Mini-Reviews in Medicinal Chemistry, Volume 3, No. 2, 2003
Contents
9-Hydroxyellipticine and Derivatives as
Chemotherapy Agents Pp.67-76
Margaret
M. Harding and Annaleise R. Grummitt
A Synthetic Overview of New Molecules with 5-HT1A
Binding Affinities Pp.77-93
Hernán
Pessoa-Mahana, Ramiro Araya-Maturana, Claudio Saitz, B. and C. David
Pessoa-Mahana
New Progresses in the Enantioselective
Synthesis and Biological Properties of Carbocyclic Nucleosides Pp.95-114
Juan
B. Rodríguez and María J. Comin
Inhibitors of Lysine Biosynthesis as
Antibacterial Agents
Pp.115-127
Craig
A. Hutton, Timothy J. Southwood and Jennifer J. Turner
Monoamine Oxidases: to Inhibit or Not to
Inhibit Pp.129-136
R.R.
Ramsay and M.B. Gravestock
Opioid Ligands Having Delayed Long-Term
Antagonist Activity: Potential Pharmacotherapies for Opioid Abuse Pp.137-144
Stephen
M. Husbands and John W. Lewis
Platelet ADP Receptors and their Antagonists Pp.145-148
Patricia
Benoit and Jean-Michel Dogné
Epothilone B and its Analogs – A New Family
of Anticancer Agents
Pp.149-158
Karl-Heinz
Altmann
Naturally Occurring Peroxides with Biological
Activities Pp.159-165
Mankil
Jung, Hanjo Kim, Kyunghoon Lee and
Abstracts
[Back to top] 9-Hydroxyellipticine and Derivatives as
Chemotherapy Agents
Margaret
M. Harding and Annaleise R. Grummitt
The hydroxy group
in 9-hydroxyellipticines increases the apparent affinity for DNA, stabilisation
of toposiomerase II-DNA cleavable complex, oxidation to reactive quinone-imine
intermediates, phosphorylation of p53 suppressor proteins and cytotoxicity
relative to the parent ellipticines. Recent studies have focused on the
mechanism of inhibition of phosphorylation of the mutant type of p53 protein,
structural characterization of the drug-DNA complex, the synthesis of
carbohydrate derivatives and calculations of physical parameters, including
dipole moments, as potential screens to allow identification of new active
derivatives. Derivatisation at the 2- and 9-positions has lead to significant
improvements in the in vivo activity of the 9- hydroxyellipticine derivatives and
has provided important insights into the mechanism of action of these
compounds.
[Back to top] A Synthetic Overview of New Molecules with
5-HT1A Binding Affinities
Hernán
Pessoa-Mahana, Ramiro Araya-Maturana, Claudio Saitz, B. and C. David
Pessoa-Mahana
The present review
discusses the synthetic strategies of new ligands exhibiting mainly 5-HT1A
binding affinities. Specifically we focused our attention in the synthesis of
compounds structurally related to arylpiperazine, 2-aminotetralin, and
benzopyran derivatives.
[Back to top] New Progresses in the Enantioselective
Synthesis and Biological Properties of Carbocyclic Nucleosides
Juan
B. Rodríguez and María J. Comin
The recent
advances in the chemistry of carbocyclic nucleosides focused on different
synthetic approaches that lead to optically pure products as well as a
comprehensive overview of their biological properties are discussed. In the
latter aspect, molecular recognition of enzymes of pharmacological importance
such as: reverse transcriptase, adenosine deaminase, thymidine kinase, DNA
cytosine-C5 methyl transferase, Sadenosylhomocysteine hydrolase, etc are
considered. The role of conformation and puckering of the glycon moiety in
modulating the biological activity and also the use of carbanucleosides as
building blocks to prepare oligonucleotides are carefully illustrated.
[Back to top] Inhibitors of Lysine Biosynthesis as
Antibacterial Agents
Craig A. Hutton, Timothy J. Southwood and Jennifer J. Turner
Bacterial
biosynthesis of lysine has come under increased scrutiny as a target for novel
antibacterial agents as it provides both lysine for protein synthesis and
meso-diaminopimelate for construction of the bacterial peptidoglycan cell wall.
Recent studies of the enzymes of the lysine biosynthetic pathway, development
of inhibitors and investigations of their antibacterial properties are
discussed.
[Back to top] Monoamine Oxidases: to Inhibit or Not to
Inhibit
R.R.
Ramsay and M.B. Gravestock
Monoamine oxidase
(MAO) inhibitors were developed as antidepressants but many drugs, including
the novel oxazolidinone antibacterial agents, share similar molecular
properties and have MAO inhibitory activity. Factors important for binding
antidepressants and modifications to decrease binding of oxazolidinones to
avoid undesirable vascular effects are discussed.
[Back to top] Opioid Ligands Having Delayed Long-Term
Antagonist Activity: Potential Pharmacotherapies for Opioid Abuse
Stephen
M. Husbands and John W. Lewis
Buprenorphine is a
partial agonist at the µ-opioid receptor with long duration of action and also
exhibits delayed antagonist activity. Buprenorphine is finding increasing use
as a treatment agent for opioid abuse, though its low efficacy is not well
tolerated by all addicts. There is interest in developing a higher efficacy
version of buprenorphine and in this mini-review some of the ligands recently
discovered, that share with buprenorphine a profile of agonism followed by
delayed antagonism, are discussed.
[Back to top] Platelet ADP Receptors and their Antagonists
Patricia
Benoit and Jean-Michel Dogné
ADP plays a
crucial role in haemostasis and thrombosis and its receptors are potential
target for antithrombotic drugs.The knowledge of the ADP-receptors has been
amplified by recent discoveries. This review highlights the ADP-receptors
models and their antagonists described in the recent literature, mainly the
thienopyridine derivatives.
[Back to top] Epothilone B and its Analogs – A New Family
of Anticancer Agents
Karl-Heinz
Altmann
Epothilones are
naturally occurring 16-membered macrolides with the ability to promote tubulin
polymerization in vitro and to stabilize preformed microtubules against Ca2+-
or cold-induced depolymerization. In contrast to paclitaxel (Taxol.®)
epothilones are also active in vitro against multidrugresistant cancer cell
lines as well as cell lines whose paclitaxel-resistance is derived from
specific b-tubulin mutations. Based on their attractive
in vitro biological profile epothilones have turned into important lead structures
in anticancer drug discovery and hundreds of analogs and derivatives of
epothilone A and B have been prepared and biologically characterized over the
past four years. A number of compounds, including natural epothilone B,
deoxyepothilone B, and epothilone B lactam (BMS-247550) have also been reported
to exhibit profound in vivo antitumor activity in animal models. Apart from
providing a brief summary of the SAR that has emerged from the above in vitro
studies, this minireview will largely focus on the biology and chemistry of
those analogs for which in vivo antitumor activity has been reported in the
literature. Two of these compounds, natural epothilone B and epothilone B
lactam (BMS-247550) have advanced to clinical studies in humans.
[Back to top] Naturally Occurring Peroxides with Biological
Activities
Mankil
Jung, Hanjo Kim, Kyunghoon Lee and
New natural
peroxides that have potent biological activities with novel diverse structures
are reviewed with classification as secondary metabolites such as terpenes,
polyketides, phenolics, and hydroperoxides. These compounds, isolated mainly
from medicinal plants and marine sponges, are valuable sources in the drug
discovery for particularly antitumor and antimalarial agents.