| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 17, Number 4, 2010
Contents
Editor’s Choice
Computational Analysis of Human Immunodeficiency Virus (HIV)
Type-1 Reverse Transcriptase Crystallographic Models Based
on Significant Conserved Residues Found in Highly Active Antiretroviral
Therapy (HAART)-Treated Patients Pp. 290-308
S. Alcaro, A. Artese, F. Ceccherini-Silberstein,
V. Chiarella, S. Dimonte, F. Ortuso and C.F. Perno
[Abstract] [Purchase
Article] [PMID:
20015046 PubMed - indexed for MEDLINE]
Cytotoxic Properties of Clofibrate and other Peroxisome
Proliferators: Relevance to Cancer Progression Pp.
309-320
F. Penna, G. Bonelli, F.M. Baccino and
P. Costelli
[Abstract] [Purchase
Article] [PMID:
20015045 PubMed - indexed for MEDLINE]
Comparative Characterization of Experimental
and Calculated Lipophilicity and Anti-Tumour Activity of Isochromanone
Derivatives Pp. 321-333
M. Huszár, A. Varga, A. Horváth, T. Loránd,
A. Agócs, M. Idei, J. Mandl, T. Vántus and
G. Kéri
[Abstract] [Purchase
Article] [PMID:
20015044 PubMed - indexed for MEDLINE]
Serotonin 5-HT3
and 5-HT4 Ligands: An Update
of Medicinal Chemistry Research in the Last Few Years Pp.
334-362
M.N. Modica, V. Pittalà, G. Romeo, L. Salerno and
M.A. Siracusa
[Abstract] [Purchase
Article] [PMID:
20015043 PubMed - indexed for MEDLINE]
New Investigational Drugs for the Management of Acute
Heart Failure Syndromes Pp. 363-390
J. Tamargo, I. Amorós, A. Barana, R. Caballero
and E. Delpón
[Abstract] [Purchase
Article] [PMID:
20015042 PubMed - indexed for MEDLINE]
Abstracts
[Back to top] [Purchase
Article] [PMID:
20015046 PubMed - indexed for MEDLINE]
Computational Analysis of Human Immunodeficiency Virus (HIV)
Type-1 Reverse Transcriptase Crystallographic Models Based
on Significant Conserved Residues Found in Highly Active Antiretroviral
Therapy (HAART)-Treated Patients
S. Alcaro, A. Artese, F. Ceccherini-Silberstein,
V. Chiarella, S. Dimonte, F. Ortuso and C.F. Perno
Reverse transcription of the viral single-stranded (+) RNA
genome into double-stranded DNA is an essential step in the
human immunodeficiency virus’ (HIV) life-cycle. Although
several viral proteins are involved in the regulation and/or
efficiency of reverse transcription, the process of retroviral
DNA synthesis is entirely dependent on the enzymatic activities
of the retroviral reverse transcriptase enzyme (RT). Due to
its crucial role in the HIV life-cycle, RT is a primary target
for anti-HIV drug development. Nonetheless, drug resistance
is the major problem affecting the clinical efficacy of antiretroviral
agents. Incomplete pharmacological pressure represents the
logical cause and not the consequence of different mutation
pathways in RT associated with approved inhibitors resistance.
In this review we have analyzed RT Protein Data Bank (PDB)
models using our innovative computational approach “GRID
Based Pharmacophore Model” (GBPM). This method was applied
to clinically relevant RT conserved residues found in a large
cohort of HAART treated patients. The PDB entries have been
selected among the unbound and the complexed models with DNA
and/or inhibitors. Such an approach has revealed itself useful
to highlight the mutation effects in the drug-RT recognition
as well as in the heterodimer stabilization of the enzyme.
Most of the clinical and biochemical evidences already reported
in the literature have been rationalized at molecular level
via the GBPM computational approach. A definite future
application of this method will be the identification of conserved
regions of critical macromolecules, such as the HIV-1 RT,
to be targeted for the development of innovative therapeutic
agents.
[Back to top]
[Purchase
Article] [PMID:
20015045 PubMed - indexed for MEDLINE]
Cytotoxic Properties of Clofibrate and other Peroxisome
Proliferators: Relevance to Cancer Progression
F. Penna, G. Bonelli, F.M. Baccino and P.
Costelli
The biological activity of peroxisome proliferators (PPs)
is mediated by a class of receptors, known as PPARs (PP-Activated
Receptor), belonging to the nuclear receptor superfamily.
Upon ligand binding, PPARs dimerize with retinoid receptors,
translocate to the nucleus, recognize specific PP-responsive
elements on DNA and transactivate a number of genes. Several
processes are regulated by PPARs, such as mitochondrial and
peroxisomal fatty acid uptake and β-oxidation,
inflammation, intracellular lipid trafficking, cell proliferation
and death. In addition, PPARs have been pro-posed to act as
tumor suppressors or as tumor promoters, depending on the
circumstances. In particular, PPs have been ex-tensively studied
for their hepatocarcinogenic action in rodents, most often
ascribed to their antiapoptotic action. Recent evidence, however,
has been provided about the antiproliferative, proapoptotic,
and differentiation-promoting activities displayed by PPAR
ligands. The present review will focus on the cytotoxic effects
exerted by several PPs, among which clofibrate, on different
types of tumor cells, with particular reference to the mechanisms
of cell death and to their relevance to cancer induction and
progression
[Back to top]
[Purchase
Article] [PMID:
20015044 PubMed - indexed for MEDLINE]
Comparative Characterization of Experimental
and Calculated Lipophilicity and Anti-Tumour Activity of Isochromanone
Derivatives
M. Huszár, A. Varga, A. Horváth, T. Loránd,
A. Agócs, M. Idei, J. Mandl, T. Vántus and
G. Kéri
Compound lipophilicity connected to ADME(T)a
has great importance in drug development and it has to be
evaluated by the generally used drug developmental process.
In addition to the importance of lipophilicity in ADMET, recently
it has been reported that lipophilicity of small molecules
correlates with their antiproliferative activity because of
certain specific hydrophobic and lipophilic interactions.
Due to the complexity of ADME(T) parameters an efficient and
fast method is needed to characterize the many promising candidate
lead molecules as a preselection in order not to be rejected
from the latter phase of drug development. In the present
paper we provide an overview of the importance of lipophilicity
of drug candidates for biological action and for ADME(T) and
describe a novel approach for drug-likeness characterization
of a molecular library using correlation study between lipophilicity
and biological activity. Lipophilicity and molecular characteristics
have been measured, predicted and optimized for a diverse
library from which the best members have been selected to
describe their biological, chemical and drug-likeness properties.
Molecules were selected from the family of α,β-unsaturated
ketones and thorough HPLC characterization for lipophilicity
and morphological, antiproliferative and flow cytometric studies
were carried out on them. Based on the results 17 member isochromanone
library including E and Z geometric isomers were selected
for further characterization. In this focused library linear
correlation has been found between the calculated and measured
lipophilicity and significant parabolic correlation was found
between the antiproliferative effect and lipophilicity. Using
our efficient and fast method, from a diverse library, we
identified an out-standingly effective inhibitor of A431 tumour
cell growth via a PARPa cleavage
dependent apoptosis. In summary the optimized HPLC analyses
of lipophilicity combined with the cell-culture assay, introduced
above, resulted in the determination of an optimal lipophilicity
range. This optimized lipophilicity range should be used in
designing novel antiproliferative compounds.
[Back to top]
[Purchase
Article] [PMID:
20015043 PubMed - indexed for MEDLINE]
Serotonin 5-HT3
and 5-HT4 Ligands: An Update
of Medicinal Chemistry Research in the Last Few Years
M.N. Modica, V. Pittalà, G. Romeo, L. Salerno and
M.A. Siracusa
The biogenic amine serotonin (5-hydroxytryptamine, 5-HT) is
one of the most studied neurotransmitters in the central nervous
system. It acts through the activation of at least fourteen
5-HT receptor subtypes. Over the last two decades, high attention
was devoted to the 5-HT3
and 5-HT4
receptors due to their colocalization in the gastrointestinal
tract and because their ligands are useful in the treatment
of intestinal serotonergic system dysfunctions. The focus
of this review is to discuss the literature concerning recent
advances on 5-HT3R
and 5-HT4R
ligands and their structure-activity relationships from a
medicinal chemistry perspective. During the last few years,
new and significant progresses have been made in the field
of novel potent and selective ligands, mixed ligands, agonists,
partial agonists, and antagonists, and a number of patents
have been filed. Furthermore several ligands targeting the
5-HT3R and
5-HT4R have
been proposed for novel therapeutic indications such as the
treatment of various psychiatric disorders.
[Back to top]
[Purchase
Article] [PMID:
20015042 PubMed - indexed for MEDLINE]
New Investigational Drugs for the Management of Acute
Heart Failure Syndromes
J. Tamargo, I. Amorós, A. Barana, R. Caballero
and E. Delpón
Acute heart failure syndromes (AHFS) enclose a broad spectrum
of conditions with different clinical presentations, heart
failure history, pathophysiology, prognosis and treatment.
AHFS represent a major public health problem because of their
high prevalence, high rates of mortality and readmissions
and significant healthcare costs, and a therapeutic challenge
for the clinicians because management strategies vary markedly.
Traditionally used drugs for the treatment of AHFS, including
diuretics, vasodilators and positive inotropics, improve clinical
signs and symptoms as well as hemodynamics, but present important
limitations, as they fail to reduce and may even increase
in-hospital and postdischarge mortality, especially in patients
with coronary artery disease. Thus, we need new pharmacological
agents to not only improve signs and symptoms and cardiac
performance, but also improve both short- and long-term outcomes
(hospitalizations/survival). In the last decade, significant
efforts have been made to identify new therapeutic targets
involved in the genesis/progression of AHFS and to develop
new therapeutic strategies that may safely improve outcomes.
As a result, several new families of drugs have been developed
and are currently studied in experimental models and in Phase
II and III clinical trials, in an attempt to define their
efficacy and safety profiles as well as their precise role
in the treatment of AHFS patients. This review firstly analyzes
the main clinical applications and limitations of conventional
drugs, and then focuses on the mechanisms of action and effects
of recently approved drugs and of new investigational agents
on signs, symptoms, hemodynamics and outcomes in AHFS patients.
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