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Medicinal Chemistry
ISSN: 1573-4064
Medicinal Chemistry
Volume 4, Number 2, March
2008
Contents
Synthesis and Cytotoxicity Studies
of New Morpholino Functionalised and N-Heteroaryl-Substituted
Titanocene Anticancer Drugs Pp. 91-99
M. Hogan, J. Claffey, C. Pampillón and M. Tacke
[Abstract]
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Photoperiod and Testosterone Modulate Growth and Melanogenesis
of S91 Murine Melanoma Pp. 100-105
P.A.A. Allil, M.A. Visconti, A.M.L. Castrucci and M.C.
Isoldi
[Abstract] [Purchase
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Cytotoxic and Apoptogenic Activity of a Methanoli
Extract from the Marine Invertebrate Ciona intestinalis
on Malignant Cell Lines Pp. 106-109
G.L. Russo, G. Ciarcia, E. Presidente, R.A. Siciliano
and E. Tosti
[Abstract]
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Quantitative Structure-Activity Relationships for
Commercially Available Inhibitors of COX-2 Pp. 110-115
P.M. Sivakumar and M. Doble
[Abstract]
[Purchase Article]
Inhibitory Feature of the Proprotein Convertases Prosegments
Pp. 116-120
Y. Bontemps, M. Lapierre, G. Siegfried, F. Calvo and A.-M.
Khatib
[Abstract] [Purchase
Article]
Synthesis and Pharmacological Profile of a Series
of 1 substituted-2-Carbonyl Derivatives of Diphenidol: Novel
M4
Muscarinic ReceptorAntagonists Pp. 121-128
L. Varoli, P. Angeli, M. Buccioni, S. Burnelli, N. Fazio,
G Marucci, M. Recanatini and S. Spampinato
[Abstract]
[Purchase Article]
Synthesis and Endothelin Receptor Binding Affinity
of a Novel Class of 2-Substituted-4-aryl-3-quinolinecarboxyli
Acid Derivatives Pp. 129-137
V. Pittalà, M. Modica, L. Salerno, M.A. Siracusa,
F. Guerrera, I. Mereghetti, A. Cagnotto, T. Mennini and G.
Romeo
[Abstract]
[Purchase Article]
Comparative Antiviral (HIV) Photoactivity of Metalize
meso- Tetraphenylsulfonated Porphyrins Pp.
138-145
F. Vargas, C. Rivas, T. Zoltan, L. Padrón, C. Izzo,
V. López, L. Gómez, F. Pujol, H. Rangel, D.
Garzaro and R. Fabbro
[Abstract] [Purchase
Article]
Synthesis of Some Thiophene, Imidazole and Pyridine
Derivatives Exhibiting Good Anti-Inflammatory an Analgesic
Activities Pp. 146-154
S.M. Sondhi, S. Jain, M. Dinodia and A. Kumar
[Abstract]
[Purchase Article]
Photoreactive DNA Probes as a Tool for Studying the
Translesion Synthesis System in Mammalian Cell Extracts
Pp. 155-162
E.A. Belousova, E. Crespan, N.A. Lebedeva, N.I. Rechkunova,
U. Hübscher, G. Maga and O.I. Lavrik
[Abstract]
[Purchase Article]
In Vitro Leishmanicidal Activity of 3-substituted
Isocoumarins: Synthesis and Structure activit Relationship
Pp. 163-169
K.M. Khan, S. Ahmed, Z.A. Khan, Zia-Ullah, M. Rani, M.I.
Choudhary and S. Perveen
[Abstract]
[Purchase Article]
Prediction of Distribution of Neutral, Acidic and
Basic Structurally Diverse Compounds Between Blood and Brain
by the Nonlinear Methodology Pp. 170-189
H. Zhang, S. Hu and Y. Zhang
[Abstract]
[Purchase Article]
Anti-Tubercular and Anti-Inflammatory Activities of
Azetidin-2-One Derivatives and Their Effects on the Activity
of Phospholipase A2
Pp. 190-193
M.C. Yerigeri, S.K. Murari, K.N. Thimmaiah, S.K.S. Math
and B.S. Vishwanath
[Abstract] [Purchase
Article]
Abstracts
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Synthesis and Cytotoxicity Studies of New Morpholino
Functionalised and N-Heteroaryl-Substituted Titanocene
Anticancer Drugs
M. Hogan, J. Claffey, C. Pampillón and M. Tacke
From the carbolithiation of 6-morpholino fulvene (3)
and different lithiated nitrogen containing heterocycles (2-N-methylimidazolyl,
2-N-(N,N-dimethylamino)methyl-imidazolyl,
and 2-N-methylindolyl), the corresponding lithium
cyclopentadienide intermediate (4a-c) was
formed. These three lithiated intermediates underwent a transmetallation
reaction with TiCl4 resulting
in morpholino-functionalised titanocenes 5a-c.
When these titanocenes were tested against LLC-PK cells, the
IC50 values obtained were
of 24, 36, and 41 μM
respectively. The most cytotoxic titanocene in this paper
(5a) with an IC50
value of 24 μM
is found to be almost ten times less cytotoxic than cis-platin,
which showed an IC50 value
of 3.3 μM
when tested on the epithelial pig kidney LLC-PK cell line,
and approximately 2 times less cytotoxic than its dimethylamino-functionalised
analogue. Encouragingly however, the IC50
value obtained for titanocene 5a is approximately
100 times better than titanocene dichloride itself.
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Photoperiod and Testosterone Modulate Growth and Melanogenesis
of S91 Murine Melanoma
P.A.A. Allil, M.A. Visconti, A.M.L. Castrucci and M.C.
Isoldi
In vivo and in vitro assays were performed with
S91 murine melanoma cells aiming to investigate the effects
of testosterone and photoperiod on tumor growth and melanogenesis
(tyrosinase activity). In vivo assays were performed
by inducing melanoma tumors in castrated mice receiving increasing
concentrations of testosterone and submitted to varying photoperiod
regimens. The results demonstrated that the increase of melanin
content was higher in animals submitted to the longest days,
thus demonstrating the importance of photoperiod length in
melanin synthesis. Increase in tumor growth and protein content
was observed in testosterone-treated animals submitted to
12L:12D; in testosterone-treated animals submitted to 4L:20D
and 20L:4D tumor growth was significantly smaller. In S91
cultured cells, testosterone increased cell proliferation
and reduced tyrosinase activity in a dose-dependent manner.
Radioactive binding assays demonstrated that the hormone was
acting through low affinity testosterone receptors, since
the presence of aromatase inhibitor did not affect the binding
assay in a statistically significant way, and all the in vitro
experiments were performed in the presence of the inhibitor.
Our in vivo data added to the in vitro results
corroborate the hypothesis that S91 melanoma cells directly
respond to testosterone and that this effect is modulated
by light.
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Cytotoxic and Apoptogenic Activity of a Methanolic Extract
from the Marine Invertebrate Ciona intestinalis on
Malignant Cell Lines
G.L. Russo, G. Ciarcia, E. Presidente, R.A. Siciliano
and E. Tosti
Marine invertebrates provide a series of natural products
with different biological activities. Several of these compounds
and their derivatives showed a potent anticancer effect. Tunicates
represent an important source of bioactive agents, leading
to the isolation of ecteinascidin-743 (ET-743), a compound
isolated from the Caribbean sea squirt Ecteinascidia turbinata
with a potent cytotoxic activity against a variety of tumours
in vitro and in vivo. Current phase II clinical
trials against soft tissue sarcomas in Europe and the United
States indicate that ET-743 represents a highly promising
anticancer agent. Another example is aplidine from the Mediterranean
tunicate Aplidium albicans, with a broad spectrum
activity against various types of cancers, such as colorectal,
lymphoma, thyroid and renal cancers. In the present work,
we reported, for the first time, that a partially purified
methanolic extract prepared from the ascidian Ciona intestinalis
inhibited cell proliferation in human cell lines of different
origin, including Caco2, HPB-ALL, U-937 and HL-60 and induced
early apoptotic events, such as caspase-3 activation and internucleosomal
DNA degradation. We suggest the presence in the Ciona
intestinalis extract of bioactive compounds possessing
anticancer activity.
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Quantitative Structure-Activity Relationships for Commercially
Available Inhibitors of COX-2
P.M. Sivakumar and M. Doble
Quantitative structure activity relationship (QSAR) studies
of selective COX-2 inhibitors of commercial interest (drugs
in market and on clinical trials) were performed. The COX-2
inhibitory activity (pIC50=-logIC50)
of these twelve compounds was correlated with nineteen descriptors
including steric, electronic and constitutional parameters.
pIC50 activity showed high
positive correlation with both volume and HOMO (Highest occupied
molecular orbital). A Biparametric model was developed that
included both these descriptors. The predictive capability
(q2 = 0.66) of this equation
was satisfactory. So it can be used to design newer templates
or modify existing templates. Volume is an important parameter
for the selective COX-2 inhibitory activity, because the secondary
pocket in the active site of this enzyme is bigger than the
active site of COX-1 enzyme (by 17%). HOMO is a measure of
the nucleophilicity of the molecule and a molecule with high
HOMO energy is ready to donate its electrons and thus is more
reactive than molecule with low values. Binding studies were
performed between the COX-2 enzyme and these molecules. The
inhibitory activity increased with decrease in binding energy
(or interaction energy) between the compounds with the COX-2
enzyme (with a correlation coefficient = -0.65). Calculated
Log BBB (Blood Brain barrier), Log P (octonol water partition)
and HBD (hydrogen bond donor) values were in the acceptable
range (i.e., BBB = -1 to 0.3; LogP= 0 to 5; HBD < 5).
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Inhibitory Feature of the Proprotein Convertases Prosegments
Y. Bontemps, M. Lapierre, G. Siegfried, F. Calvo and A.-M.
Khatib
The proprotein convertases (PCs) are serine proteases
involved in various physiological processes and their overactivity
or inactivity has been linked to different disorders. PCs
are responsible for the proteolytic processing of various
polypeptide precursors. Here, we discuss the effect of their
N-terminal prosegments on various PC substrates processing
and functions.
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Synthesis and Pharmacological Profile of a Series of 1-substituted-2-Carbonyl
Derivatives of Diphenidol: Novel M4
Muscarinic ReceptorAntagonists
L. Varoli, P. Angeli, M. Buccioni, S. Burnelli, N. Fazio,
G. Marucci, M. Recanatini and S. Spampinato
Novel 2-carbonyl analogues of diphenidol (1)
- bearing lipophylic 1-substituents (2) -
were synthesized starting from previously investigated diphenidol
derivatives acting as M2
-selective muscarinic antagonists. These compounds were tested
for receptor binding affinity versus human muscarinic M1-M5
receptors stably expressed in CHO-K1 cells. Their activity
in functional assays carried out on CHO-K1 cells expressing
human M4 receptors (CHO-hM4)
and on classical models of M1-M3
receptors, in guinea pig and rabbit tissue preparations, was
also evaluated. Compound 2d showed an affinity
of pKi = 7.73 at the human
M2-receptor subtype with
selectivity ratios ranging from 31-fold (M4/M5)
to 60-fold (M4/M2).
Interestingly this compound, in CHO-hM4
cells, blocked the inhibition of forskolin-activated cAMP
accumulation produced by carbachol (IC50=
61 nM) whereas it was a weak muscarinic antagonist in functional
tests carried out in guinea-pig and rabbit tissue expressing
M1 (pKb
= 5.96), M2 (pKb
= 6.43) and M3 (pKb
= 6.09) receptors. In conclusion, the modifications performed
in this work on reference compounds led us to obtain surprisingly
a M4 selective antagonist.
Considering the therapeutic indications for M4
selective antagonists, compound 2d may serve
as a novel lead compound for further optimization.
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Synthesis and Endothelin Receptor Binding Affinity of a Novel
Class of 2-Substituted-4-aryl-3-quinolinecarboxylic Acid Derivatives
V. Pittalà, M. Modica, L. Salerno, M.A. Siracusa,
F. Guerrera, I. Mereghetti, A. Cagnotto, T. Mennini and G.
Romeo
The 21-amino acid peptide endothelin-1 (ET-1) is the
predominant isoform of the endothelin peptide family, which
includes ET-2, and ET-3. These peptides display a variety
of physiological activities including vasoconstriction and
the stimulation of cell proliferation in tissues both within
and outside of the cardiovascular system. They exert their
actions via activation of two distinct receptor subtypes,
ETA and ETB,
belonging to the G protein-coupled receptor (GPCR) superfamily.
Ligands of these receptors have received numerous citations
in the recent pharmaceutical literature. In particular receptor
antagonists, both ETA- and
ETB-selective, as well as
non-selective, have been described due to their wide therapeutic
potential. As a part of our program toward the development
of selective ETB ligands
we have designed and we now report new molecules based on
2-substituted-4-aryl-3-quinolinecarboxylic acid moiety. Binding
profile for some compounds (40, 44, 46, and
47) of this class showed a reasonable affinity
and selectivity for ETA receptors.
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Comparative Antiviral (HIV) Photoactivity of Metalized meso-
Tetraphenylsulfonated Porphyrins
F. Vargas, C. Rivas, T. Zoltan, L. Padrón, C. Izzo,
V. López, L. Gómez, F. Pujol, H. Rangel, D.
Garzaro and R. Fabbro
We have carried out the study of the photochemical properties
of a series of synthetic meso-tetraphenylsulfonated
porphyrins (TPPMS4) bonded
to several metal ions such as: Cu(II), Zn(II), Pd(II), Mn(II),
Fe(III), Ni(II) and Co(II) for the optimization of their clinical
applications as antiviral agents against the human immunodeficiency
virus (HIV-1) as well as the study of the in vitro
antiviral photoinactivation mechanisms with future application
in blood sterilization. A selective inhibition has been determined
in the viral growth (HIV-1) when this is irradiated in the
presence of the complex TPPFeS4
and TPPMnS4 (photosensitizer-mediated
Type I reaction) as well as in the 1
O2-mediated (Type II reaction)
in the presence of TPPPdS4
and TPPZnS4, remaining cellular
viability unaltered in each case.
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Synthesis of Some Thiophene, Imidazole and Pyridine Derivatives
Exhibiting Good Anti-Inflammatory and Analgesic Activities
S.M. Sondhi, S. Jain, M. Dinodia and A. Kumar
A series of thiophene derivatives 1a-d &
2a-c were synthesized by condensation of 5-nitro-2-thiophene
carboxaldehyde with mono and diamines respectively. Various
imidazole derivatives 3a-c were obtained
by condensing 4-(2-ethylamino)-1H-imidazole with 4-acetylpyridine,
2-acetylpyridine and 4-acetylbenzonitrile respectively. Pyridine
derivatives 4a-e were synthesized by condensing
2-hydrazino-pyridine with various carbonyl compounds; 5a-c
by condensing 2, 6-pyridine dicarbonyl dichloride with various
aryl sulfonylhydrazides; 6, 7 by condensing
2, 6-dialdehyde pyridine with 2-hydrazinopyridine and anthranilonitrile
respectively and compound 8 by condensing
2, 5-thiophene dialdehyde with hydrazinopyridine. All the
compounds were characterized by IR, 1HNMR,
Mass spectra and elemental analysis. Compounds 1a-d;
2a-c; 3a-c; 4a-e; 5a-c, 6, 7 and 8
were screened for anti-inflammatory and analgesic activities.
Compounds 1b and 2c exhibited good anti-inflammatory
(26.5% and 33.4% at 50mg/kg p.o. respectively) and 3a,
3c good analgesic (100% and 75% at 100 mg/kg p.o.
respectively) activities.
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Photoreactive DNA Probes as a Tool for Studying the Translesion
Synthesis System in Mammalian Cell Extracts
E.A. Belousova, E. Crespan, N.A. Lebedeva, N.I. Rechkunova,
U. Hübscher, G. Maga and O.I. Lavrik
Translesion synthesis (TLS) is one of the DNA damage
tolerance strategies that has evolved to enable organisms
to replicate their genome despite the presence of unrepaired
damage. TLS complexes are dynamic systems composed of DNA
polymerases and associated protein factors. Therefore, it
is hard to study these assembles by X-ray analysis or other
instrumental methods. Here, we have suggested applying the
photoaffinity labeling technique for studying the TLS system
in nuclear/cellular extracts. As a tool we proposed to use
partial DNA duplexes containing base-substituted photoreactive
deoxynucleotides at the 3’ end of primer opposite to
DNA damage at the template strand. We demonstrated that photoreactive
dNTPs can be potentially used to synthesize photoreactive
DNA probes mimicking the DNA intermediates of the first stage
of translesion synthesis by specialized DNA polymerases. We
used synthetic apurinic/apyrimidinic site (AP-site) –
tetrahydrofuran (THF) and 8 oxoguanine as damages in +1 position
of the template strand with respect to 3’ end of primer.
Activity of human DNA polymerases β
and λ
was exploited for construction of photoreactive DNAs using
photo derivatives of dNTPs. The kinetic parameters of the
elongation reaction in model systems were estimated. Using
photoaffinity crosslinking we found that only a few proteins
in the bovine testis nuclear extract were strongly labeled
by TLS probes.
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In Vitro Leishmanicidal Activity of 3-substituted Isocoumarins:
Synthesis and Structure activity Relationship
K.M. Khan, S. Ahmed, Z.A. Khan, Zia-Ullah, M. Rani, M.I.
Choudhary and S. Perveen
Twenty-five 3-substituted isocoumarins were synthesized
using cutting edge microwave-assisted technology in high yields.
The syntheses of different isocoumarins were carried out in
a single step by the direct condensation of homophthalic acid
with aryol and acyl chlorides under the solvent-free conditions
without any solid support. The structures of all the synthesized
compounds were characterized using different spectroscopic
techniques including UV, IR, 1HNMR
and EIMS and purity was confirmed by CHN analysis. All the
synthesized compounds were tested for in vitro leishmanicidal
activity. Compounds 3a, 3b, 3g, 3l, 3m, 3r, 3t, 3w,
3x, and 3y displayed potential in
vitro leishmanicidal activity with IC50
values in the range of 0.56-84.38 μg/ml,
whereas standard inhibitors amphotericine B have IC50
= 0.24 μg/ml.
The compounds 3b, 3g, 3m, 3t, 3w, 3x, and
3y having IC50
values 27.86, 28.88, 36.49, 34.37, 28.68, 0.89 and 0.56 μg/ml,
respectively, were most active among the present series while
remaining others were found less active. The compound 3x
and 3y can act as potential lead molecules
for further development of isocoumarin-based new drugs for
the treatment of leishmaniasis.
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Prediction of Distribution of Neutral, Acidic and Basic Structurally
Diverse Compounds Between Blood and Brain by the Nonlinear
Methodology
H. Zhang, S. Hu and Y. Zhang
The methodology for predicting the distribution of compounds
between Blood and Brain, i.e. their brain/blood partition
coefficients (logBB values), was studied using a nonlinear
regression analysis in this work. The equations were established
on the basis of the different states (neutral, cationic and
anionic) of the compounds distributing into the three dominating
composition (lipid, protein and water) of the brain. The equations
bear strong fitting and predictive power for the distribution
of compounds (total set: n=160, r=0.906, s=0.326; training
set: n=139, r=0.908, s=0.320; testing set: n=21, r=0.903,
s=0.297), and can describe the distribution of the different
states of the compounds in three compositions of brain. The
compounds in the dataset contained many different types, such
as drug molecules, small structure-simple molecules, carboxylic
acids and also alkaloids. Therefore the equations were very
useful and instructional for the prediction of the compound
distribution into the brain and blood. Finally, the percentages
of the amount of a compound in lipid, protein and water in
brain were calculated using the model, such subdivision will
be very useful in drug research and discovery. By an analysis
of the percentages a conclusion can be obtained that a well
distributed drug is mainly affected by distribution of lipid
and protein.
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Anti-Tubercular and Anti-Inflammatory Activities of Azetidin-2-One
Derivatives and Their Effects on the Activity of Phospholipase
A2
M.C. Yerigeri, S.K. Murari, K.N. Thimmaiah, S.K.S. Math
and B.S. Vishwanath
The title compounds have been synthesized and tested
for structure activity relationship for Phospholipase A2
(PLA2) [E.C. 3.1.1.4] enzyme
inhibition. The in vitro anti-tubercular, PLA2
enzyme inhibitory activities of azetidin-2-one derivatives
and in vivo anti-inflammatory studies using mice
are highlighted. The analogues of azetidin-2-one were prepared
based on the initial activity against Mycobacterium tuberculosis
(Mtb). Certain azetidin-2-one analogues described herein showed
moderate to good anti-tubercular activity. In particular,
two compounds (4f)
and (4g) exhibited MIC values of 1.56 and
0.78 µg/mL respectively against the Mtb H37
Rv strain. Chloro substitution on aryloxy acid
apparently enhanced the antimycobacterial activity and also
PLA2 inhibition in the azetidin-2-one
series described herein. The ability of azetidin-2-one analogues
as anti-inflammatory agents has also been determined. The
results show some correlation between anti-inflammatory, anti-tubercular
activity and expression of PLA2
enzyme.
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