Mini-Reviews in Medicinal Chemistry, Volume 3, No. 5, 2003
Contents
Human Insulin Genome Sequence Map,
Biochemical Structure of Insulin for Recombinant DNA Insulin Pp. 375-385
Chiranjib
Chakraborty and Ashish A. Mungantiwar
Recent Advances in the Development of
Phytoestrogens and Derivatives: An Update of the Promising Perspectives in the
Prevention of Postmenopausal Diseases Pp. 387-400
Y.
Jacquot , C. Rojas , B. Refouvelet , J.F. Robert , G. Leclercq and A. Xicluna
Marine Natural Products as Lead Anti-HIV
Agents Pp. 401-424
D.J.
Gochfeld , K.A. El Sayed , M. Yousaf , J.F. Hu , P. Bartyzel , D.C. Dunbar ,
S.P. Wilkins , J.K. Zjawiony , R.F. Schinazi , S. Schlueter Wirtz , P.M.
Tharnish and M.T. Hamann
Terpenoids and Glycolipids from Euphorbiaceae Pp. 425-437
F.
Cateni , G. Falsone and J. Zilic
Crystallography of Membrane Proteins, Major
Targets in Drug Design Pp.
439-448
J.
Wouters
Microwave-Assisted Solid-phase Synthesis (MASS):
Parallel and Combinatorial Chemical Library Synthesis Pp. 449-460
Fahad Al-Obeidi , Richard E. Austin, John F. Okonya and Daniel R. S. Bond
The Medicinal Chemistry Implications of the
Anticancer Effects of Aspirin and Other NSAIDs Pp. 461-470
P.S. Gardiner and J.F. Gilmer
O6-Alkylguanine-DNA Alkyltransferase
Inactivation in Cancer Chemotherapy Pp. 471-485
R.S. McElhinney , T.B.H. McMurry and G.P. Margison
Review in Quantitative Structure Activity
Relationships on Lipoxygenase Inhibitors Pp. 487-499
Pontiki Eleni and Hadjipavlou-Litina Dimitra
Abstracts
[Back to top] Human Insulin Genome Sequence Map,
Biochemical Structure of Insulin for Recombinant DNA Insulin
Chiranjib
Chakraborty and Ashish A. Mungantiwar
Insulin is a
essential molecule for type I diabetes that is marketed by very few companies.
It is the first molecule, which was made by recombinant technology; but the
commercialization process is very difficult. Knowledge about biochemical
structure of insulin and human insulin genome sequence map is pivotal to large
scale manufacturing of recombinant DNA Insulin. This paper reviews human
insulin genome sequence map, the amino acid sequence of porcine insulin,
crystal structure of porcine insulin, insulin monomer, aggregation surfaces of
insulin, conformational variation in the insulin monomer, insulin X-ray
structures for recombinant DNA technology in the synthesis of human insulin in
Escherichia coli.
[Back to top] Recent Advances in the Development of
Phytoestrogens and Derivatives: An Update of the Promising Perspectives in the
Prevention of Postmenopausal Diseases
Y.
Jacquot , C. Rojas , B. Refouvelet , J.F. Robert , G. Leclercq and A. Xicluna
Phytoestrogens
constitute a promising alternative in the treatment of diseases associated with
menopause. Nevertheless, the lack of data concerning their pharmacology and
their toxicology requires use precautions. After reminding the pharmacology of
estrogen receptors, this review outlines the estrogenicity and the therapeutic
potentialities of phytoestrogens according to their structure.
[Back to top] Marine Natural Products as Lead Anti-HIV
Agents
D.J.
Gochfeld , K.A. El Sayed , M. Yousaf , J.F. Hu , P. Bartyzel , D.C. Dunbar ,
S.P. Wilkins , J.K. Zjawiony , R.F. Schinazi , S. Schlueter Wirtz , P.M.
Tharnish and M.T. Hamann
Current anti-HIV
drugs have extreme side effects and resistance to these drugs develops rapidly.
The marine environment holds an unprecedented number of unusual chemical
structural classes with activity against HIV. We review the literature on
anti-HIV activity of marine natural products and discuss the efficacy of
different structural classes.
[Back to top] Terpenoids and Glycolipids from
Euphorbiaceae
F. Cateni , G. Falsone and J. Zilic
The family
Euphorbiaceae is widely distributed throughout both hemispheres and ranges in
morphological form from large desert succulents to trees and even small
herbaceous types. Many species contain a milky juice which is more or less
toxic, especially for cold-blooded animals, and can produce a dermatitis
similar to that from poison ivy.
Separation
procedures and characterization of the less polar fractions of the plant
extracts have been widely described in the literature for their content in
diterpene derivatives.
In the continuing
research on biologically active compounds from Euphorbiaceae, a series of
studies on the isolation and structure elucidation of glyceroglycolipids (GGLs)
and glycosphingolipids (GSLs) have been carried out in order to develop the
novel medicinal resources from natural Euphorbiaceae products.
Glyceroglycolipids
are major constituents of the chloroplast membrane in the plant kingdom.
Recently, glycolipids were found to possess antitumor-promoting activity while
glyceroglycolipids isolated from Euphorbiaceae have shown an interesting
anti-inflammatory activity in vivo.
Glycosphingolipids
are present at the outer layer of the lipid-bilayer in biological membranes and
are thought to partecipate in antigen-antibody reactions and transmission of
biologically informations. Sphingolipid breakdown products, sphingosine and
lysosphingolipids, inhibit protein kinase C, a pivotal enzyme in cell
regulation and signal transduction. Sphingolipids and lysosphingolipids affect
significantly cellular responses and exhibit antitumor promoter activities in
various mammalian cells. These molecules may function as endogenous modulators
of cell function and possibly as second messengers.
[Back to top] Crystallography of Membrane Proteins, Major
Targets in Drug Design
J.
Wouters
Protein
crystallography has the potential to accelerate drug discovery greatly.
High-resolution structures of membrane proteins of pharmaceutical interest open
new perspectives in drug design. Recent structural data obtained for
cyclooxygenases, monoamine oxidase, squalene cyclase, rhodopsine, porins,
aquaporins, and ABC transporters are presented and briefly discussed.
[Back to top] Microwave-Assisted Solid-phase Synthesis (MASS): Parallel and
Combinatorial Chemical Library Synthesis
Fahad
Al-Obeidi , Richard E. Austin, John F. Okonya and Daniel R. S. Bond
The use of
microwave technology in solid-phase organic synthesis has attracted much
attention in recent years. The combination of solid support, either as a medium
for chemical synthesis or as a carrier for organic reagents, with microwave
heating offers several advantages over conventional techniques. Rapid and
elevated heating of reaction mixtures can induce the completion of chemical
transformations in minutes while several hours or days may be required for the
same chemistry under conventional conditions. With decreased time of exposure
to high temperatures and lessened thermal degradation, microwave accelerated
chemistries often deliver products of higher purity when compared to
conventional heating techniques. Several chemical syntheses on solid-phase
employing microwave irradiation have been reported in the literature. The
reagents, solvents, and equipment selected for microwave-mediated synthesis are
important contributors to the success of the chemical transformation. Owing to
the timesavings in performing chemical synthesis under microwave irradiation,
the technique has become an emerging partner in solid-phase organic synthesis.
[Back to top] The Medicinal Chemistry Implications of the Anticancer Effects of
Aspirin and Other NSAIDs
P.S.
Gardiner and J.F. Gilmer
The regular intake
of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been
associated with decreased incidence of certain types of cancer particularly
those with an inflammatory component. The protective effects of these drugs in
colorectal cancer are particularly marked, with a 40–50% reduction in risk.
Research in this area has focussed on understanding and optimising these
cytoprotective effects. NSAIDs are believed to operate by inhibiting COX-2, an
enzyme that appears to be involved in a number of cancer promoting processes.
This hypothesis is consistent with the observation that the COX-2 selective
inhibitors dramatically decrease tumour formation in human and animal studies.
Surprisingly aspirin, which is selective for COX-1 over COX-2, and sulindac,
which is an equipotent inhibitor of the COX isoenzymes, appear to have a
similar anticancer profile to the COX-2 selective NSAIDs. A number of
mechanisms have been proposed to explain the anomalous effects of aspirin. The
first of these relates to the unique mode of action of aspirin, which acetylates
the COX-2 enzyme and generates the cancer-suppressing
15R-hydroxyeicosatetraenoic acid at the site of a potential tumour. The
alternative rationale relates to the metabolism of aspirin to salicylic acid,
which has a cyclooxygenase independent anti-inflammatory mechanism, preventing
the inflammatory response at the gene transcription level. A new generation of
drugs could evolve from approaches to improving the therapeutic index of
aspirin or by modifications to known therapies such as sulindac and celecoxib.
[Back to top] O6-Alkylguanine-DNA Alkyltransferase Inactivation in Cancer
Chemotherapy
R.S.
McElhinney , T.B.H. McMurry and G.P.
Margison
The protein O6-alkylguanine-DNA alkyltransferase is the basis of an important process for
repairing damage to cellular DNA, which renders cells resistant to drugs that
alkylate at the O6-position of guanine residues. The development of various
pseudosubstrates which inactivate this protein is reviewed, from a chemical
standpoint. Study of the influence of pseudosubstrate molecular structure on
their interaction with the active site cysteine has progressed together with
direct investigation of protein structure. Combination therapy using a powerful
inactivator with a suitable alkylating agent shows great clinical promise in
the treatment of cancer, particularly when some degree of selectivity is
possible.
[Back to top] Review in Quantitative Structure Activity Relationships on Lipoxygenase
Inhibitors
Pontiki
Eleni and Hadjipavlou-Litina Dimitra
This paper reviews
and evaluates all the published QSAR treatments of LOX inhibitors. This reveals
that in almost all cases, the clog P parameter plays an important part in the
QSAR relationships. In some cases the steric factors (B1, B5 and L) as well as
the overall molar refractivity (CMR) or the substitutents molar refractivity
(MR) are important. Electronic effects except for the Hammet’s constant ó, are
comparatively unimportant. The study shows that log P as calculated from the
Clog P program is suitable for this form of QSAR study. Log Po of 2.77-3.76 was
found to be ideal, for the biological response.