, Muhammad Taha, Farzana Naz, Salman Siddiqui, Sajjad Ali, Fazal Rahim, Shahnaz Perveen and M. Iqbal Choudhary
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00041]


The Preformulation Stability Studies of a Proline Prodrug of Methotrexate
Ann Stephenson, Zhiqian Wu and Xudong Yuan
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00042]


Synthesis of a Biodegradable Magnetic Nanomedicine Based on the Antitumor Molecule Tegafur
José L. Arias, Eva Sáez-Fernández, Margarita López-Viota, Rafael A. Biedma-Ortiz and M Adolfina Ruiz
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00043]


Monodisperse Nanoparticles from Self-Assembled Amphiphilic Cyclodextrins: Modulable Tools for the Encapsulation and Controlled Release of Pharmaceuticals
Alejandro Mendez-Ardoy, Marta Gómez-García, Annabelle Gèze, Jean-Luc Putaux, Denis Wouessidjewe, Carmen Ortiz Mellet, Jacques Defaye, José M. García Fernández and Juan M. Benito
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00044]


Use of Flow Focusing^® Technology to Produce Tobramycin-Loaded Plga Microparticles for Pulmonary Drug Delivery
L. Martín-Banderas, M.A. Holgado, J. Álvarez-Fuentes and M. Fernández-Arévalo
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00045]


Preparation, Chemical and Electrical Characterizations of Lipid Nanoparticles Loaded with Dihydroxybenzophenone
Hierrezuelo Jesús, Benavente Juana, López–Romero Juan Manuel, Martínez de Yuso Maria del Valle and Rodríguez–Castellón Enrique
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00046]


Diagnosis of Alterations of Serum Calcium Metabolism
F. Lumachi, P. Cappelletti, R. Tozzoli, S.M.M. Basso, G. Luisetto and V. Camozzi
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00047]


Treatment of Acute Hypercalcemia
S.M.M. Basso, F. Lumachi, F. Nascimben, G. Luisetto and V. Camozzi
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00048]


Treatment of Chronic Hypercalcemia
V. Camozzi, G. Luisetto, S.M.M. Basso, P. Cappelletti, R. Tozzoli and F. Lumachi
[Abstract] [FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00049]



Abstracts


Four-Component Synthesis of 1,2-Dihydropyridine Derivatives and their Evaluation as Anticancer Agents
Mohamed A. O. Abdelf-Fattah, Mahmoud A. M. El-Naggar, Rasha M. H. Rashied, Bernard D. Gary, Gary A. Piazza and Ashraf H. Abadi
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00001]

Two series of compounds with the general formula of 4,6-diaryl-2-oxo-1,2 dihydropyridine-3-carbonitriles and their isosteric imino derivatives were synthesized through a one pot reaction of acetophenone, aldehyde and ammonium acetate with ethyl cyanoacetate or malononitrile, respectively. The synthesized compounds were evaluated for tumor cell growth inhibitory using  the human HT-29 colon and MDA-MB-231 breast tumor cell lines. Compound 4-(2-Ethoxyphenyl)-2-imino-6-(4-fluorophenyl)-1,2-dihydropyridine-3 carbonitrile (6) showed IC₅₀ value of 0.70 μM versus HT-29. Meanwhile, compound 4-(2-Hydroxyphenyl)-2-imino-6-(4-fluorophenyl)-1,2-dihydropyridine-3-carbonitrile (4) showed IC₅₀ value of 4.6 μM versus MDA-MB-231. Docking compound 10 to  possible molecular targets, survivin and PIM1 kinase showed appreciable interactions with both, which suggest possible targets for the antitumor activity of this novel class of anticancer compounds.
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CoMFA and CoMSIA Studies of 1,2-Dihydropyridine Derivatives as Anticancer Agents
Ismail Salama, Mohamed A. O. Abdel-Fattah, Marwa S. Hany, Shaimaa A. El-Sharif, Mahmoud A. M. El-Naggar, Rasha M. H. Rashied, Gary A. Piazza and Ashraf H. Abadi
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00002]

Taking advantage of our in-house experimental data on 3-cyano-2-imino-1, 2-dihydropyridine and 3-cyano-2-oxo-1,2-dihydropyridine derivatives as inhibitors of the growth of the human HT-29 colon adenocarcinoma tumor cell line, we have established a highly significant CoMFA and CoMSIA models (q² _cv =0.70/0.639). The models were investigated to assure their stability and predictivity (r² _pred= 0.65/0.61) and successfully applied to design a new potential cell growth inhibitory agent with IC50s in the submicromolar range.
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First Study on Antimicriobial Activity And Synergy between Isothiocyanates And Antibiotics Against Selected Gram-Negative And Gram-Positive Pathogenic Bacteria From Clinical And Animal Source
Carla Dias, Alfredo Aires, Richard N. Bennett, Eduardo A. S. Rosa and Maria J. Saavedra
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00003]

The emergence of new diseases and the resurgence of several infections that were controlled in the past, associated with recent increase of bacterial resistance have created the necessity for more studies towards to the development of new antimicrobials and new treatment strategies. The aim of the present study was to evaluate the in vitro synergy between different classes of important glucosinolates hydrolysis products-isothiocyanates with antibiotics (gentamycin and vancomycin), against important pathogenic bacteria: Escherichia coli, Enterococcus faecalis, Listeria monocytogenes, Pseudomonas aeruginosa and Staphylococcus aureus. A disc diffusion method was used to evaluate the antibacterial activity. The antimicrobial activity of phytochemicals and combinations between gentamycin, vancomycin and phytochemicals were quantitatively assessed by measuring the inhibitory halos. The results showed a selective antimicrobial effect of isothiocyanates, and this effect was strictly related with their chemical structure. In general the benzylisothiocyanate was the most effective compound against both Gram-positive and Gram-negative bacteria. The Listeria monocytogenes and Staphylococcus aureus were the bacteria most affected either by the phytochemicals alone or by the combination phytochemical-antibiotic. The bacteria Pseudomonas aeruginosa was the less affected pathogen. The most important synergism detected occurred between the commercial antibiotics with benzylisothiocyanate and 2-phenylethylisothiocyanate. In conclusion, some isothiocyanates are effective inhibitors of in vitro bacterial growth, and they can act synergistically with antibiotics.
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In vitro Anti-glycation and Anti-oxidant Properties of Synthesized Schiff Bases
Sabina Jhaumeer-Laulloo, Minu Gupta Bhowon, Shabneez Mungur, Mohamad Fawzi Mahomoodally andAnwar Hussein Subratty
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00004]

A series of mono, bis and mixed Schiff bases (1-7) were synthesised and evaluated for potential anti-glycation and anti-oxidant activities using the bovine serum albumin - glucose assay and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical assay respectively.  All compounds showed significant (p < 0.05) antiglycating activities with IC₅₀ values (4.02 × 10^-24 ± 0.1 – 2.88×10^-1 ± 1.35 mM) which were  lower than the standard positive control aminoguanidine (IC₅₀ : 1.51×10^-3 ± 2.11 mM).  Moreover, compounds 1-7 were found to possess significant (p < 0.05) DPPH radical scavenging  properties with SC₅₀ values (1.31 × 10^-19 ± 0.05 to 2.25×10^-1 ± 1.24 mM) lower than the standard ascorbic acid (SC₅₀ : 5.50 × 10^-3 ± 2.11 mM).  Compound 6 was found to be the most potent anti-glycating molecule (IC₅₀ value: 4.02 ×10^-24 ± 0.1 mM) while compound 5 was the most potent anti-oxidant molecule (SC₅₀:1.31× 10^-19 ± 0.05 mM); both being significantly lower (p < 0.05) than the respective positive controls used. The present data showed that the number of phenolic OH together with structural changes influence both the anti-glycation and anti-oxidant observed herein. This study provides for the first time a series of potential template molecules for possible pharmaceutical applications that warrant further investigation as potential anti-glycation and anti-oxidant agents which could be of importance in metabolic diseases including diabetes mellitus.
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Synthesis and Biological Evaluation Of The Salicylamide and Salicylic Acid Derivatives As Anti-Estrogen Agents
Yasemin Dündar, Yasemin Özatik, Orhan Özatik, Volkan Ergin, Tijen Önkol, Adnan Menevşe, Kevser Erol and M. Fethi Şahin
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00005]

Alkylphenols have xenoestrogenic activity, which mimic the action of physiological estrogens and these mimicking activities are mainly mediated by nongenomic pathway. Nongenomic pathway plays a pivotal role in breast, endometrial and ovarian cancers’ growth and development. In this study, various alkylphenol derivatives were prepared and screened for their anti-uterotrophic and uterotrophic activity. Among these compounds, 2-hydroxy-5-nonanoylbenzamide (compound 1b) showed 93.99% inhibitory activity in the anti-uterotrophic test performed, and was found inactive in the uterotrophic activity test. Moreover, all test compounds were examined for the effect on uterine histopathological changes, and plasma 17β-estradiol (E₂) level. Compound 1b was also tested for in vitro anti-cancer activity against ER+, human breast cancer cell line MCF-7, and it reduced cell viability to 74.01% at 50 nM concentration.
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Synthesis and Activity of [{Cis-PtCl(NH3)2}2µ{Trans-Pt(3-Hydroxypyridine)2(H2N(CH2)6NH2)2}]Cl4 in the Human Ovarian Tumour Models
Shahnaz AH Hamad, Philip Beale, Jun Qing Yu, Keith Fisher and Fazlul Huq
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00006]

A novel trinuclear platinum compound with a cis-geometry for terminal metal centres coded as QH1 has been synthesized, characterized and investigated for activity against the human ovarian A2780, A2780^cisR and A2780^ZD0473R cancer cell lines. The cellular accumulation of platinum, level of platinum-DNA binding and the nature of interaction of the compound with pBR322 plasmid DNA have also been determined. QH1 is found to be more active against the resistant cell lines than the parent cell line, thus indicating that the compound has been able to overcome mechanisms of resistance operating in the A2780^cisR and A2780^ZD0473R cell lines. The high activity of QH1 is associated with high platinum accumulation and high level of platinum-DNA binding in all the three ovarian cancer cell lines. Provided QH1 has the right toxicity profile and its in vitro activity is matched with sufficient activity in vivo, the compound has the potential for development as a novel platinum-based anticancer drug targeted to the ovarian cancer.
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Biological and Anti-inflammatory Evaluation of Two Thiazole Compounds in RAW Cell Line: Potential Cyclooxygenase-2 Specific Inhibitors
Eva Hamade, Aida Habib, Ali Hachem, Alaa H. Hussein, Malak Abbas, Taghreed Hirz, Mirvat Al Masri and Wissam H. Faour
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00007]

The anti-inflammatory effect of two new thiazoles derivatives CX-32 (N-[4-(4-hydroxy-3-methoxyphenyl)-1,3-thiazol-2-yl]acetamide ) and CX-35 (4-(2-amino-1,3-thiazol-4-yl)-2-methoxyphenol), was investigated in LPS-stimulated RAW 264.7 cell line. Synthesis, structure analysis and purity of these compounds were evaluated by high performance liquid chromatography, H1 NMR, and C13 NMR. Assessment of CX-32 and CX-35 inhibitory effect on cyclooxygenase-2 (COX-2) activity was achieved by incubating LPS-activated RAW cells with 25 ÂμM, 50ÂμM or 100ÂμM of CX-32 or CX-35 respectively. Levels of secreted PGE2 were evaluated by enzyme immunoassay (EIA) and levels of COX-2 protein were measured by western blot. Finally, cell viability experiments were undertaken to assess the toxicity of each compound. Treatment of LPS-activated RAW cells with 25 ↑¼M, 50 ↑¼M, or 100 ↑¼M of CX-35 or CX-32 respectively, prevented the production of prostaglandins, but was without effect on COX-2 protein levels. Moreover, CX-35 and CX-32 reduced PGE2 production to levels comparable to those obtained in LPS-activated RAW cells incubated with the selective COX-2 inhibitor NS 398. Furthermore, both CX-32 and CX-35 showed no toxic effects, since viability of non-treated Hela cells was similar to Hela cells incubated with either CX-35 or CX-32. Our data demonstrated that CX-32 and CX-35 significantly blocked prostaglandin production induced during inflammatory cellular stress, possibly acting through specific COX-2 inhibition; confirmation of this hypothesis requires further investigation.
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New Adamantane Derivatives with Sigma Affinity and Antiproliferative Activity
Stefanos Riganas, Ioannis Papanastasiou, George B. Foscolos, Andrew Tsotinis, Kostas Dimas, Vassilios N. Kourafalos, Andreas Eleutheriades, Vassilios I. Moutsos, Humaira Khan, Prassa Margarita, Stavroula Georgakopoulou, Angeliki Zaniou, Maria Theodoropoulou, Athanasios Mantelas, Stavroula Pondiki and Alexandre Vamvakides
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00008]

The synthesis of 4-(1-adamantyl)-4,4-diarylbutylamines 1, 5-(1-adamantyl)-5,5-diarylpentylamines 2 and 6-(1-adamantyl)-6,6-diarylhexylamines 3 is described and the σ1, σ2-receptors and sodium channels binding affinity of compounds 1 were investigated. The in vitro activity of compounds 1, 2 and 3 against main cancer cell lines is significant. One of the most active analogs, 1a, had an interesting in vivo anticancer profile against  the ovarian cancer cell line IGROV-1, which was associated with an anagelsic activity against the neuropathic pain induced by the main anticancer drugs.
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Synthesis of Novel 4-Aryl-1,2,3,4-tetrahydroisoquinolines as Probes for Dopamine Receptor Ligands
Gianfabio Giorgioni, Dario Ambrosini, Giovanni Filippo Palmieri, Barbara Costa, Antonio Di Stefano and Claudia Martini
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00009]

Dopamine (DA) agonists, bearing catechol or phenol rings, are endowed with low oral bioavailability and short effect duration. In this report, the synthesis of novel differently substituted 4-(3-pyridyl)-1,2,3,4-tetrahydroisoquinolines and (1,2,3,4-tetrahydroisoquinolin-4-yl)phenylmethanols as potential non phenolic and non catecholic DA receptor ligands is reported. The new compounds, evaluated by binding tests on cerebral striatal membranes, bound to DA receptors with moderate affinity. Anyhow, they may represent a starting point to develop new DA ligands endowed with better pharmacokinetic and metabolic properties.
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A Quantitative Structure-Activity Relationship Study on a Few Series of Anti-hepatitis C Virus Agents
Jonish Varshney, Anjana Sharma and Satya P. Gupta
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00010]

A 2-Dimensional Quantitative Structure-Activity Relationship has been performed on 2 series of hepatitis C virus (HCV) inhibitors, i.e., Isothiazoles and Thiazolones. In each case significant correlations are found between the anti-HCV potencies and some physicochemical, electronic and steric properties of the compounds, indicating that for the first series the activity is controlled by density and two indicator parameters (one for halogen and other for methyl), while for the second series density, Hammett constant and Kier’s first order valence molecular connectivity index are important for anti-HCV activity. The validity of the correlation has been judged by leave-one-out jackknife procedure and predicting the activity of some test compounds. Using the correlations obtained some new compounds of high potency have been predicted in each series.
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Synthesis and Antiglycation Activity of Kaempferol-3-O-rutinoside (Nicotiflorin)
Sajan Lal Shyaula, Ghulam Abbas, Hina Siddiqui, Samina A. Sattar, M. Iqbal Choudhary and Fatima Z. Basha
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00011]

Kaempferol-3-O-α-L-rhamanopyranosyl-(1′′′-6′′)-β-D-glucopyranoside (1) (Nicotiflorin or kaempferol-3-O-rutinoside), isolated from the aerial parts of Osyris wightiana Wall. ex Wight,exhibited a potent antiglycation activity in vitro. A short and efficient route to kaempferol-3-O-rutinoside (1) is also described in this paper. To study the structure-activity relationship, few other derivatives of kaempferol were also evaluated for their antiglycation activity. Moreover the cytotoxicity analysis was also performed for these compounds. The Structure-Activity Relationship (SAR) studies showed that sugar derivatives of kaempferol possess a promising antiglycation activity.
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Synthesis and β-Glucuronidase Inhibitory Potential of Benzimidazole Derivatives
Khalid Mohammed Khan, Momin Khan, Nida Ambreen, Fazal Rahim, Shagufta Naureen, Shahnaz Perveen, M. Iqbal Choudhary and Wolfgang Voelter
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00012]

Benzimidazole derivatives 1-24 have been synthesized and their in vitro β-glucuronidase inhibitory activitiy was evaluated. Compounds 15 (IC₅₀ = 6.33 ± 0.40μM), 7 (IC50 = 22.0 ± 0.33μM), 2 (IC₅₀ = 23.1 ± 1.78 μM), 17 (IC₅₀ = 23.9 ± 1.46 μM), and 3 (IC₅₀ = 33.8 ± 1.61 μM) showed more potent b-glucuronidase inhibitory activity than the standard (D-saccharic acid 1,4 lactone, IC₅₀ = 48.4 ± 1.25 μM). This study has identified a new series of potential β-glucuronidase inhibitors. A structure-activity relationship has also been studied.
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Synthesis and Biological Evaluation of Some New N4-Aryl Substituted 5-Chloroisatin-3 thiosemicarbazones
Humayun Pervez, Muhammad Ramzan, Muhammad Yaqub, Faiz-Ul-Hassan Nasim and Khalid Mohammed Khan
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00013]

A new series of sixteen N4-aryl substituted 5-chloroisatin-3-thiosemicarbazones 2a-2p has been synthesized, characterized and tested for selected biological activities i.e. cytotoxicity, phytotoxicity and urease inhibition. In the brine shrimp bioassay, all the synthesized compounds gave LD₅₀ values >2.30 X 10^-4 M - 2.79 X 10^-4 M and were, therefore, found to be almost inactive, whereas in phytotoxicity assay, regardless of the nature of aryl substituents, they displayed weak to moderate (5-40%) phytotoxic activity at the highest tested concentrations (500 or 1000 μg/mL). In urease inhibition bioassay, compounds 2a, 2c, 2e, 2f, 2k and 2m exhibited relatively a higher degree of urease inhibition with IC₅₀ values ranging from 38.91 μM to 76.65 μM and thus proved to be potent inhibitors of the enzyme. Of these, 2f and 2m displayed pronounced inhibition with IC₅₀ values 38.91 μM and 39.50 μM, respectively, and may act as lead compounds for further studies. Structure-activity relationship (SAR) studies revealed that electronic effects of the substituents about the phenyl ring at N4 of the thiosemicarbazone moiety played an important role in enhancing the urease inhibitory potential of some of the synthesized compounds.
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2,4,6-Trichlorophenylhydrazine Schiff Bases as DPPH Radical and Super Oxide Anion Scavengers
Khalid Mohammed Khan, Zarbad Shah, Viqar Uddin Ahmad, Momin Khan, Muhammad Taha, Fazal Rahim, Sajjad Ali, Nida Ambreen, Shahnaz Perveen, M. Iqbal Choudhary and Wolfgang Voelter
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00014]

Syntheses of thirty 2,4,6-trichlorophenylhydrazine Schiff bases 1-30 were carried out and evaluated for their in vitro DPPH radical and super oxide anion scavenging activities. Compounds 1-30 have shown a varying degree of DPPH radical scavenging activity and their IC₅₀ values range between 4.05-369.30 μM. The compounds 17, 28, 18, 14, 8, 15, 12, 2, 29, and 7 exhibited IC₅₀ values ranging between 4.05 ± 0.06-24.42 ± 0.86 μM which are superior to standard n-propylgallate (IC₅₀ = 30.12 ± 0.27 μM). Selected compounds have shown a varying degree of superoxide anion radical scavenger activity and their IC₅₀ values range between 91.23-406.90 μM. The compounds 28 8, 17, 15, and 14, showed IC₅₀ values between 91.23 ± 1.2-105.31 ± 2.29 μM which are superior to standard n-propylgallate (IC₅₀ = 106.34 ± 1.6 µM).
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Application of Artificial Neural Networks for the Prediction Of Antitumor Activity of A Series of Acridinone Derivatives
Marcin Koba
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00015]

Artificial neural networks (ANNs) have been applied for the quantitative structure-activity relationships (QSAR) studies of antitumor activity of acridinone derivatives. Molecular modeling studies were performed with the use of HyperChem and Dragon computer programs and molecular geometry optimization using MM+ molecular mechanics and semi-empirical AM1 method, and several molecular descriptors of agents were obtained. A high correlation resulted between the ANN predicted antitumor activity and that one from biological experiments for the data used in the testing set of acridinones was obtained with correlation coefficient on the level of 0.9484. Moreover, the sensitivity analysis indicated that molecular parameters describing geometrical properties as well as lipophilicity of acridinone derivative molecule are important for acridinones antitumor activity.
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Synthesis and Biological Evaluation of 3΄-C-Ethynyl and 3΄-C-(1,4-disubstituted-1,2,3-triazolo) Double-Headed Pyranonucleosides
Christos Kiritsis, Stella Manta, Ioannis Papasotiriou, Evdoxia Coutouli-Argyropoulou, Sakellarios Trakossas, Jan Balzarini  and Dimitri Komiotis
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00016]

A novel series of 3΄-C-ethynyl and 3΄-C-(1,4-disubstituted-1,2,3-triazolo) double-headed pyranonucleosides has been designed and synthesized. Reaction of 3-keto glucoside 1 with ethynyl magnesium bromide gave the desired precursor 3-C-ethynyl-1,2:5,6-di-O-isopropylidene-α-D-allofuranose (2). Hydrolysis followed by acetylation led to the 1,2,4,6-tetra-O-acetyl-3-C-ethynyl-β-D-allopyranose (3). Compound 3 was condensed with silylated 5-fluorouracil, uracil, thymine, N⁴-benzoylcytosine and N⁶-benzoyladenine, respectively and deacetylated to afford the target 1-(3΄-C-ethynyl-β-D-allopyranosyl)nucleosides 5a-c,f,g. Copper-Catalyzed Azide-Alkyne Cycloaddition (CuAAC) reaction was utilized to couple the 3΄-C-ethynyl pyranonucleoside derivatives with azidoethyl adenine, 5-fluorouracil and thymine, respectively to afford novel triazole double-headed nucleoside analogs 8a-h. 3΄-C-Ethynyl pyranonucleosides and the new double-headed analogues were evaluated for their antiviral and cytostatic activities. Although none of the compounds showed pronounced cytostatic activity and were devoid of a significant antiviral potential, the double-headed nucleoside derivatives 8a, 8c and 8e showed a moderate cytostatic activity against human cervix carcinoma HeLa cells which may be the basis for the synthesis of analogous derivatives with improved cytostatic potential.
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Structure-Activity Relationships of Pyrrole Hydrazones as New Anti-Tuberculosis Agents
Iglika Lessigiarska, Ilza Pajeva, Penka Prodanova, Maya Georgieva and Atanas Bijev
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00017]

Preliminary investigations of our research team have shown that some pyrrole hydrazones posses strong inhibitory activity against the tuberculosis bacilli, and thus represent a new perspective for development of anti-tuberculosis agents. In this work the anti-tuberculosis activity of an in-house series of pyrrole hydrazones was investigated by quantitative structure-activity relationships (QSAR) analysis and by pharmacophore modelling. Different constitutional, topological, physicochemical, and quantum-mechanical descriptors of the chemical structure were calculated. The QSAR models included the number of chlorine, fluorine and nitrogen atoms, molecular flexibility and shape indexes, and magnitudes of charged molecular surfaces areas and hydrophobic volumes, suggesting importance of these structural characteristics for the activity. Next, a pharmacophore analysis was applied. A possible pharmacophore responsible for the compound interactions with their biological target in the 3D space consisted of five features, including hydrophobic centres, a potential H-bond acceptor and a potential metal ligator.
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S-Ntrosylation and Attenuation of Excessive Calcium Flux by Pentacycloundecane Deriva Tives
Hendrik, J.R. Lemmer, Jacques Joubert, Sandra van Dyk, Francois, H. van der Westhuizen and Sarel, F. Malan
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00018]

A novel series of polycyclic amines, containing nitrogen monoxide donating moieties, were synthesised and tested for calcium channel and N-methyl-d-aspartate receptor modulating activity. The synthesised compounds were classified into two groups, based on their nitrogen monoxide donating moieties:  unsaturated nitro compounds (1, 2 and 3) and nitro esters, or nitrates (4, 5 and 6). The nitrates were obtained via the reaction of hydroxyl functionalities with thionylchloride nitrate. All of the compounds synthesised exhibited significant (p < 0.01) S-nitrosylation capacity. The calcium channel activity of the polycyclic amines was evaluated using a KCl mediated fluorescent calcium flux assay. All the compounds exhibited better calcium channel antagonism than the lead structure, NGP1-01, with compound 1 exhibiting calcium channel blockade comparable to the commercially available nimodipine at concentrations of 10 μM and 1 μM. Compounds 3 and 4 inhibited calcium flux to these levels at 10 μM concentrations. NMDA/glycine mediated N-methyl-d-aspartate receptor (NMDAR) calcium influx inhibition was evaluated at a 100 μM concentration using a fluorescent calcium flux assay. All the compounds exhibited NMDAR antagonism with compounds 1 (25.4 %), 2 (20.24 %), 3 (33.14 %) and 6 (24.55 %) showing the most significant NMDAR inhibitory activity (p < 0.01). No clear correlation was observed between the S-nitrosylation capabilities of the compounds and their calcium channel activity or NMDAR channel antagonism, indicating that other factors probably play a more decisive role in the mechanism of pentacycloundecylamine channel modulation. This could include the geometric and steric bulk considerations that have been described to contribute to the channel activities of the pentacycloundecylamines. All the compounds synthesised exhibited promising calcium channel and NMDAR channel inhibitory activity and show promise as potential lead compounds for drug development against neurodegeneration.
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Serum Specific Vasopressin-Degrading Activity is Related to Blood Total Cholesterol Levels in Men But not In Women
Ramírez-Expósito  María Jesús, Arrazola  Marcelina, Carrera- González María Pilar, Arias de Saavedra  José Manuel, Sánchez-Agesta  Rafael, Mayas María Dolores and Martínez-Martos José Manuel
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00019]

The role of vasopressin (AVP) in the pathophysiology of cardiovascular disease is controversial, but this peptide hormone is elevated in heart failure and some forms of hypertension. Also, AVP has vasoconstrictor, mitogenic, hyperplasic and renal fluid retaining properties which, by analogy with angiotensin II, may have deleterious effects when present in chronic excess. Furthermore, cholesterol blood levels are also associated with hypertension, although the underlying mechanism is not known. Here we analyze the relationship between blood total cholesterol levels and serum vasopressin-degrading cystyl-aminopeptidase activity (AVP-DA) in healthy humans, and the differences between men and women. Linear correlation coefficients were calculated to test relationships between AVP-DA and blood total cholesterol levels. Sex differences were observed for AVP-DA, being this activity higher in men than in women. According to the linear model of the regression analysis, AVP-DA showed a significant negative correlation with blood total cholesterol levels in men, whereas no correlation was observed in women. Several studies in humans demonstrate the existence of greater plasma AVP concentrations in normal men compared to normal women, which could explain the gender-differences observed in the present work in relation with AVP-DA. However, AVP-DA is related to blood cholesterol levels only in men, although in our hands, women showed higher blood cholesterol levels than men. This could indicate that the risk of high cholesterol-related hypertension is more probable in men than in women. Although AVP-DA misregulation could be involved in the pathogenesis of hypertension, its relation with cholesterol levels appears only in men, but not in women.
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SAR Analysis of New Dual Targeting Fluoroquinolones. Implications of the Benzenesulfonyl Group
Marcelo J. Nieto, Adriana B. Pierini, Nidhi Singh, Christopher R. McCurdy, Ruben H. Manzo and María R. Mazzieri
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00020]

When a benzenesulfonyl moiety (BS) was bound to the N-piperazinyl ring of antibacterial fluoroquinolones (AMFQs) norfloxacin (NOR) or ciprofloxacin (CIP), the resulting benzenesulfonyl-fluoroquinolone (BSFQs) analogs showed an improved in vitro activity against Gram-positive strains. A bioisosterical replacement of the sulfonyl group for a carbonyl group led to the benzenecarboxamide-fluoroquinolones (BCFQs) that showed a similar trend in the antibacterial activity and spectrum. The BSFQs and BCFQs are considered members of the “dual targeting” fluoroquinolones, targeting both DNA gyrase and topoisomerase IV. To disclose the real contribution of the BS/BC moiety in anti-staphylococcal activity, a 3D-QSAR analysis that included calculation of theoretical molecular descriptors and pharmacophore generation was performed. Previous and present QSAR results have confirmed the positive influence on activity of small electron donating p-substituent on the BS or BC moiety. The generated phamacophore model showed that both phenyl and SO₂/CO groups are involved in the interaction with receptor. We postulate that the enhanced potency of BSFQs against Staphylococcus aureus compared to CIP and NOR could be caused by the presence of the BS moiety that resulted in enhanced binding to DNA gyrase of Sa. Additionally, their greater ability to enter bacterial cells by diffusion and a reduced susceptibility to FQ-specific efflux pumps could also make a contribution.
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Prodrug Strategies in Ocular Drug Delivery
Megha Barot, Mahuya Bagui, Mitan R. Gokulgandhi and Ashim K. Mitra
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00021]

Poor bioavailability of topically instilled drug is the major concern in the field of ocular drug delivery. Efflux transporters, static and dynamic ocular barriers often possess rate limiting factors for ocular drug therapy. Different formulation strategies like suspension, ointment, gels, nanoparticles, implants, dendrimers and liposomes have been employed in order to improve drug permeation and retention by evading rate limiting factors at the site of absorption. Chemical modification such as prodrug targeting various nutrient transporters (amino acids, peptide and vitamin) has evolved a great deal of interest to improve ocular drug delivery. In this review, we have discussed various prodrug strategies which have been widely applied for enhancing therapeutic efficacy of ophthalmic drugs. The purpose of this review is to provide an update on the utilization of prodrug concept in ocular drug delivery. In addition, this review will highlight ongoing academic and industrial research and development in terms of ocular prodrug design and delivery.
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Synthesis and Biological Evaluation of Naloxone and Naltrexone-Derived Hybrid Opioids
Bahman E. Nassim and Ming-Lei Wang
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00022]

The synthesis and biological evaluation of hybrid opioids consisting of Naloxone or Naltrexone and a partial opioid peptide are described. These compounds were synthesized in a homogeneous solution as well as in solid phase.  A hydrazone linkage was employed to connect the alkaloids to the tetrapeptides. In synthesizing the peptides some non-traditional methods, which provided excellent results, were explored. The solid phase synthesis was achieved by anchoring the Fmoc-Phe to the 2-chlorotrityl resin, followed by stepwise addition of two Fmoc-Gly units. Each addition step preceded by standard piperidine removal of the Fmoc from the prior amino acid (AA) residue. The final AA, Tyr, was added as its Boc derivative. The Boc-tetrapeptide was then separated from the resin with a TFE/AcOH/CH₂Cl₂ mixture. In the solution synthesis, each peptide elongation step was accomplished by one-pot removal of the Fmoc from the prior AA residue and addition of the next Fmoc-AA. TBAF-thiol was used to cleanly remove the Fmoc, before adding the next Fmoc-AA in the presence of DIPEA and TBTU. All prepared hybrid ligands exhibited high affinities toward all three opioid receptors; moderate preferences for κand m receptors over d receptor were observed. [³⁵S]GTPγS binding assays indicated that these hybrid opioids are δ and μ antagonists but partial κ agonist.
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A QSAR Analysis of 2-phenoxy-N-substituted acetamide Analogues as Hypoxia-Inducible Factor-1(HIF-1) inhibitors: A Rational Approach to Anticancer Drug Design
Malleshappa N. Noolvi, Harun M. Patel and Sarita Kamboj
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00023]

A set of thirty one substituted 2-phenoxy-N-phenylacetamide derivatives with HIF-1 inhibitory activities was subjected to 2D and 3D Quantitative Structure Activity Relationship (QSAR) studies using various combinations of descriptors. 2D-QSAR was performed using Multiple Linear Regression (MLR), Principal Component Regression (PCR) and Partial Least Squares Regression (PLS) methods. Among these three methods Multiple Linear Regression (MLR) led to the statistically significant best 2D-QSAR Model-I having correlation coefficient r² = 0.9469 and cross validated squared correlation coefficient q² = 0.8933 with external predictive ability of pred_r² = 0.7128 with the descriptors like SssNHE-index, slogp, T_O_N_1 and T_2_Cl_1. 3D-QSAR study was performed using the simulated annealing variable selection procedures k-nearest neighbor molecular field analysis approach. 3D-QSAR shows interesting results in terms of internal and external predictability. Molecular field analysis was applied for the generation of steric, hydrophobic and electrostatic descriptors based on aligned structures which shows good correlative and predictive capabilities in terms of q² = 0.9672 and pred_r² = 0.8480. Hence the model proposed in this work provides important structural insight in designing novel derivatives with specific HIF-1 inhibitory activity.
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Synthesis, In Vitro And In Silico Ns5b Polymerase Inhibitory Activity Of Benzimidazole Derivatives
Vaishali M. Patil, Gurukumar K. R., Maksim Chudayeu, Satya Prakash Gupta, Subeer Samanta, Neeraj Masand and Neerja Kaushik-Basu
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00024]

Hepatitis C virus (HCV) NS5B polymerase is the key replicating protein of the virus and thus an attractive target for drug development. Here we report on the synthesis and biological evaluation of a new series of benzimidazole derivatives as HCV NS5B inhibitors. This yielded compound 6b and 6d bearing 2-(2-benzyloxy)phenyl and 2-(4-methylbenzyloxy)phenyl moieties, respectively, as promising leads. Binding mode of compound 6d in allosteric pocket (AP)-1 of NS5B will form the basis for future structure-activity relationship optimization.
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A new Class of Anticonvulsants Possessing 6 Hz Psychomotor Seizure Test Activity: 2-(1H-Benzotriazol-1-yl)-N'-[Substituted] Acetohydrazides
Praveen Kumar, Birendra Shrivastava, Surendra Nath Pandeya, Laxmi Tripathi  and James P. Stables
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00025]

A series of 2-(1H-Benzotriazol-1-yl)-N'-[substituted]acetohydrazides were designed & synthesized keeping in view the structural requirement of pharmacophore and evaluated for anticonvulsant activity and neurotoxicity. The new compounds were characterized using FT-IR, 1H NMR, mass spectral data and elemental analysis. The anticonvulsant activity of the titled compounds was assessed using the 6 Hz psychomotor seizure test. The neurotoxicity was assessed using the rotorod method. The most active compound of the series was N'-[4-(1,3-Benzodioxol-5-yloxy)benzylidene]-2-(1H-benzotriazol-1-yl)acetohydrazide (BTA 9), which showed good activity with 75 % protection (3/4, 0.5 h) at a dose of 100 mg/kg in mice. All the compounds exhibited no neurotoxicity. A computational study was carried out for calculation of pharmacophore pattern and prediction of pharmacokinetic properties. Titled compounds have also exhibited good binding properties with epilepsy molecular targets such as glutamate, GABA (A) delta, GABA (A) alpha-1 receptors and Na/H exchanger, in Lamarckian genetic algorithm based flexible docking studies.
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Synthesis and Biological Evaluation of a Series of 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-2-substituted Tetrahydroisoquinoline Derivatives
Zhi-hong Zou, Xiao-bu Lan, Chun-lei Tang, Xiao-yun Zhu, Bao-min Liu, Hai Qian, Wen-long Huang and Yun-man Li
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00026]

Multidrug resistance in cancer is a major cause of failure in cancer chemotherapy. In search of new compounds with strong reversal activity and simple molecular structure, we have synthesized a series of compounds in which different substituents were linked to the 2-position of the 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)- tetrahydroisoquinoline system. Compounds were analyzed for their cytotoxicity by MTT in K562 cell line in vitro , all of the derivatives exhibited little cytotoxic activity. In the meantime, these compounds were evaluated by MTT in K562/A02 cell line in vitro, 6e, 6h and 7c exhibited similar or more potent activities than verapamil with the IC₅₀ values at 0.66, 0.65 and 0.96μM, and with the ratio factor of 24.13, 24.50 and 16.59, respectively.
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Generation of Pharmacophore and Atom Based 3D-QSAR Model of Novel Isoquinolin-1-one and Quinazolin-4-one-type Inhibitors of TNFα
Pradeep Hanumanthappa, Mahesh K. Teli and Rajanikant G. Krishnamurthy
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00027]

In the present report, 3D-QSAR analysis was executed on the previously synthesized and evaluated derivatives of isoquinolin-1-ones and quinazolin-4-ones; potent inhibitors of tumor necrosis factor α (TNFα). Statistically significant 3D-QSAR models were generated using 42 molecules in the training set. The predictive ability of models was determined using a randomly chosen test set of 16 molecules, which gave excellent predictive correlation coefficients for 3-D models, suggesting good predictive index. Pharmacophore prediction generated a five point pharmacophore (AAHRR): two hydrogen bond acceptor (A), one hydrophobic (H) and two ring (RR) features. This pharmacophore hypothesis furnished a statistically meaningful 3D-QSAR model with partial least-square (PLS) factors seven having R² = 0.9965, Q² = 0.6185, Root Mean Squared Error = 0.4284 and Pearson-R = 0.853. Docking study revealed the important amino acid residues (His 15, Tyr 59, Tyr 151, Gly 121 and Gly 122) in the active site of TNFα that are involved in binding of the active ligand. Orientation of the pharmacophore hypothesis AAHRR.25 corresponded very closely with the binding mode recorded in the active site of ligand bound complex. The results of ligand based pharmacophore hypothesis and atom based 3D-QSAR furnished crucial structural insights and also highlighted the important binding features of isoquinolin-1-ones and quinazolin-4-ones derivatives, which may provide guidance for the rational design of novel and more potent TNFα inhibitors.
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A QSAR Study of Biphenyl Analogues of 2-Nitroimidazo-[2, 1-b] [1, 3] - oxazines as Antitubercular Agents using Genetic Function Approximation
Supratim Ray and Partha Pratim Roy
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00028]

A QSAR study was performed on ninety eight substituted biphenyl analogues of 2-nitroimidazo-[2, 1-b] [1, 3]-oxazines as antitubercular agents to explore the importance of topological, thermodynamic, spatial and physicochemical properties of the molecules towards the antitubercular activity. Genetic function approximation (GFA) was used as the chemometric tool for the study. The study shows that ortho and meta linked attachments of the biphenyl analogs to 2-nitroimidazo-[2, 1-b] [1, 3]-oxazines are detrimental for the antitubercular activity. Hydrophobicity, branching and presence of electronegative atoms enhance the activity. Based on the r_m²_(overall) criterion, which considers both internal  validation and external validation, a GFA model with spatial, thermodynamic and topological descriptors  appears to be the  best model (rr_m²_(overall) =0.556).
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Differences in Vanadocene Dichloride And Cisplatin Effect on MOLT-4 Leukemia and Human peripheral Blood Mononuclear Cells
Havelek Radim, Siman Pavel, Cmielova Jana, Stoklasova Alena, Vavrova Jirina, Vinklarek Jaromir, Knizek Jiri and Rezacova Martina
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00029]

Modern chemotherapy is interested in developing new agents with high efficiency of treatment in low-dose medication strategies, lower side toxicity and stronger specificity to the tumor cells. Vanadocene dichloride (VDC) belongs to the group of the most promising metallocene antitumor agents; however, its mechanism of action and cytotoxicity profile is not fully understood. In this paper we assess cytotoxic effects of VDC in comparison to cisplatin using opposite prototype of cells; human peripheral blood mononuclear (PBMCs) cells and human acute lymphoblastic leukemia cell line (MOLT-4). Our findings showed cytotoxic effect of VDC on leukemia cells, but unfortunately on human peripheral blood mononuclear cells as well. VDC induces apoptosis in leukemia cells; the induction is, however, lower than that of cisplatin, and in contrary to cisplatin, VDC does not induce p53 up-regulation. Cytotoxic effect of VDC on leukemia cells is less pronounced than that of cisplatin and more pronounced in PBMCs than in MOLT-4 cells.
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In Vitro Synergy Testing of Anidulafungin with Fluconazole, Tioconazole,  5-Flucytosine and Amphotericin B  Against Some Candida spp
Antonio Rosato,  Monica Piarulli,  Brigida Immacolata Pia Schiavone,  Maria Teresa Montagna,  Giuseppina Caggiano,  Marilena Muraglia,  Addolorata Carone, Carlo Franchini and Filomena Corbo
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00030]

In this paper the authors investigate a synergistic antimycotic effect between four antifungal drugs Amphotericin B, Fluconazole, Tioconazole, and Flucytosine individually combined with Anidulafungin compound. This latter is considered a drug of choice in the treatment of fungal infections; in vitro and in vivo it has good activity against yeasts and moulds, as Candida and Aspergillus. The goal of this study is to evaluate the in vitro interaction  of Anidulafungin  in the synergic combinations with previously reported drugs against 12 Candida strains  according to CLSI M27-A3 protocol. A synergistic interaction was observed against the most antifungal strains; in particular an increasing of the antimycotic efficacy was obtained from the association between Anidulafungin and Amphotericin B or Fluconazole  (Mixture 4:6). In contrast the association Tioconazole/Anidulafungin was less effective on fungal species growth. The reduction of MIC values of the antimycotics drugs was more evident against some strains as C. glabrata, C. krusei, C. tropicalis and C. parapsilosis.
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Structural Insight for Imidazopyridazines as Malarial Kinase PfPK7 Inhibitors Using QSAR Techniques
Nitendra K. Sahu and D. V. Kohli
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00031]

With a view to the rational design of a series of selected 35 imidazopyridazine derivatives, 2D and 3D QSAR models have been developed for the prediction of antimalarial activity. The statistically significant 2D QSAR model having r² = 0.9242 and q² = 0.8691 with pred_r² = 0.9206 was developed by SW-MLR and best 3D QSAR model having q² = 0.8607 with pred_r² = 0.8332 was developed by k-nearest neighbor molecular field analysis (kNN-MFA). Finally, molecular docking analysis was carried out to better understand of the interactions between PfPK7 target and inhibitors in this series. The docking studies suggest that the PfPK7 inhibitors interact with Met120, Lys55, Tyr117, Asp123, Leu179, Leu34, Asn35, Ala53, Glu88, Leu101, Tyr119, Ser124, Ser189 and Asp190 amino acid residues. Both QSAR and docking study of such derivatives provide guidance for further lead optimization and designing of more potent PfPK7 inhibitors.
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Substituted Urea Derivatives: A Potent Class of Antidepressant Agents
Shahnaz Perveen, Sana Mustafa, Muhammad A. Khan, Ahsana Dar Khalid M. Khan and Wolfgang Voelter
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00032]

A series of fourteen (14) N-nitrophenyl-N’-(alkyl/aryl)urea and symmetrical 1,3-disubstituted urea derivatives were synthesized and evaluated for their antidepressant activity in mice. Among them, N-(4-nitrophenyl)-N’-(1’-phenylethyl)urea (1), demonstrated profound antidepressant property as reflected by significant reduction in the immobility time (89.83%), whereas  compounds 2-6 showed activity values between 36 to 59% which were also larger than the standard phenelzine. Compounds 7-9 were less effective in reducing the immobility period of mice 26.20 to 31.01%). This variable magnitude of antidepressant activity appears to be related to the position of the nitro group to the parent molecules 1, 2, and 8. Compound 1 with the nitro group at para position showed to be the most effective antidepressant. However, the activity declined, if the nitro is attached to ortho and meta positions.
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A QSAR Study on Novel Series of Carbonic Anhydrase Inhibitors  hCA IX—Tumor-Associated (Hypoxia)
Shalini Singh
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00033]

This paper presents results of QSAR (Quantitative Structure Activity Relationship) studies realized with the PRECLAV (Property Evaluation by Class Variables) software. The database contains 66 derivatives of aromatic benzene sulfonamides incorporating 1, 3, 5-triazine moieties, fluorophenyl sulfamates, S-substituted-2-mercapto-benzenesulfonamide and diazenylbenzenesulfonamides with clinically used CA inhibitors.For each molecule over 3600 descriptors were calculated using programs MOPAC, PRECLAV and DRAGON. A heuristic algorithm selects the best multiple linear regression (MLR) equation showed that the correlation between the observed values and the calculated values of activity is very good (N = 66, Se = 0.263, r² = 0.884, F = 92.98, r²_cv = 0.859, Q = 0.794). The virtual molecular fragments that lead to a significant increase of the inhibitor activity of hCA IX are C₃H₂N₅Cl, NH₂, C₆H₄, C₃H₅N₆, COOH, and C₃HN₆. The virtual fragment – HO, C₅H₂NO, C3HN6, leads to a significant decrease of the inhibitor activity value. With a view to external validation, the calibration set includes 50 molecules (Se = 0.256, r² = 0.885, F = 69.501, r²_cv = 0.852) and the validation set includes 16 molecules (Se =0.261, r² = 0.881, F = 66.294, r²_cv = 0.85). Identification of molecules in validation set with high estimated value of inhibitory activity of hCA IX  is correct enough to have practical value, even if the calibration/validation set contains aromatic benzene sulfonamides incorporating 1,3,5-triazine moieties and fluor phenyl sulfamates derivatives with very different chemical structures.
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Synthesis and ¹⁸⁸Re Radiolabelling of Dendrimer Polyamide Amine (PAMAM) Folic Acid Conjugate
Wei Cui, Yuanqing Zhang, Xiaoping Xu and Yu-Mei Shen
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00034]

Folic acid receptors (FR) are usually over expressed in many cancer cells and considered as potential targeted therapy agent. Generation five polyamido amine (PAMAM) dendrimer folic acid conjugate was synthesesed and radiolabelled with 188Re, furthermore the in vitro/in vivo stability was evaluated accordingly. The labeling yield of the conjugate G5-FA-DTPA-188Re was 67.1 % and its radiochemical purity exceeded 95 %. The conjugate also showed high in vitro stability and potential value for further structure modifications and evaluations.
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Computational Approaches To Improve Aggrecanase-1 Inhibitory Activity Of (4-Keto) Phenoxy) Methyl biphenyl-4-Sulfonamide: Group Based QSAR and Docking Studie
Ponnurengam Malliappan Sivakumar, J. Mohanapriya, Naga Vignesh Selva Raj, G. Ramesh  and Mukesh Doble
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00035]

Group based Quantitative Structure Activity Relationship (GQSAR) was developed for thirty (4-keto-phenoxy) methyl biphenyl-4-sulfonamides which exhibit aggrecanase-1 enzyme inhibitory activity. This enzyme is involved in osteoarthritis. The data is divided into training and test sets, where the latter is used for validating the model. Substitution in the R₁ position plays a major role when compared to substitution in R₂ position. The former position is influenced by two descriptors, namely electrotopological and connectivity indices. R₂ position is influenced by radius of gyration. The statistical parameters for the training set (r² = 0.80, r₂adj = 0.77, q₂ = 0.69, F-ratio = 26.80 and standard error = 0.24) and the predicted r² (r²_test =0.95) are satisfactory. Docking of the compounds with aggrecanase-1 enzyme showed that there is a strong negative correlation between the binding energy and aggrecanase -1 inhibitory activity. Compounds with the carbonyl substitution interact with the S'1 pocket which is needed for enhanced activity. The two methodologies described here can help in lead optimization.
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In vitro Antibacterial and Antifungal Activity of Salicylanilide Pyrazine-2-Carboxylates
Martin Krátký, Jarmila Vinšová and Vladimír Buchta
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00036]

The development of new antimicrobial agents for the treatment of infectious diseases remains challenging due to the increasing impact of antibiotic resistance. Since salicylanilides and esters of pyrazine-2-carboxylic acid have been described as potential antimicrobials, we have designed and synthesized a series of 2-(phenylcarbamoyl)phenyl pyrazine-2-carboxylates. These were evaluated in vitro for the activity against fungi and Gram-positive and Gram-negative bacteria. All derivatives showed significant antibacterial activity against Gram-positive strains (MIC ≥ 0.98 μmol/L) including methicillin-resistant Staphylococcus aureus. The most active molecule was 5-chloro-2-(3-chlorophenylcarbamoyl)phenyl pyrazine-2-carboxylate. With one exception these esters were at least partly active against fungi tested strains, in particular against mould strains (MIC ≥ 1.95 μmol/L). The most active antifungal agent overall proved to be 2-(4-bromophenylcarbamoyl)-4-chlorophenyl pyrazine-2-carboxylate.
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Design, Synthesis and Multidrug Resistance Reversal Activity Evaluation of 8-Oxocoptisine Derivatives
Jian Bo Wu, Fan Lei, Xiang Juan Cui, Yun He, Li Hai, Juan Zhang and Yong Wu
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00037]

Fifteen derivatives of 8-oxocoptisine were prepared based on that 8-oxocoptisine showed potent reversing effect against human cancer cells charactering multidrug resistance (MDR). The derivatives were evaluated for their growth inhibition and effects on reversing P-gp-mediated MDR against MCF-7/AMD cells. 12, 13-dinitro-8-oxocoptisine (6c), the most potential candidate with weak growth inhibition, significantly increased the sensitivity of adriamycin (ADM) against MCF-7/ADM cells by 213-fold at 10μM that was compared to the reference compound verapamil. The preliminary structure-activity relationships (SARs) of these derivatives were discussed on the basis of the in vitro MDR reversal activities.
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Design, Synthesis and Antiproliferative Studies Of 2-Acetylamino-Thiazole-5-Carboxamide Derivatives
Wukun Liu, Jinpei Zhou, Yu Zheng, Fan Qi, Huibin Zhang, Hai Qian, Jing Wang, Yanhua Chen and Ronald Gust
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00038]

In order to develop a new series of dual inhibitors of SRC and ABL, and to investigate whether the pyrimidin-4-ylamino moiety is critical for dasatinib’s activity, acetyl substitution was adopted as alternate scaffold at the 2-amino group. Eighteen novel dasatinib derivatives were developed by a parallel synthesis approach and evaluated for their antiproliferative effects. Preliminary tests showed that some of the target compounds IId, IIe and IIf manifested strong antiproliferative activity against MCF-7, MDA-MB 231 and HT-29 cells, especially IId proved to be the most potent compound. Structure-activity relationship studies indicate that the introduction of acetyl substitution as alternate scaffold of pyrimidin-4-ylamino reduced the activity.
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Synthesis of 3-(2, 8, 9-Trioxa-5-Aza-1-Germatricyclo [3.3.3.0] Undecane-1-Yl)-3-(4-Hydroxyl-3- Methoxyphenyl)-Propionic Acid and its Inhibitory Effect on the Cervical Tumor U14 In Vitro and In Vivo
Lianbao Ye, Xiaomin Ou, Xuedong Peng and Yan Luo
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00039]

In this study, the novel germatrane compound, 3-(2, 8, 9-trioxa-5-aza-1- germatricyclo [3.3.3.0] undecane-1-yl)-3-(4-hydroxy-3- methoxyphenyl)-propionic acid (1), has been synthesized and its activities against cervical tumor U14 were evaluated in vitro and in vivo. The results have demonstrated that the compound posed significant inhibition on U14 tumor with IC₅₀ values of 48.57 mg/L in cell-based assay and tumor inhibitory rates of 38.50 %, 47.17 % and 64.02 % (from low dose to high dose) in animal experiment.
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A QSAR Study on a Series of Pyrrole Derivatives Acting as Lymphocyte-Specific Kinase (Lck) Inhibitors
Zaihra Anwe and Satya P. Gupta
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00040]

A quantitative structure-activity relationship (QSAR) study has been made on a novel series of pyrrole derivatives acting as lymphocyte-specific kinase (Lck) inhibitors. The Lck inhibition activity of compounds is found to be significantly correlated with their molar volume (MV) and surface tension (ST) and the hydrophobic constant of one of their substituents. Both the molar properties MV and ST of the compounds are found to have the negative effect but the hydrophobic property of R₂-substituen is found to have the positive effect. This leads to suggest that the bulky molecules and the tose with high surface tension will not be advantageous to the Lck inhibition, rather their R₂-substituent with hydrophobic property will be conducive to the activity.
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Acylhydrazide Schiff Bases: DPPH Radical and Superoxide Anion Scavengers
Khalid Mohammed Khan, Muhammad Taha, Farzana Naz, Salman Siddiqui, Sajjad Ali, Fazal Rahim, Shahnaz Perveen and M. Iqbal Choudhary
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00041]

Acylhydrazide Schiff bases 1-27 were evaluated for their in vitro DPPH radical and superoxide anion scavenging activity. They showed a varying degree of DPPH radical scavenging activity with IC50 values between 31.25 - 473.59 μM. Compounds 8, 2, and 10 have IC50 values 31.25 ± 1.32, 34.40 ± 0.66, and 37.24 ± 0.4 μM, respectively. Standard npropylgallate showed an IC50 value 30.12 ± 0.27 μM. Acylhydrazides 1-27 exhibited in vitro superoxide anion scavenging activities with IC50 values in the range of 175.6 - 450.89 μM. Results demonstrated that acylhyrazides 8, 2, and 10 have DPPH scavenging activity, comparable to standard n-propyl gallate while acylhyrazides 1-27 were found to be less superoxide anion scavenging active than the standard n-propyl gallate (IC50 = 106.34 ± 1.6 μM).
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The Preformulation Stability Studies of a Proline Prodrug of Methotrexate
Ann Stephenson, Zhiqian Wu and Xudong Yuan
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00042]

In order to reduce toxicity of methotrexate and improve bioavailability, permeability, and explore other delivery routes, a proline prodrug of methotrexate was synthesized and preformulation stability studies were conducted under accelerated conditions to assess compound liability and possible conversion to the parent drug. Forced degradation studies showed that the prodrug will degrade in the presence of water, acid, and heat (70 °C), generating the parent compound methotrexate. It was also found that this conversion is temperature dependant. In addition, the prodrug is extremely light and oxidative labile. Therefore, future formulation studies should be light protected and stabilized by a suitable anti-oxidant. It was also found that the prodrug is stable in the HPLC diluent, consisting of water and acetonitrile; stored bench-top and protected from light for up to two weeks.
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Synthesis of a Biodegradable Magnetic Nanomedicine Based on the Antitumor Molecule Tegafur
José L. Arias, Eva Sáez-Fernández, Margarita López-Viota, Rafael A. Biedma-Ortiz and M Adolfina Ruiz
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00043]

The introduction of magnetic nanocarriers in chemotherapy aims to enhance the anticancer activity of antitumor molecules whereas keeping their toxicity to a very minimum. Magnetite/poly(hexylcyanoacrylate) (core/shell) nanoplatforms were synthesized by an emulsion/polymerization procedure. An exhaustive physicochemical characterization (including infrared spectrometry, electrophoresis, and thermodynamic analysis) suggested that the magnetite nuclei were embedded into a polymeric nanomatrix. The very good magnetic responsiveness of such core/shell nanoparticles was defined by the hysteresis cycle. To improve the intravenous delivery of tegafur to cancer, we investigated its incorporation into the nanoplatform. Compared to surface adsorption, drug entrapment into the polymeric shell yielded higher tegafur loading values, and a much slower release profile. A high frequency alternating magnetic gradient was used to elucidate the heating characteristics of the nanoparticles: a stable maximum temperature of 46 °C was successfully achieved within 32 min. Thus, we put forward that such kind of multifunctional nanomedicine hold very important characteristics (i.e., high drug loading, little burst release, hyperthermia, and magnetically targeted tegafur delivery), suggestive of its potential for combined antitumor therapy against cancer.
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Monodisperse Nanoparticles from Self-Assembled Amphiphilic Cyclodextrins: Modulable Tools for the Encapsulation and Controlled Release of Pharmaceuticals
Alejandro Mendez-Ardoy, Marta Gómez-García, Annabelle Gèze, Jean-Luc Putaux, Denis Wouessidjewe, Carmen Ortiz Mellet, Jacques Defaye, José M. García Fernández and Juan M. Benito
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00044]

Selective chemical functionalization of cyclodextrins (CDs) is a readily amenable methodology to produce amphiphilic macromolecules endowed with modulable self-organizing capabilities. Herein, the synthesis of well-defined amphiphilic CD derivatives, with a “skirt-type” architecture, that incorporate long-chain fatty esters at the secondary hydroxyl rim and a variety of chemical functionalities (e. g. iodo, bromo, azido, cysteaminyl or isothiocyanato) at the primary hydroxyls rim is reported. Nanoprecipitation of the new CD facial amphiphiles, or binary mixtures of them, resulted in nanoparticles with average hydrodynamic diameters ranging from 100 to 240 nm that were stable in suspension for several months. The precise size, zeta potential and topology of the nanoparticles are intimately dependent on the functionalization pattern at the CD scaffold. Highly efficient molecular encapsulation capabilities of poorly bioavailable drugs such as diazepam (DZ) were demonstrated for certain derivatives, the drug release profile being dependent on the type of formulation (nanospheres or nanocapsules). The efficiency and versatility of the synthetic strategy, together with the possibility of exploiting the reactivity of the functional groups at the nanoparticle surface, offer excellent opportunities to further manipulate the carrier capabilities of this series of amphiphilic CDs from a bottom-up approach.
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Use of Flow Focusing^® Technology to Produce Tobramycin-Loaded Plga Microparticles for Pulmonary Drug Delivery
L. Martín-Banderas, M.A. Holgado, J. Álvarez-Fuentes and M. Fernández-Arévalo
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00045]

In the present work, a promising formulation of an inhaled powder based on tobramycin-loaded microparticles has been reported. Biodegradable microparticles with controlled diameters in the range of 1-5 μm and narrow size distribution were synthesized by Flow Focusing^® technology. Particles production was planned and optimized with the aid of a well-established mathematic model. Close agreements between theoretical an experimental sizes were obtained. To deliver a high payload of tobramycin to the lungs, the influence of surfactant concentration, polymer-drug ratio and initial drug concentration were investigated. For chosen formulations, drug delivery profiles were also studied. In some cases, it was found a controlled drug delivery for more than ten days, which could represent an important advance in the treatment of chronic lung infections. Other particles factors affecting deposit of an aerosol in the lung were also studied, such as surface charge and density.
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Preparation, Chemical and Electrical Characterizations of Lipid Nanoparticles Loaded with Dihydroxybenzophenone
Hierrezuelo Jesús, Benavente Juana, López–Romero Juan Manuel, Martínez de Yuso Maria del Valle and Rodríguez–Castellón Enrique
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00046]

Lipid nanoparticles loading the sunscreen 2,4-dihydroxybenzophenone (DHB-LNPs) have been prepared by high-pressure homogenization and ultrasound techniques. The combination of both methodologies improves the entrapment efficiency percentage reaching 95%. The morphology of the DHB-LNPs was studied with scanning electron microscopy (SEM) and atomic force microscopy (AFM), while the surface and interior chemical composition was analyzed by X-ray photoelectron spectroscopy (XPS) at different irradiation times. Conductivity of aqueous dispersions of the DHB-LNPs was determined by impedance spectroscopy. A possible DHB-LNPs application related to drug release in a system simulating skin-properties is shown.
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Diagnosis of Alterations of Serum Calcium Metabolism
F. Lumachi, P. Cappelletti, R. Tozzoli, S.M.M. Basso, G. Luisetto and V. Camozzi
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00047]

Calcium is essential to homeostasis and functioning of multiple organ systems. Its circulating concentration is maintained within a very tight physiologic range: 2.25 and 2.50 mmol/L. Under physiological conditions, the ionized calcium concentration is regulated by the parathyroid hormone (PTH), and 1,25(OH)₂ vitamin D through interactions on target organs such as kidney, bone and intestine. In mild, moderate, and severe hypercalcemia, laboratory findings are essential in assessing and monitoring disease course and therapy. The main tools are specific standard biochemical tests able to assess calcium balance and renal function, and some specific biochemical tests, such as PTH, 25(OH) vitamin D, and genetic sequencing, used to clarify the cause of hypercalcemia and, subsequently, to determine appropriate therapy. Once hypercalcemia is confirmed by ionized calcium measurement, the intact PTH assay plays a crucial role to differentiate PTH-mediated from non-PTH-mediated hypercalcemia. Mild hypercalcemia is also present in up to 10-20% of patients treated with lithium for bipolar disorders, in 7-8% of those treated with thiazide diuretics, and in patients with prolonged immobilization, while very high (>3.5 mmol/L) serum calcium levels, together with low PTH, and a rapid increase of hypercalcemia, usually suggest a malignancy-associated hypercalcemic syndrome. The measurement of PTH-related protein, a tumor product that mimics certain action of PTH, is useful only in selected cases. The role of biochemical markers of bone turnover for predicting metastatic bone disease, and monitoring bone metabolic changes, and their usefulness as a predictive mean of the likelihood of bone loss or fractures risk is still unclear.
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Treatment of Acute Hypercalcemia
S.M.M. Basso, F. Lumachi, F. Nascimben, G. Luisetto and V. Camozzi
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00048]

Acute hypercalcemia is a life-threatening rather rare condition.  This condition may represent an acute decompensation of a pre-existing hypercalcemia, or may be acute at the first instance of the electrolyte disturbance. Hypercalcemic patients can present with a broad spectrum of symptoms, but most of them are mild and non-specific. Hypercalcemia affects a group of organs, which are considered together as a syndrome. The supportive care and ABC assessment are the first step to preserve vital functions. Severity index criteria should be considered at admission: severe dehydratation, mental status alteration, renal impairment, cardiac arrhythmias, ionized calcium level, nausea or vomiting, low social level. The neurological status and the main parameters (arterial blood pressure, cardiac pulses, oxygen saturation, temperature) must be monitored in all patients. Five keystones in the treatment of the hypercalcemic crisis should be considered: (1) Restore normovolemia to prevent renal impairment, (2) Restore renal function and enhance renal excretion of calcium, (3)  Dialysis, (4) Inhibit osteoclastic bone resorption, and (5)  Reduce intestinal calcium absorption. Currently, bisphosphonates are the drugs of choice in most of the patients after adequate hydration, while non-bisphosphonates drugs, such as calcitonin, gallium nitrate and mithramycin, are now rarely used. It is pivotal to recognize and treat the disease, according to evidence-based guidelines. At the same time, a short diagnostic program should be started to focus to the appropriate treatment of the underlying disease.
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Treatment of Chronic Hypercalcemia
V. Camozzi, G. Luisetto, S.M.M. Basso, P. Cappelletti, R. Tozzoli and F. Lumachi
[FULL-TEXT INQUIRY] [BSP/MC/E-Pub/00049]

Hypercalcemia is a relatively frequent alteration, mostly associated to primary hyperparathyroidism (PHPT) and malignancy-associated hypercalcemia (MAH). Treatment first includes rehydration and loop diuretics, as general measures. Bisphosphonates are considered the drugs of choice due to their long-term management. Calcitonin is preferable in the short-term control of severe hypercalcemia. The antireabsorptive action of bisphosphonates has been considered the most effective in the disorders characterized by an excessive bone resorption. Zoledronate is superior to both clodronate or pamidronate in the treatment of MAH. Calcimimetic agents has been recently introduced to control hypercalcemia in selected cases of PHPT. They are used when surgery is not possible or patients do not meet surgical criteria. Malignancy-associate hypercalcemia is broadly divided into two categories: humoral MAH and osteolytic MAH. The first concerns the paraneoplastic release of humoral factors, mainly parathyroid hormone-related peptide (PTHrP). Recently a humanized monoclonal antibody against human PTHrP has been generated and is still under evaluation. The receptor activator of nuclear factor-κ ligand (RANKL) has a critical role in the etiology of malignancy skeletal complications. The fully humanized anti-RANKL antibody (denosumab) would seem to be even more effective than bisphosphonates to suppress bone resorption, as shown in preliminary results.
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