Mini-Reviews in Medicinal Chemistry, Volume 2, No. 6, 2002
Contents
Tubulin as an Antiprotozoal Drug Target Pp.519-529
Karl
A. Werbovetz
Vitronectin Receptor –aVb3
Integrin– Antagonists:Chemical and Structural Requirements for Activity and
Selectivity Pp.531-542
Christophe
Henry, Nicolas Moitessier and Yves Chapleur
Structural Development of Biological Response
Modifiers Based on Retinoids and Thalidomide Pp.543-551
Yuichi
Hashimoto
Polyamine Metabolism as Chemotherapeutic
Target in Protozoan Parasites
Pp.553-563
C.J.
Bacchi and N. Yarlett
Structure-activity Relationship, Conformation
and Pharmacology Studies of Morphiceptin Analogues -Selective m-Opioid Receptor
Ligands Pp.565-572
Anna
Janecka, Jakub Fichna, Marek Mirowski and Tomasz Janecki
Malaria: New Chemotherapeutic Peroxide Drugs Pp.573-583
Kristina
Borstnik, Ik-hyeon Paik and Gary H. Posner
Nitric Oxide in Atherosclerosis Pp.100%-593
E.A.
Rekka and M.C. Chrysselis
Protection Against Cancer by Plant
Phenylpropenoids: Induction of Mammalian Anticarcinogenic Enzymes Pp.595-610
A.T.
Dinkova-Kostova
Recent Advances in Topoisomerase I-Targeting
Agents, Camptothecin Analogues
Pp.611-619
Dae-Kee
Kim and Namkyu Lee
Abstracts
[Back to top] Tubulin as an Antiprotozoal Drug Target
Karl
A. Werbovetz
Since tubulin is a
known anticancer and anthelmintic drug target, the investigation of protozoal
tubulin could lead to the development of new antiparasitic drugs. This review
outlines the current state of knowledge concerning drug-mammalian tubulin
interactions, the effects of antimicrotubule agents on parasites and parasite
tubulin, and our current hypotheses regarding the development of selective
ligands for protozoal tubulin as antiparasitic drug candidates.
[Back to top] Vitronectin Receptor –aVb3
Integrin– Antagonists:Chemical and Structural Requirements for Activity and
Selectivity
Christophe
Henry, Nicolas Moitessier and Yves Chapleur
aVb3 integrin, a
cell surface protein, has been targeted by a variety of natural and synthetic
antagonists in the search for potential cancer and osteoporosis drug
candidates. This review discusses chemical and structural requirements for
activity and selectivity deduced from SAR studies and draws a tentative picture
of the pharmacophore.
[Back to top] Structural Development of Biological Response
Modifiers Based on Retinoids and Thalidomide
Yuichi
Hashimoto
The full-scale commercial
appearance of antibiotics in the 1950's caused a shift of the nature of our
lethal diseases from infectious/acute to non-infectious/chronic. In this
situation, biological response modifiers (BRM's), which are not based on
selective toxicity, are expected to be useful. There exist several types of
BRM's, including retinoids which act directly on cells at the gene expression
level, and thalidomide (and related molecules) which modulate internal
circumstances of our body. We have been engaged in medicinal
chemical/structural development studies based on these bio-active compounds.
Retinoids include all-trans-retinoic acid (ATRA), a major active form of
vitamin A (retinol), and its bio-isosters, which elicit their biological
effects by binding to their nuclear receptors, RAR's. ATRA has been used in
differentiation therapy [typically for the treatment of acute promyelocytic
leukemia (APL)] and the treatment of dermatological diseases. Our structural
development studies of retinoids, including computer-assisted molecular design
has yielded class/subtype selective
agonists, synergists and antagonists of RAR's and their partner nuclear
receptors, RXR's. Thalidomide elicits a wide range of pharmacological effects,
including anticachexia, anti-angiogenic and anti-metastatic activities. We have
found that thalidomide is a multi-target drug. Hypothetical target
events/molecules of thalidomide include TNF-a
production, nuclear androgen receptor, aminopeptidases, and a-glucosidase. Specific and potent compounds for
each of these target phenomena/molecules have been prepared by appropriate
modification of the thalidomide structure, and are expected to be superior lead
compounds for novel immunomodulators, anti-angiogenic agents, and anti-tumor
promoting agents.
[Back to top] Polyamine Metabolism as Chemotherapeutic
Target in Protozoan Parasites
C.J. Bacchi and N. Yarlett
Polyamines are
essential cell constituents for all organisms. The present review highlights
important differences in the synthesis, degradation, and interconversion of
polyamines between the protozoan parasites (Trypanosoma brucei, Trypanosoma
cruzi, Cryptosporidium parvum and Trichomonas vaginalis) and their mammalian
hosts. Approaches include development of mono- and di-substituted polyamine
analogs targeting polyamine interconversion, as well as more traditional
targeting of synthetic enzymes and related pathways.
[Back to top] Structure-activity Relationship, Conformation
and Pharmacology Studies of Morphiceptin Analogues -Selective m-Opioid Receptor
Ligands
Anna
Janecka, Jakub Fichna, Marek Mirowski and Tomasz Janecki
Morphiceptin
(Tyr-Pro-Phe-Pro-NH2) is one of the most selective agonists for the m-opioid
receptor. In this review structure-activity relationships of morphiceptin
analogues and studies resulting in defining low energy conformations are
discussed. Finally, new developments in the control of tumour growth and cell
proliferation by morphiceptin analogues are surveyed, which open future
perspectives in the diagnosis and treatment of various cancers.
[Back to top] Malaria: New Chemotherapeutic Peroxide Drugs
Kristina
Borstnik, Ik-hyeon Paik and Gary H. Posner
Chemical insights
into artemisinin's biological mechanism of action have allowed rational design
of some new trioxane and endoperoxide antimalarial drug candidates that are
efficacious and safe. This review summarizes recent achievements in this area
of peroxide drug development for malaria chemotherapy.
[Back to top] Nitric Oxide in Atherosclerosis
E.A.
Rekka and M.C. Chrysselis
NO is produced
endogenously from L-arginine by NOSs. Among its multiple activities, the
nhomeostatic control of the vascular endothelium is crucial for
atherosclerosis, a pathogenic condition connected with elevated levels of LDL,
the main plasma cholesterol carrier. Oxidised LDL is proatheromatic, and toxic
peroxidation products contribute to further endothelial damage. .NO controls
vascular tone, inhibits LDL oxidation and has hypocholesterolaemic activity.
This review is referred to the chemistry, biology and role of .NO on
atherosclerosis and its treatment by .NO donors or modulators.
[Back to top] Protection Against Cancer by Plant
Phenylpropenoids: Induction of Mammalian Anticarcinogenic Enzymes
A.T.
Dinkova-Kostova
Chemoprotection
has established itself as a “major arm“ in the “war against cancer“ and
induction of phase 2 detoxification enzymes as an effective strategy. Prominent
among inducers are Michael reaction acceptors. Such functionalities are
intrinsic to many phenylpropanoids present in edible plants, where they play
roles in plant defense. This minireview focuses on the ability of such plant
metabolites to elevate phase 2 enzymes in various cell culture and animal
models and ultimately to protect against carcinogenesis.
[Back to top] Recent Advances in Topoisomerase I-Targeting
Agents, Camptothecin Analogues
Dae-Kee
Kim and Namkyu Lee
The present review
concentrates on camptothecin (CPT) analogues, the most extensively studied
topoisomerase I (topo I) inhibitors, and provides concise information on the
structural features of human topo I enzyme, mechanisms of interaction of CPT
with topo I, structure-activity relationship study of CPT analogues including
the influence of lactone stability on antitumor activity, and recent updates of
valuable CPT analogues.