Mini-Reviews in Medicinal Chemistry, Volume 2, No. 2, 2002
Molecular Pharmacophore Determination of
Lipid Lowering Drugs with the Receptor Mapping Method Pp.97-102
M.
Ablise, A. Cartier, G. Siest, S. Visvikis and V. Loppinet
Biomolecular Targets for Platinum Antitumor
Drugs Pp.103-111
Rathindra
N. Bose
Synthesis and Antimalarial Activity of
1,2,4,5-Tetraoxanes
Pp.113-123
Yuxiang
Dong
Medicinal Chemistry of Nicotinamide in the
Treatment of Ischemia and Reperfusion Pp.125-134
J.
Yang, L. K. Klaidman and J. D. Adams
Gas Chromatographic Determination of
Prostaglandins Pp.135-144
R.
Baranowski and K. Pacha
QRAR Models for Central Nervous System Drugs
using Biopartitioning Micellar Chromatography Pp.145-161
C.
Quiñones-Torrelo, Y. Martin-Biosca, J.J. Martínez-Pla,S. Sagrado, R.M.
Villanueva-Camañas and M.J. Medina-Hernández
Highlights in the Development of New
Antiviral Agents Pp.163-175
E.
De Clercq
Selective Agonists and Antagonists for
Kainate Receptors Pp.177-184
Paola
Conti, Marco De Amici and Carlo De Micheli
Daphnane-Type Diterpene Orthoesters and their
Biological Activities
Pp.185-200
Weidong
He, Miroslav Cik, Giovanni Appendino,Luc Van Puyvelde, Josée E. Leysen and
Norbert De Kimpe
[Back to top] Molecular Pharmacophore Determination of
Lipid Lowering Drugs with the Receptor Mapping Method
M. Ablise, A. Cartier, G. Siest, S. Visvikis and V.
Loppinet
Hypolipidemic
pharmacophoric moieties of statins, fibrates, ACAT inhibitors and
beta-sitosterol analog series were identified by computational modeling, and
compared with the computed structure of new potential glycyrrhetinic acid
derivatives lipid-lowering drugs. Their electronic and geometric domains,
similar to those of fibrates, suggest a fibrate -like mechanism matching
biochemical data.
[Back to top] Biomolecular Targets for Platinum Antitumor
Drugs
Rathindra N. Bose
Cis-diamminedichloroplatinum(II)
(cisplatin) is widely used for the treatment of testicular, ovarian,and other
forms of cancer. Several second generation platinum centered antitumor drugs
have been approved or undergoing phase-3 clinical trial. Cisplatin arrests the
cell cycle at the G2 phase by a mechanism commonly known as apoptosis. At the
molecular level, it is generally believed that the anticancer properties of
these compounds are due to the covalent binding to DNA. In addition to DNA
binding, the platinum drugs bind and interact with proteins and enzymes. The
toxic effects of the drugs have been usually attributed to protein binding.
However, a growing body of work points to much more complex anticancer
mechanisms involving direct and indirect interactions of platinum compounds
with proteins and enzymes. In this review, a discussion on the strength and
weaknesses of DNA binding mechanism followed by enzymes and protein
interactions with the drugs are presented for the comprehensive understanding
of apoptosis. The purpose of this review is to encourage researchers to explore
metallobiochemistry of platinum drugs focusing attention to cellular and
molecular events beyond DNA binding.
[Back to top] Synthesis and Antimalarial Activity of
1,2,4,5-Tetraoxanes
Yuxiang Dong
Methods for
formation of 1,2,4,5-tetraoxanes are summarized and antimalarial activities of
1,2,4,5- tetraoxanes are discussed.
[Back to top] Medicinal Chemistry of Nicotinamide in the
Treatment of Ischemia and Reperfusion
J. Yang, L. K. Klaidman and J. D. Adams
Nicotinamide can
facilitate DNA repair by inhibiting poly(ADP-ribose) polymerase, increasing NAD
levels and adjusting other related enzyme activities. This review will
summarize recent work on the design of poly(ADP-ribose) polymerase inhibitors,
poly(ADP-ribose) glycohydrolase inhibitors and will discuss the possible use of
drugs that interact with NAD synthetic enzymes.
[Back to top] Gas Chromatographic Determination of
Prostaglandins
R. Baranowski and K. Pacha
Progress in
separation and detection of prostaglandins and the other metabolites of
arachidonic acid by means of GC-ECD, GC-MS, and GC-MS-MS in the course of the
past fifteen years was reviewed. One discussed the problems of sample
preparation, selection of proper chromatographic conditions, and detection
modes available. Finally, applications of the methods developed to detection
and quantification of prostanoids in biological material was presented.
[Back to top] QRAR Models for Central Nervous System Drugs
using Biopartitioning Micellar Chromatography
C. Quiñones-Torrelo, Y. Martin-Biosca, J.J.
Martínez-Pla,S. Sagrado, R.M. Villanueva-Camañas and M.J. Medina-Hernández
The capability of
biopartitioning Micellar Chromatography, BMC, to describe and estimate
pharmacokinetic and pharmacodynamic parameters of central nervous system drugs
is reviewed in this article.BMC is a mode of micellar liquid chromatography,
MLC, that uses micellar mobile phases of Brij35 (polyoxyethilene(23) lauryl
ether) prepared in physiological conditions (pH, ionic strength). The retention
of a drug in this system depends on its hydrophobic, electronic and steric
properties, which also determine its biological activity. The results of BMC
studies suggest that this in vitro approach is an attractive useful tool to be
implemented into the lead optimization step of drug development scheme.
[Back to top] Highlights in the Development of New
Antiviral Agents
E. De Clercq
The potential of a
large variety of new compounds and new strategies for the treatment of
virtually all major virus infections has been addressed. This includes, for the
treatment of HIV infections, virus adsorption inhibitors (cosalane derivatives,
cyanovirin-N), co-receptor antagonists (TAK-100%, AMD3100), viral fusion
inhibitors (pentafuside T-20, betulinic acid derivatives), viral uncoating
inhibitors (azodicarbonamide), nucleoside/nucleotide reverse transcriptase
inhibitors (NRTIs: emtricitabine, amdoxovir, dOTC, d4TMP prodrugs, tenofovir
disoproxil fumarate), non-nucleoside reverse transcriptase inhibitors (NNRTIs:
thiocarboxanilide UC-781, capravirine, SJ-3366, DPC 083, TMC 125/R165335),
integrase inhibitors(diketo acids), transcription inhibitors (temacrazine,
flavopiridol), protease inhibitors (atazanavir, mozenavir, tipranavir); for the
treatment of RSV and paramyxovirus infections, viral fusion inhibitors
(R170591, VP-14637, NMS03); for the treatment of picornavirus infections, viral
uncoating inhibitors (pleconaril); for the treatment of pesti- (hepaci-,
flavi-) virus infections, RNA replicase inhibitors (VP-32947); for the
treatment of herpesvirus (HSV, VZV, CMV) infections, DNA polymerase inhibitors
(A-5021, L- and Dcyclohexenylguanine); for the treatment of VZV infections,
bicyclic furopyrimidine analogues; for the treatment of CMV infections,
fomivirsen; for the treatment of DNA virus infections at large (papilloma-,
polyoma-, herpes-, adeno- and poxvirus infections), cidofovir; for the
treatment of influenza, neuraminidase inhibitors (zanamivir, oseltamivir,
RWJ-270201); for the treatment of HBV infections, adefovir dipivoxil; for the
treatment of HBV and HCV infections, N-glycosylation inhibitors
(N-nonyl-deoxynojirimycin); and, finally, IMP dehydrogenase inhibitors and
S-adenosylhomocysteine hydrolase inhibitors, for the treatment of various virus
infections, including hemorrhagic fever virus infections.
[Back to top] Selective Agonists and Antagonists for
Kainate Receptors
Paola Conti, Marco De Amici and Carlo De Micheli
Kainate receptors
have only recently been characterized both from the pharmacological and
biological point of view. Due to the limited number of truly kainate selective
ligands, most of the known agonists and antagonists are generally classified as
AMPA/kainate receptors ligands. The increasing interest in the search for
selective kainate ligands aims at understanding the physiological role played
by these receptors and finding out potential therapeutic approaches for the
treatment of a number of neurological pathologies, i.e. schizophrenia, as well
as acute and chronic neurodegenerative diseases, i.e. epilepsy, cerebral
ischaemia, Parkinson’s and Alzheimer’s diseases. This review will focus on the
recently discovered ligands for kainate receptors, with a particular attention
given to those molecules displaying a selectivity for the different subunits of
the kainate receptors and, on the other hand, to the role played by these receptor
subtypes in the pathophysiology of the central nervous system.
[Back to top] Daphnane-Type Diterpene Orthoesters and their
Biological Activities
Weidong He, Miroslav Cik, Giovanni Appendino,Luc Van
Puyvelde, Josée E. Leysen and Norbert De Kimpe
Daphnane
orthoesters are the active ingredients of plant remedies from the Western,
Chinese and African traditional medicine, and have provided important tools to
investigate medicinally relevant processes like tumour promotion, apoptosis,
neurotrophism, and VR1 activation. The occurrence, biological activity, and
molecular pharmacology of these compounds will be reviewed.