Mini-Reviews in Medicinal Chemistry, Volume 3, No. 4, 2003
Contents
Functionalized S-Thio-di- and
S-Oligosaccharide Precursors as Templates for Novel SLex/a Mimetic
Antimetastatic Agents
Pp.271-280
P.
Markus Dey and Zbigniew J. Witczak
Electronic-Topological Study of Structurally
Diverse Cyclooxygenase-2 Inhibitors Pp.281-294
A.
Dimoglo , E. Sim, N. Shvets and V. Ahsen
The Prevention of Preterm Labour –
Corticotropin Releasing Hormone Type 1 Receptors as a Target for Drug Design
and Development Pp.295-303
P.A.
Keller , K. Kirkwood , J. Morgan , S. Westcott
and A. McCluskey
Biological Activity of Some Monocyclic- and
Bicyclic b-Lactams with Specified Functional Groups Pp.305-313
Jih
Ru Hwu ,
Quantitative Structure-Activity Relationships
of Renin Inhibitors
Pp.315-321
Satya
P. Gupta
Recent Developments in Novel
Pyrrolo[2,1-c][1,4]Benzodiazepine Conjugates: Synthesis and Biological
Evaluation Pp.323-339
Rohtash Kumar and J.William Lown
Application of Pharmacophore Models for the
Design and Synthesis of New Anticonvulsant Drugs Pp.341-348
Barbara Malawska
Molecular Diversity of Hydroxamic Acids:
Kexin Yang and Boliang Lou
Non-Peptidic Inhibitors of Cysteine Proteases Pp.361-373
T. Schirmeister and U. Kaeppler
Abstracts
[Back to top] Functionalized S-Thio-di- and
S-Oligosaccharide Precursors as Templates for Novel SLex/a Mimetic
Antimetastatic Agents
P.
Markus Dey and Zbigniew J. Witczak
Adhesive
interactions between molecules expressed on vascular endothelium and
circulating tumor cells are key early events in cancer metastasis. Best
characterized to date is the selectin family of cell adhesion molecules, which
can bind to and stabilize blood-borne cells on organ vasculature, facilitating
the cell-cell and cell-substratum interactions leading to tumor seeding and
proliferation. Major ligands of E-selectin, the selectin family member
expressed on vascular endothelial cells, include sialylated, fucosylated
glycans such as Sialyl Lewis type carbohydrate complexes (SLex and
SLea). These carbohydrate antigens are ubiquitously expressed on
tumor cells with high metastatic potential, including colon and pancreatic
carcinomas, and have been found to selectively and avidly bind E-selectin.
Compounds that
prevent E-selectin-SLex/a binding represent an attractive tool in
the prevention of cancer dissemination. Review of preclinical in vitro and in
vivo studies suggest that SLex/a 'mimetics' may serve as a potent
class of anti-metastatic compounds. These agents are designed to outcompete SLex/a
antigens expressed on tumor cell surfaces to prevent initial vascular adhesion.
Critical in generating exogenous oligosaccharides as SLex/a mimetics
is the stereoselective joining of specific mono- and di- saccharides that
express functional groups integral in E-selectin-SLex/a binding.
Employing sulfur linkages to couple saccharide units enhances the biological
stability of these complex carbohydrates. The synthesis of novel
S-thiodisaccharides and Cdisaccharides as SLex/a precursors using
the chiral sugars levoglucosenone, isomeric isolevoglucosenone and their
functionalized analogs is described. The highly stereoselective
functionalization of both enones at the C- 4, C-3 and C-2 positions by the set
of Michael addition reactions of reactive 1-thiosugars is reviewed. These
functionalized S-thio di- and S-oligosaccharide precursors have direct
application for use as templates in the synthesis of novel SLex/a mimetics.
[Back to top] Electronic-Topological Study of Structurally
Diverse Cyclooxygenase-2 Inhibitors
A.
Dimoglo , E. Sim, N. Shvets and V. Ahsen
A large series of
cyclooxygenase-2 (COX-2) inhibitors with diverse skeletons were investigated by
means of the Electronic-Topological Method. A system for the COX-2 inhibitor
activity prognostication was built with 6 pharmacophores and 6
anti-pharmacophores. The forecasting ability of the system was also tested on
different structures, which differ from those that characterize the series
studied.
[Back to top] The Prevention of Preterm Labour –
Corticotropin Releasing Hormone Type 1 Receptors as a Target for Drug Design
and Development
P.A.
Keller , K. Kirkwood , J. Morgan , S. Westcott
and A. McCluskey
The role of the
corticotropin releasing hormone in the onset of labour and the subsequent
medicinal chemistry implications of CRH antagonists for the prevention of
premature birth, and identification of the CRH type 1 receptor as the target
for this drug design, are reviewed here.
[Back to top] Biological Activity of Some Monocyclic- and
Bicyclic b-Lactams with Specified Functional Groups
Jih
Ru Hwu ,
This Review
contains our recent studies on evaluation of biological activities associated
with monocyclic b-lactams and bicyclic b-lactam antibiotics containing various
heteroatoms. A series of bicyclic â-lactams was synthesized, which possessed
electron-withdrawing groups, such as an ester, mesylate, and triflate
functionality. These b-lactams exhibited
enhanced antibacterial activity.
[Back to top] Quantitative Structure-Activity Relationships
of Renin Inhibitors
Satya
P. Gupta
A review is presented
on quantitative structure-activity relationships (QSARs) of renin inhibitors
which have potential as antihypertensive and cardiovascular agents. They
inhibit the renin, an enzyme that is involved in the rate-limiting first step
of the renin angiotensin system (RAS). Most of the renin inhibitors are
peptidomimetics but recently some nonpeptidomimetic renin inhibitors with low
molecular weight have also been developed. In both types of renin inhibitors,
the QSARs have exhibited that their inhibition activity would largely depend
upon the molecular weight of the compounds, van der waals radius related
parameters of the substituents, and the localized electronic effects,
particularly of the side chain of the residues substituted in the peptides.
[Back to top] Recent Developments in Novel
Pyrrolo[2,1-c][1,4]Benzodiazepine Conjugates: Synthesis and Biological
Evaluation
Rohtash
Kumar and J.William Lown
The biological
activity of many low molecular weight antitumor compounds appear to be related
to their mode and specificity of interaction with particular DNA sequences.
Such small molecules are of considerable interest in chemistry, biology and
medicine. Most of the anticancer drugs employed clinically exert their antitumor
effect by inhibiting nucleic acid (DNA or RNA) or protein synthesis. Inhibition
can occur for example through cross-linking of bases in DNA or binding to and
inactivation of enzymes necessary for the synthetic processes. It is evident
that DNA is an important cellular target for many anticancer agents. Much
information has been obtained from molecular genetics, i.e. replication of DNA
and its transcription to RNA, which provides the template for protein
synthesis. DNA is a well-characterized intracellular target but its large size
and sequential nature makes it an elusive target for selective drug action.
Binding of low molecular weight ligands to DNA causes a wide variety of
potential biological responses. In this context PBDs (pyrrolo[2,1- c][1,4]benzodiazepines),
a group of potent naturally occurring antitumor antibiotics produced by various
Streptomyces species, are one of the most promising types of lead compounds.
They differ in the number, type and position of substituent in both their
aromatic A-ring and Py C-rings, and in the degree of saturation of the C-rings
which can be either fully saturated or unsaturated at either C2-C3 (endocyclic)
or C2 (exocyclic). There is either an imine or carbinolamine methyl ether at
the N10-C11 position. This latter is an electrophilic center responsible for
alkylating DNA. In the search for compounds with better antitumor selectivity
and DNA sequence specificity many PBD analogues have been synthesized in an
attempt to increase their potency against tumor cells. We review here recent
progress on pyrrolo[2,1-c][1,4]benzodiazepine (PBDs) analogues and their
conjugates, also the progress and developments of PBD conjugates with
polyamides (information reading molecules in the minor groove of DNA). For
example, the cross-linking efficiency of PBD dimers is much greater than that
of other cross linkers including cisplatin and melphalan. A large number of PBD
dimmers and polyamide conjugates with varying linker lengths and bearing
different heterocycles at different positions in the PBD ring synthesized in
our group and their pharmacological properties have been reviewed.
[Back to top] Application of Pharmacophore Models for the
Design and Synthesis of New Anticonvulsant Drugs
Barbara
Malawska
The chemical
diversity and various mechanisms of action of anticonvulsants make it difficult
to identify a common pharmacophore. The present review outlines different
pharmacophore models for anticonvulsant activity with emphasis on the
development of new drugs. Some of them represent models for structurally
different classes of compounds with similar mechanisms of action. Others
represent pharmacophore models for similar chemical classes of compounds for
which the mechanism of anticonvulsant action is not clear. A pharmacophore
model for sodium channel blocking compounds, anticonvulsants with the
phthalimide pharmacophore, a model for anticonvulsant semicarbazones, and a
model for GABA uptake inhibitors are presented.
[Back to top] Molecular Diversity of Hydroxamic Acids:
Kexin
Yang and Boliang Lou
Hydroxamic acid
derivatives are an important class of molecules with a variety of
pharmaceutical properties. Over the last decade steady progress has been made
in the development of efficient methods for the syntheses of hydroxamic acid
derivatives. This mini-review covers the most recent publications that
highlight current strategies and syntheses of bioactive molecules containing the
hydroxamate moiety in both solutionand solid-phase.
[Back to top] Non-Peptidic Inhibitors of Cysteine Proteases
T.
Schirmeister and U. Kaeppler
In comparison to the huge number of peptidic and peptidomimetic inhibitors of cysteine proteases which have been developed during the last twenty years the number of non-peptidic compounds with cysteine protease inhibiting properties is restricted to a few substance classes. In contrast to peptidic and peptidomimetic inhibitors the non-peptidic lead structures have mainly been discovered by computational or enzymatic industrial screenings and not by a rational approach. But, the growing number of resolved X-ray structures of the target enzymes as well as molecular modeling methods have supported the further development of potent inhibitors beginning from these lead structures. In this review we will focus on new non-peptidic cysteine protease inhibitors which have been developed during the last years. Discovery, structure-activity-relationship and inhibition mechanisms will be discussed.