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Mini-Reviews
in Medicinal Chemistry
ISSN: 1389-5575
Mini-Reviews in Medicinal
Chemistry
Volume 6, Number 6, June 2006
Contents
Medicinal Plants as Potential Sources of Lead Compounds with
Anti-Platelet and Anti-Coagulant Activities Pp. 611-624
T.K. Chua and H.L. Koh
[Abstract]
Solid-Phase Synthesis of Quinazoline-2,4-Diones
and their Analogues from Resin-Bound Compounds with Primary
Amines Pp. 625-632
Shingo Makino
[Abstract]
2-(4-Aminophenyl) Benzothiazole: A Potent and Selective Pharmacophore
with Novel Mechanistic Action Towards Various Tumour Cell
Lines Pp. 633-637
Raghvendra Dubey, Prabhat K. Shrivastava, Pawan
K. Basniwal, Snehendu Bhattacharya and Narayana S. Hari Narayana
Moorthy
[Abstract]
Molecular Symmetry: A Structural Property
Frequently Present in New Cytotoxic and Proapoptotic Drugs
Pp. 639-650
Carmen Sanmartín, María Font and
Juan Antonio Palop
[Abstract]
Adiponectin, Structure, Function and
Pathophysiological Implications in Non- Alcoholic Fatty Liver
Disease Pp. 651-656
N. Méndez-Sánchez, N.C. Chavez-Tapia,
D. Zamora-Valdés and M. Uribe
[Abstract]
Pharmacophore Identification: The Case
of the Ser/Thr Protein Phosphatase Inhibitors Pp.
657-665
David A. Colby and A. Richard Chamberlin
[Abstract]
The Role of Vascular Endothelial Growth
Factor in Neurogenesis in Adult Brain Pp. 667-669
Veronica Galvan, David A. Greenberg and Kunlin
Jin
[Abstract]
Sphingolipids as Targets for Microbial
Infections Pp. 671-680
Travis J. McQuiston, Charles Haller and Maurizio Del Poeta
[Abstract]
Src Inhibitors as Potential Therapeutic Agents for
Human Cancers Pp. 681-687
Jose G. Trevino, Justin M. Summy and Gary E. Gallick
[Abstract]
Small Molecular Weight Inhibitors of Stress-Activated
and Mitogen-Activated Protein Kinases Pp. 689-698
C.J. Malemud
[Abstract]
Ceramide Involvement in Apoptosis and Apoptotic Diseases Pp.
699-709
Karin Thevissen, Isabelle E.J.A. François,
Joris Winderickx, Christophe Pannecouque and Bruno P.A. Cammue
[Abstract]
Recent Progress in Development of Non-ATP Competitive
Small-Molecule Inhibitors of Protein Kinases Pp. 711-717
Alex Kiselyov, Konstantin V. Balakin, Sergey E. Tkachenko
and Nikolay P. Savchuk
[Abstract]
Mechanisms of Action and Targets for Actual and
Future Antiplatelet Drugs Pp. 719-726
Kathleen Freson, Chantal Thys, Christine Wittevrongel
and Chris Van Geet
[Abstract]
HIV-1 RNase H: Recent Progress in an Exciting, yet Little
Explored, Drug Target Pp. 727-737
Enzo Tramontano
[Abstract]
Abstracts
[Back to top]
Medicinal Plants as Potential Sources of Lead Compounds
with Anti-Platelet and Anti-Coagulant Activities
T.K. Chua and H.L. Koh
Medicinal plants are potential sources of lead compounds
which can be further developed or optimised into novel therapeutics.
This paper gives an overview of drug discovery from plants
and an up-to-date and comprehensive review of plants and phytoconstituents
reported to have anti-platelet and anti-coagulant activities.
[Back to top]
Solid-Phase Synthesis of Quinazoline-2,4-Diones
and their Analogues from Resin-Bound Compounds with Primary
Amines
Shingo Makino
Solid-phase organic synthesis of heterocyclic compounds on
solid-support has been a focus of recent investigations because
of the potential applicability of these compounds toward a
variety of drug targets. Among the various heterocycles, we
have been especially interested in quinazoline-2,4-diones
because of the wide range of their bioactivities. Therefore,
in this article we review methods for the solid-phase synthesis
of quinazoline-2,4-diones and their analogues. Since all of
these heterocycles can be speedily derivatized from resin-bound
primary amines, incorporating the amines at the 3N-position
of quinazoline-2,4-diones or corresponding positions of its
analogues, it becomes possible to efficiently compare the
bioactivities of these quinazoline-2,4-diones and their analogues.
Various methods of solid-phase synthesis described herein
should be practical and useful tools for the medicinal chemist
in supporting drug discovery initiatives.
[Back to top]
2-(4-Aminophenyl) Benzothiazole: A Potent and Selective Pharmacophore
with Novel Mechanistic Action Towards Various Tumour Cell
Lines
Raghvendra Dubey, Prabhat K. Shrivastava, Pawan
K. Basniwal, Snehendu Bhattacharya and Narayana S. Hari Narayana
Moorthy
2-(4-aminophenyl) benzothiazole (CJM -126) (Table 1
(1) and its analogues represent a potent and highly selective
class of antitumor agents. These compounds in nanomolar range
elicit potent growth inhibition in human-derived breast, colon,
ovarian and renal tumour cell lines. Metabolism of benzothiazole
plays a central role in its mode of action. Cytocrome P450
isoform, CYP1A1, biotransforms benzothiazoles, to active,
as well as inactive metabolites. In vitro studies
had confirmed that N-oxidation and N-acetylation (only 3'
halogen congener) as main active metabolic transformation
(generating cytotoxic electrophilic species), while C-6 oxidation
and N-acetylation (except 3' halogen congener) as inactive
metabolic transformation pathway. Generation of an inactive
metabolite 2-(4-aminophenyl)-6-hydoxybenzothiazole [6-OH 126,
(Table 1) (10)] is blocked by fluorinated analogue, substituted
around benzothiazole nucleus, especially at 5-position. National
Cancer Institute (NCI), USA, confirms this series as a unique
mechanistic class distinct from clinically used chemotherapeutic
agents. Benzothiazoles are potent aryl hydrocarbon receptor
(AhR) agonists, binding to AhR results in induction of CYP1A1,
causes generation of electrophilic reactive species which
forms DNA adduct, ultimately resulting in cell death by activation
of apoptotic machinery. To overcome the poor physiochemical
and pharmaceutical properties (bioavailability problem) of
this compounds, prodrug of benzothiazole derivatives were
synthesized, which are introduced in clinical trails.
[Back to top]
Molecular Symmetry: A Structural Property Frequently Present
in New Cytotoxic and Proapoptotic Drugs
Carmen Sanmartín, María Font and
Juan Antonio Palop
In recent years, a large number of new potent symmetrical
cytotoxic agents that act through different mechanisms have
been described. Apoptosis induction is one of the most representative
of these mechanisms. Recent articles have revealed that the
activation of apoptosis pathways is the key mechanism by which
cytotoxic tumor cells are killed. The present review highlights
the importance of the molecular symmetry of several chemical
structures and their relation with cytotoxic and apoptotic
activity.
[Back to top]
Adiponectin, Structure, Function and Pathophysiological
Implications in Non- Alcoholic Fatty Liver Disease
N. Méndez-Sánchez, N.C. Chavez-Tapia,
D. Zamora-Valdés and M. Uribe
Obesity is a major risk factor for the development of the
metabolic syndrome, a cluster of diseases including insulin
resistance, type 2 diabetes, dyslipidemia, hypertension, microalbuminuria,
atherosclerosis, and non-alcoholic steatohepatitis. On the
other hand, it is now generally accepted that adipose tissue
acts as an endocrine organ producing a number of substances
with an important role in the regulation of food intake, energy
expenditure and a series of metabolic processes. Adiponectin
is a recently discovered hormone produced exclusively by adipocytes.
In fact, adiponectin is considered currently as a major factor
in obesity-related insulin resistance and atherosclerosis.
This new hormone differs from other adipocytokines in that
its production and concentrations are actually decreased in
insulin resistant subjects. The aim of this review is to summarize
the current knowledge about the chemistry and physiology of
adiponectin and to discuss its implications in the pathophysiology
and potential treatment of insulin resistance and non-alcoholic
fatty liver disease.
[Back to top]
Pharmacophore Identification: The Case of
the Ser/Thr Protein Phosphatase Inhibitors
David A. Colby and A. Richard Chamberlin
This review provides a chronological account of the identification
and refinement of the pharmacophore for inhibition of two
key serine/threonine protein phosphatases, PP1 and PP2A. The
dramatic impact of natural product isolation, molecular modeling,
analogue design, biochemical studies, and crystallography
on the evolution of the pharmacophore will be described.
[Back to top]
The Role of Vascular Endothelial Growth Factor
in Neurogenesis in Adult Brain
Veronica Galvan, David A. Greenberg and Kunlin
Jin
VEGF is a canonical angiogenic factor. In addition, its role
as a stimulator of neurogenesis was recently uncovered. Vascular
and nervous networks share common molecular mechanisms underlying
their morphogenesis. VEGF is likely to regulate both processes
during development and in adult organisms.
[Back to top]
Sphingolipids as Targets for Microbial Infections
Travis J. McQuiston, Charles Haller and Maurizio Del Poeta
Sphingolipids had long been regarded as merely structural
components of eukaryotic cellular membranes. Research has
discovered sphingolipids to have crucial roles in cellular
processes as bioactive molecules. Lately, there has also been
an increased interest in sphingolipids and sphingolipid-metabolizing
enzymes as mediators of microbial pathogenicity and as potential
targets for the development of new therapeutics. This minireview
will provide a comprehensive analysis of sphingolipid pathways
in mammalian and microbial cells, highlighting their uniqueness
and discussing their potential as therapeutic targets for
microbial infections.
[Back to top]
Src Inhibitors as Potential Therapeutic Agents for Human Cancers
Jose G. Trevino, Justin M. Summy and Gary E. Gallick
Selective inhibitors of the Src family of protein tyrosine
kinases have been developed as therapeutic agents for human
tumors, some of which are now in various stages of clinical
trial. In this review, recently described novel small molecule
ATP-competitive Src inhibitors are discussed, with an emphasis
on their potential use as therapeutic inhibitors for advanced-stage
malignancies.
[Back to top]
Small Molecular Weight Inhibitors of Stress-Activated
and Mitogen-Activated Protein Kinases
C.J. Malemud
The stress-activated protein kinase (SAPK) and mitogen-activated
protein kinase (MAPK) sub-families are crucial to environmental
stress responses and responses to growth factors that cause
transcriptional activation of genes required for cell proliferation,
differentiation and programmed cell death. Small molecular
compounds with specific structure/activity characteristics
have been developed that competitively block SAPK/MAPK binding
to ATP. Chemically modified compounds based on ATP binding
pocket characteristics have improved selectivity and specificity
for SAPK/MAPK isoforms. In addition, site-specific mutagenesis
of MAPKs has helped identify the MAPK structures required
for binding recognition and selectivity of these inhibitors.
A group of extracellular-signal regulated protein kinase (ERK)
inhibitors has been constructed based almost exclusively on
their ability to inhibit the ERK activation cascade. Inhibitors
have been employed in vitro to identify protein targets
and mechanism of action of SAPKs/MAPKs. The efficacy of SAPK/MAPK
inhibitors in animal models of inflammation, arthritis, heart
failure, cancer and neurological degeneration has provided
the impetus for using them in human studies of inflammation
and in clinical trials.
[Back to top]
Ceramide Involvement in Apoptosis and Apoptotic Diseases
Karin Thevissen, Isabelle E.J.A. François,
Joris Winderickx, Christophe Pannecouque and Bruno P.A. Cammue
Apoptosis is implicated in a number of diseases, including
neurodegenerative diseases and AIDS. More and more, evidence
is accumulating pointing to the critical role of ceramides
in the induction of apoptosis. The present review summarizes
(i) the molecular basis and regulation of the apoptotic machinery,
(ii) the molecular role of ceramides in the induction or execution
of apoptotic pathways, and (iii) evidence linking ceramide
generation to various apoptotic diseases. Additionally, this
review discusses putative therapeutic approaches inhibiting
ceramide production in apoptotic diseases.
[Back to top]
Recent Progress in Development of Non-ATP Competitive Small-Molecule
Inhibitors of Protein Kinases
Alex Kiselyov, Konstantin V. Balakin, Sergey E. Tkachenko
and Nikolay P. Savchuk
The majority of marketed and late stage development kinase
inhibitors are reported to be ATP-competitive. As a result,
many promising drug candidates display non-specific activity
that results in unde-sired physiological effects. There is
growing interest towards non-ATP competitive kinase inhibitors,
as they are expected to yield highly specific and efficacious
molecules devoid of non-mechanistic toxicity. Recent developments
in this area are summarized in our review.
[Back to top]
Mechanisms of Action and Targets for Actual and
Future Antiplatelet Drugs
Kathleen Freson, Chantal Thys, Christine Wittevrongel
and Chris Van Geet
Platelets are key players in arterial thrombosis and have
become important targets in the primary and secondary prevention
of atherothrombosis. Antiplatelet drugs are primarily directed
against platelets and inhibit platelet activation by a number
of different mechanisms. They are used for the prevention
and treatment of thrombotic processes, especially in the arterial
vascular system. Antiplatelet drugs in clinical use and experimental
drugs are discussed.
[Back to top]
HIV-1 RNase H: Recent Progress in an Exciting, yet Little
Explored, Drug Target
Enzo Tramontano
HIV-1 reverse transcriptase-associated ribonuclease H (RNase
H) is an attractive non traditional target for drug development
which has been, so far, little explored. All drugs shown to
inhibit HIV-1 RNase H are reported, including the recently
described classes of compounds that interact with the metal
ions in the active site.
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