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Mini-Reviews
in Medicinal Chemistry
ISSN: 1389-5575
Mini-Reviews in Medicinal
Chemistry
Volume 6, Number 4, April 2006
Contents
Synthetic and Natural Coumarins as Antioxidants Pp.
365-374
Irena Kostova
[Abstract]
Structural Features of New Quinolones
and Relationship to Antibacterial Activity Against Gram-positive
Bacteria Pp. 375-386
Saeed Emami, Abbas Shafiee and Alireza Foroumadi
[Abstract]
Towards the Targeted Therapy of Melanoma
Pp. 387-393
K.S.M. Smalley and M. Herlyn
[Abstract]
Ifosfamide. Metabolic Studies, New
Therapeutic Approaches and New Analogs Pp.
395-400
Konrad Misiura
[Abstract]
The Role of Genistein and Synthetic
Derivatives of Isoflavone in Cancer Prevention and Therapy
Pp. 401-407
Fazlul H. Sarkar, Shreelekha Adsule, Subhash Padhye, Sudhir
Kulkarni and Yiwei Li
[Abstract]
Calcium Signalling and Reactive Oxygen
Species in Non-Excitable Cells Pp. 409-415
Juan A. Rosado, Pedro C. Redondo, Gines M. Salido and José
A. Pariente
[Abstract]
Review in Pharmacokinetic Models on
Corticosteroids Pp. 417-428
Nabil Semmar and Nicolas Simon
[Abstract]
Recent Advances in Anti-Influenza Agents with Neuraminidase
as Target Pp. 429-448
Jie Zhang and Wenfang Xu
[Abstract]
Prediction of Compounds with Specific Pharmacodynamic, Pharmacokinetic
or Toxicological Property by Statistical Learning Methods
Pp. 449-459
C.W. Yap, Y. Xue, H. Li, Z.R. Li, C.Y. Ung, L.Y. Han,
C.J. Zheng, Z.W. Cao and Y.Z. Chen
[Abstract]
Geminin as A Molecular Target for the Development of New Anticancer
Drugs Pp. 461-462
Kenichi Yoshida
[Abstract]
Functional Chemokine Receptors in Allergic Diseases: Is CCR8
a Novel Therapeutic Target? Pp. 463-466
E. Mitsuyama, Y. Kunori, T. Kamimura and O. Kaminuma
[Abstract]
A Classical QSAR Study on Some Platelet Aggregation Inhibitors
Pp. 467-482
Rajeshwar P. Verma
[Abstract]
Allosteric Modulation of Drug Binding to Human Serum Albumin
Pp. 483-489
Paolo Ascenzi, Alessio Bocedi, Stefania Notari, GabriellaFanali,
RiccardoFesce and Mauro Fasano
[Abstract]
Abstracts
[Back to top]
Synthetic and Natural Coumarins as Antioxidants
Irena Kostova
Coumarins, an old class of compounds, are naturally occurring
benzopyrene derivatives. A lot of coumarins have been identified
from natural sources, especially green plants. These natural
compounds have served as valuable leads for further design
and synthesis of more active analogs. The pharmacological
and biochemical properties and therapeutic applications of
simple coumarins depend upon the pattern of substitution.
Coumarins have attracted intense interest in recent years
because of their diverse pharmacological properties. Among
these properties, their antioxidant effects were extensively
examined. In this review, plant derived coumarins and their
synthetic analogs will be systematically evaluated based on
their plant origin, structure-activity relationship and antioxidant
efficacy. Owing their diverse effects and inconclusive results
from different in vitro studies, the mechanism of
their action has not yet been fully understood and the correlation
of effects with chemical structure is not conclusive at the
moment. It is the objective of this review will be to summarize
experimental data for different coumarins used as antioxidant
agents, because promising data have been reported for a series
of these agents. In addition, their ability to bind metal
ions represents an additional means of modulating their pharmacological
responses.
[Back to top]
Structural Features of New Quinolones and
Relationship to Antibacterial Activity Against Gram-positive
Bacteria
Saeed Emami, Abbas Shafiee and Alireza Foroumadi
A major recent focus of quinolone antibacterials has been
the development of agents with enhanced activity against Gram-positive
bacteria. The extensive research efforts have enabled a better
definition of the structural features of quinolones that offer
the best combination of clinical efficacy and reduced resistance
selection in Gram-positive bacteria. This review considers
the structural features of new quinolones and relationship
to antibacterial activity against Gram-positive bacteria,
while trying to position them in the context of recent and
possible future advances based on an understanding of their
chemical structure and how these impact on target specificity,
avoidance of efflux and prevention of emergence of quinolone-resistant
mutants in Gram-positive bacteria.
[Back to top]
Towards the Targeted Therapy of Melanoma
K.S.M. Smalley and M. Herlyn
Novel anti-cancer treatments use knowledge about the underlying
biology of the tumor to find suitable molecular targets. The
recent years have seen great advances in understanding the
biology of melanoma. In the current review we discuss the
most promising molecular targets for melanoma and suggest
possible strategies for overcoming resistance.
[Back to top]
Ifosfamide. Metabolic Studies, New Therapeutic
Approaches and New Analogs
Konrad Misiura
Ifosfamide (IFO), an oxazaphosphorine-type anticancer alkylating
agent, was found to be particularly useful in the treatment
of a wide variety of neoplasm in adults and children. IFO
is a positional isomer of cyclophosphamide (CPA) and was introduced
into clinical practice in the ‘80s and has recently
attracted much attention. Therapeutic application of high-dose
IFO is limited by several side-effects; among them neurotoxicity
and nephrotoxicity give the greatest concern. The presence
of these side-effects is likely to be connected with the metabolism
of this drug. In recent years there have been many studies
aiming better understanding metabolism of this drug, employing
new therapeutic approaches and preparing new analogs.
[Back to top]
The Role of Genistein and Synthetic Derivatives
of Isoflavone in Cancer Prevention and Therapy
Fazlul H. Sarkar, Shreelekha Adsule, Subhash Padhye, Sudhir
Kulkarni and Yiwei Li
Genistein, one of the predominant soy isoflavones, has been
shown to compete with 17β-estradiol
for estrogen receptor binding because of its structural similarity,
resulting in agonistic or antagonistic activity. It causes
inhibition of cell growth in breast and prostate cancers
in vivo and in vitro. From gene expression profiles,
genistein has been found to regulate the genes that are critical
for the control of cell proliferation, cell cycle, apoptosis,
oncogenesis, transcription regulation, and cell signal transduction
pathways. It has been reported that genistein induces apoptosis
and inhibits activation of NF-κB
and Akt signaling pathways, both of which are known to maintain
a balance between cell survival and apoptosis. Recently, we
found that genistein sensitized cancer cells to apoptosis
induced by chemotherapeutic agents including docetaxel, gemcitabine
and cisplatin through inactivation of NF-κB
in multiple cancer cell lines. To enhance the anti-cancer
activity of genistein, we have synthesized structurally-modified
derivatives of isoflavone based on the structural requirements
for optimal anti-cancer effect. We found that these synthetic
derivatives of isoflavone exerted higher anti-cancer activity
with lower IC50. These derivatives of isoflavone
also induced more apoptosis compared to genistein. These results
suggest that genistein and synthetic structurally-modified
derivatives of isoflavone may be promising agents for cancer
chemoprevention and therapy either alone or in combination
with existing chemotherapeutic agents.
[Back to top]
Calcium Signalling and Reactive Oxygen Species
in Non-Excitable Cells
Juan A. Rosado, Pedro C. Redondo, Gines M. Salido and José
A. Pariente
Reactive oxygen species can induce several biological processes
by stimulating signal transduction components such as cytosolic
free calcium concentration. The physiological significance
of the role of biological oxidants in the regulation of calcium
signalling pathway as well as the mechanisms of the oxidant-stimulation
of signal transduction are discussed in this review.
[Back to top]
Review in Pharmacokinetic Models on Corticosteroids
Nabil Semmar and Nicolas Simon
The pharmacokinetics of corticosteroids provides a large
set of mathematical models which led to analyse many kinetic
profiles corresponding to many clinical and/or physiological
situations. In this paper, we present a review on the usefulness,
advantages and limits of such models which could find a large
application in medicinal chemistry.
[Back to top]
Recent Advances in Anti-Influenza Agents
with Neuraminidase as Target
Jie Zhang and Wenfang Xu
Neuraminidase (NA) is the major surface glycoprotein of the
influenza virus. It has been considered a suitable target
for designing agents against influenza viruses. Rational drug
design of NA inhibitors is now in the clinic and is effective
for the treatment of influenza. Recently, research of structure-based
NA inhibitors is becoming an interesting field, leading to
a breakthrough in the control of influenza. Here we review
a series of neuraminidase inhibitors and the recent progress
in this field.
[Back to top]
Prediction of Compounds with Specific Pharmacodynamic, Pharmacokinetic
or Toxicological Property by Statistical Learning Methods
C.W. Yap, Y. Xue, H. Li, Z.R. Li, C.Y. Ung, L.Y. Han,
C.J. Zheng, Z.W. Cao and Y.Z. Chen
Computational methods for predicting compounds of specific
pharmacodynamic, pharmacokinetic, or toxicological property
are useful for facilitating drug discovery and drug safety
evaluation. The quantitative structure-activity relationship
(QSAR) and quantitative structure-property relationship (QSPR)
methods are the most successfully used statistical learning
methods for predicting compounds of specific property. More
recently, other statistical learning methods such as neural
networks and support vector machines have been explored for
predicting compounds of higher structural diversity than those
covered by QSAR and QSPR. These methods have shown promising
potential in a number of studies. This article is intended
to review the strategies, current progresses and underlying
difficulties in using statistical learning methods for predicting
compounds of specific property. It also evaluates algorithms
commonly used for representing structural and physicochemical
properties of compounds.
[Back to top]
Geminin as A Molecular Target for the Development of New
Anticancer Drugs
Kenichi Yoshida
The unique biological properties of Geminin, particularly
as an inhibitor of DNA replication initiation, have been recognized,
and this has prompted a number of investigations into this
molecule to explore its potential therapeutic as well as diagnostic
usefulness. This review summarizes the possibility of Geminin
serving as a new molecular target in the development of new
anticancer drugs.
[Back to top]
Functional Chemokine Receptors in Allergic Diseases: Is
CCR8 a Novel Therapeutic Target?
E. Mitsuyama, Y. Kunori, T. Kamimura and O. Kaminuma
CC chemokine receptor (CCR) 8, which is expressed on Th2
cells and eosinophils, has been implicated in allergic diseases.
This review represents an overview of the functional roles
of CCR8 in the pathogenesis of eosinophilic inflammation and
debates the potential of recently developed CCR8 antagonists
to treat allergic disorders.
[Back to top]
A Classical QSAR Study on Some Platelet Aggregation Inhibitors
Rajeshwar P. Verma
Cardiovascular diseases are still the main cause of morbidity
and mortality in the world. Anti-platelet drugs have found
clinical application in the secondary prevention of vascular
events including acute myocardial infarction, stroke and cardiovascular
death. In the present review, we have developed sixteen quantitative
structure-activity relationships (QSAR) for different sets
of compounds that are X-phenols (I), X-catechols
(II), caffeic acid amides (III),
X-alcohols (IV), 1,4-naphthoquinones (V),
tetrahydronaphthalenes (VI), phenoxyacetaldehyde
guanylhydrazones (VII), pyrrolobenzylisoquinolines
(VIII) and phosphonic acids (IX)
with respect to their anti-platelet activities. QSAR results
have shown that the anti-platelet activities of these compounds
are largely dependent not only on their hydrophobicity, but
also on the influence of their molar refractivity.
[Back to top]
Allosteric Modulation of Drug Binding to Human Serum
Albumin
Paolo Ascenzi, Alessio Bocedi, Stefania Notari, GabriellaFanali,
RiccardoFesce and Mauro Fasano
Human serum albumin (HSA), the most prominent protein in
plasma, is best known for its extraordinary ligand binding
capacity. The three homologous domains of HSA (labeled I,
II, and III), each in turn composed of two subdomains (named
A and B), give rise to the three-dimensional structure of
HSA. This flexible structural organization allows the protein
structure to adapt to a variety of ligands. As conformational
adaptability of HSA extends well beyond the immediate vicinity
of the binding site(s), cooperativity and allosteric modulation
arise among binding sites; this makes HSA similar to a multimeric
protein. Although kinetic and thermodynamic parameters for
ligand binding to HSA calculated by quantitative structure-activity
relationship models are in excellent agreement with those
obtained in vitro, cooperative and allosteric equilibria
between different binding sites and competition between drugs
or between drugs and endogenous ligands make difficult the
interpretation of HSA binding properties in vivo.
Binding of exogenous and endogenous ligands to HSA appears
to be relevant in drug therapy and management. Here, the allosteric
modulation of drug binding to HSA is briefly reviewed.
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