|
Mini-Reviews
in Medicinal Chemistry
ISSN: 1389-5575
Mini-Reviews in Medicinal
Chemistry
Volume 6, Number 1, January 2006
Contents
Recent Advances in the Solid-Phase Organic Synthesis
of Biologically Interesting Compounds
Executive Editor: Ernesto G. Mata
Editorial Pp. 1-1
Solid-Phase Synthesis in the Twenty-First
Century Pp. 3-10
A. Ganesan
[Abstract]
Solid-Phase Chemistry in the Total
Synthesis of Non-Peptidic Natural Products Pp. 11-25
Pablo Cironi, Mercedes Álvarez and Fernando Albericio
[Abstract]
Solid-Phase Synthesis of Biologically
Interesting Compounds Containing Hydroxamic Acid Moiety
Pp. 27-36
Viktor Krchnák
[Abstract]
Solid-Phase Organic Synthesis (SPOS)
of Modulators of Estrogenic and Androgenic Action Pp.
37-52
Donald Poirier and René Maltais
[Abstract]
Recent Advances in the Solid-Phase
Combinatorial Synthetic Strategies for the Benzodiazepine
Based Privileged Structures Pp. 53-69
Ahmed Kamal, K. Laxma Reddy, V. Devaiah, N. Shankaraiah and
D. Rajasekhar Reddy
[Abstract]
Recent Advances in the Solid-Phase
Combinatorial Synthetic Strategies for the Quinoxaline, Quinazoline
and Benzimidazole Based Privileged Structures Pp.
71-89
Ahmed Kamal, K. Laxma Reddy, V. Devaiah, N. Shankaraiah and
M.V. Rao
[Abstract]
Recent Advances in Combinatorial Chemistry
Applied to Development of Anti-HIV Drugs Pp. 91-108
S. Pettersson, I. Clotet-Codina, J.A. Esté, J.I.
Borrell and J. Teixidó
[Abstract]
The Polymer-Supported and Combinatorial
Synthesis of β-Lactam Compounds: An Update Pp.
109-120
María A. Laborde and Ernesto G. Mata
[Abstract]
Abstracts
[Back to top]
Editorial
Solid-phase chemistry has been used for the synthesis of
organic molecules for more than 30 years. However, this powerful
approach remained unappreciated until the work by Bunin and
Ellman in 1992 on solid-phase synthesis of arrays of 1,4-benzodiazepine-2-ones.
Similar work on other drug-like molecules followed and a major
revival in the study of solid-phase organic synthesis (SPOS)
began. For developing high throughput synthesis, chemistry
on a solid support is attractive from different perspectives:
(i) filtration can be used for rapid purification; (ii) excess
reagents can be used so the reactions can be driven to completion;
(iii) automation is easily accomplished; and (iv) relative
site isolation is achieved getting the “pseudo-dilution
effect” which makes intramolecular macrocyclization
a suitable reaction that could be carried out efficiently
on solid-phase rather than in solution.
Nowadays, combinatorial synthesis of small organic molecules
using solid-phase approaches is recognized as a powerful tool
for the rapid development of novel lead compounds and for
the optimization of therapeutic efficacy.
The present issue of Mini-Reviews in Medicinal Chemistry
consists of eight invited review articles that cover different
areas of research dealing with the application of SPOS to
the preparation of biologically interesting compounds.
The first article of this issue by A. Ganesan describes recent
achievement of his group in different aspects of solid-phase
synthesis including synthesis of unsymmetrical guanidines,
tetrahydro-β-carbolines
and kahalalide A. In the next article, Cironi, Álvarez
and Albericio present an overview of recent examples of the
use of chemistry on solid support in the preparation of non-peptidic
natural products and related compounds. In the third article,
gives an update on the application of solid-phase methodologies
for the preparation of biologically interesting compounds
containing hydroxamic acid moiety. The fourth article by Poirier
and Maltais provides a comprehensive review on the solid-phase
synthesis of steroidogenic enzyme inhibitors and steroid receptor
modulators. Next, Kamal and colleagues contribute with two
reviews dealing with the recent advances in the solid-phase
synthesis of benzodiazepines in their first article, and quinoxaline,
quinazoline and benzimidazole in their second article. In
the seventh article, Pettersson, Clotet-Codina, Esté,
Borrell and Teixidó give a compilation of the combinatorial
methodologies applied to the development of anti-HIV drug.
In the final article, we provide an update on the application
of solid-phase and combinatorial synthesis to the preparation
of β-lactam
compounds.
Finally, I would like to express my sincere thanks to the
authors, all experts in their fields, for setting aside time
to write these excellent reviews that give prestige to this
issue. It has been an honor for me to work with such outstanding
scientists. I fully anticipate that their effort will be appreciated
by the scientific community interested in this important area
of research.
Ernesto G. Mata
Instituto de Química Orgánica de Síntesis,
Facultad de Ciencias Bioquímicas y Farmacéuticas,
CONICET – Universidad Nacional de Rosario
Suipacha 531. 2000 Rosario, Argentina;
E-mail: emata@fbioyf.unr.edu.ar
[Back to top]
Solid-Phase Synthesis in the Twenty-First
Century
A. Ganesan
Solid-phase synthesis is a powerful tool for achieving high-throughput
chemistry. This review discusses recent diverse examples from
my group: the solid-phase synthesis of unsymmetrical guanidines,
polymer-supported versions of cyclooctadiene and 9-BBN, a
triflate-like linker, the synthesis of tetrahydro-β-carbolines
by the acyliminium Pictet-Spengler reaction, and a total synthesis
of the antimycobacterial cyclic depsipeptide natural product
kahalalide A.
[Back to top]
Solid-Phase Chemistry in the Total Synthesis
of Non-Peptidic Natural Products
Pablo Cironi, Mercedes Álsvarez and Fernando Albericio
Solid-phase chemistry, first introduced for peptide synthesis
in the 1960’s, has become an integral part of organic
synthetic methodology. Presented herein is an overview of
recent examples of the use of solid-phase in the preparation
of non-peptidic natural products and related compounds, encompassing
on-resin total syntheses as well as the use of polymer-supported
reagents in solution.
[Back to top]
Solid-Phase Synthesis of Biologically Interesting
Compounds Containing Hydroxamic Acid Moiety
Viktor Krchnák
Chemical strategies developed for the solid-phase synthesis
of hydroxamates are divided into four groups: (i) the traditional
synthesis of hydroxamates via cleavage of resin-bound
esters by hydroxylamine and its derivatives, (ii) introduction
of hydroxamic acid moiety on the resin-bound precursor, (iii)
transformation of polymer-supported hydroxylamine, attached
to a solid supported linker either by oxygen (O-linking
strategy) or by nitrogen (N-linking strategy), and
(iv) synthesis of N-alkyl hydroxamates. The scope
and limitation of individual approaches are discussed.
[Back to top]
Solid-Phase Organic Synthesis (SPOS) of Modulators
of Estrogenic and Androgenic Action
Donald Poirier and René Maltais
Estrogens and androgens are key growing factors involved
in a large series of disorders. Two main strategies are possible
for controlling their undesirable agonist effects: (1) blocking
their biosynthesis by using selective enzyme inhibitors, and
(2) antagonizing their hormonal action on a receptor with
an antiestrogen or an antiandrogen. In this review, we will
briefly discuss the identification of a series of important
therapeutic targets, through the study of steroidogenesis
of potent estrogens, estrone and estradiol, and potent androgens,
testosterone and dihydrotestosterone, as well as of their
nuclear receptors. We will next review the solid-phase synthesis
of steroidogenic enzyme (steroid sulfatase and 17β-hydroxysteroid
dehydrogenases) inhibitors and steroid (estrogen and androgen)
receptor modulators, all being potential therapeutic agents
for the treatment of hormone-sensitive diseases.
[Back to top]
Recent Advances in the Solid-Phase Combinatorial
Synthetic Strategies for the Benzodiazepine Based Privileged
Structures
Ahmed Kamal, K. Laxma Reddy, V. Devaiah, N. Shankaraiah and
D. Rajasekhar Reddy
Benzodiazepine based heterocycles can be prepared efficiently
on solid-support by employing different approaches. In this
review, an effort has been made to highlight academic and
industrial examples of combinatorial synthesis for this type
of heterocycles published in the last decade. Therefore, it
describes synthetic strategies for the generation of benzodiazepine
privileged structures employing the corresponding resin-bound
substrates. Further, the most relevant biological properties
of these heterocycles have also been incorporated.
[Back to top]
Recent Advances in the Solid-Phase Combinatorial
Synthetic Strategies for the Quinoxaline, Quinazoline and
Benzimidazole Based Privileged Structures
Ahmed Kamal, K. Laxma Reddy, V. Devaiah, N. Shankaraiah and
M.V. Rao
Quinoxaline, quinazoline and benzimidazole based templates
have been synthesized on solid-support employing different
methodologies. This review enlightens academic and industrial
examples of combinatorial synthesis for this type of heterocycles
that appeared in the literature in the last decade. Hence,
some of the important synthetic strategies for the generation
of quinoxaline, quinazoline and benzimidazole based privileged
structures, and the important biological activities for these
heterocycles have been highlighted. Further, benzothiadiazinone,
thioxoquinazolinone, cinnoline and indazole are also examined
in this review.
[Back to top]
Recent Advances in Combinatorial Chemistry
Applied to Development of Anti-HIV Drugs
S. Pettersson, I. Clotet-Codina, J.A. Esté, J.I.
Borrell and J. Teixidó
A compilation of combinatorial chemistry techniques applied
to anti-HIV drug development is presented in this review.
This synthetic strategy together with high throughput screening
assays has allowed the discovery and optimization of novel
lead anti-HIV compounds.
[Back to top]
The Polymer-Supported and Combinatorial Synthesis
of β-Lactam Compounds: An Update
María A. Laborde and Ernesto G. Mata
Solid-phase organic synthesis (SPOS) has become an effective
synthetic tool for the preparation of combinatorial libraries
of non-oligomeric small molecules. Owing to their high efficacy
and extremely safe toxicological profile, β-lactam
antibiotics are the first choice for bacterial infectious
diseases. Moreover, β-lactam
compounds have also showed other biological activities that
include inhibition of prostate specific antigen, thrombin,
human cytomegalovirus protein, human leukocyte elastase and
cholesterol absorption. Thus, the application of combinatorial
and related methodologies to the chemistry of the β-lactam
ring has been recognized as a very attractive challenge by
different research groups around the world. This review covers
the solid-phase and combinatorial chemistry related to mono-and
multicyclic β-lactam
compounds that has been reported in the literature from 1999
to 2004.
|
