Mini-Reviews in Medicinal Chemistry, Volume 3, No. 6, 2003
Contents
Inhibitors of Sialyltransferases: Potential
Roles in Tumor Growth and Metastasis Pp.501-517
N.B.
Drinnan , J. Halliday and T. Ramsdale
Recent Developments in the Synthesis of
Acetylcholinesterase Inhibitors Pp.518-524
Jose
L. Marco and M. Carmo Carreiras
A Review of Natural and Modified Betulinic,
Ursolic and Echinocystic Acid Derivatives as Potential Antitumor and Anti-HIV Agents Pp.525-539
I.
Baglin, A.-C. Mitaine-Offer, M. Nour, K. Tan, C. Cave and M.-A. Lacaille-Dubois
Plant-Derived Triterpenoids as Potential
Antineoplastic Agents Pp.540-556
W.N.
Setzer and M.C. Setzer
7-Keto-.D5-Steroids: Key-Molecules Owning Particular Biological and Chemical
Interest Pp.557-567
E.S.
Arsenou, M.A. Fousteris, A.I. Koutsourea and S.S. Nikolaropoulos
Systemic Lupus Erythematosus and Other
Autoimmune Diseases from Endogenous and Exogenous Agents: Unifying Theme
of Oxidative Stress Pp.568-575
Peter Kovacic and Jason D. Jacintho
Selective ACAT Inhibitors as Promising
Antihyperlipidemic, Antiatherosclerotic and Anti-Alzheimer Drugs Pp.576-584
M.P. Giovannoni , V. Dal Piaz , C. Vergelli and D. Barlocco
Cysteine Protease Inhibitors Containing Small
Rings Pp.100%-596
T. Schirmeister and A. Klockow
DNA Topoisomerases as Targets for
Antiprotozoal Therapy Pp.597-608
R.P. Bakshi and T.A. Shapiro
Molecular Diversity of Hydroxamic Acids: Part
II. Potential Therapeutic Applications Pp.609-620
Boliang Lou and Kexin Yang
Advances in Angiotensin Converting Enzyme
Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs) Pp.621-631
K.M.K. Swamy, Mei-Jung Lin and Chung-Ming Sun
Abstracts
[Back to top] Inhibitors of Sialyltransferases: Potential
Roles in Tumor Growth and Metastasis
N.B.
Drinnan , J. Halliday and T. Ramsdale
For over thirty
years it has been evident that there is altered glycosyltransferase activity in
neoplastic tissue when compared to healthy tissue. It has also long been
speculated that disruption of the neoplastic expression of sialic acid on
cellular glycoconjugates, is a valid target in anti-metastatic therapeutic
development. Over the years attempts have been made to synthesize inhibitors of
sialyltransferases in a effort to assist in the validation or dissolution of
these enzymes as potential therapeutic targets.
[Back to top] Recent Developments in the Synthesis of
Acetylcholinesterase Inhibitors
Jose
L. Marco and M. Carmo Carreiras
The
acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory
activities of a series of pyrano[2,3-b]quinolines (2, 3), [1,8]naphthyridines
(5, 6), 4-amino-2,3-diaryl-5,6,7,8-tetrahydrofuro[2,3- b]quinolines (11-13)/
4-amino-6,7,8,9-tetrahydro-2,3-diphenyl-5H-cyclohepta[e]furo[2,3-b]pyridine
(14), 4-amino-5,6,7,8-tetrahydro-2,3-diphenylthieno[2,3-b]quinoline (15)/
4-amino-6,7,8,9-tetrahydro-2,3-diphenyl- 5H-cyclohepta[e]thieno[2,3-b]pyridine
(16) are described. These compounds are tacrine analogues that have been
prepared from readily available polyfunctionalized ethyl
[6-amino-5-cyano-4H-pyran]-3-carboxylates (9, 10), ethyl
[6-amino-5-cyanopyridine]-3-carboxylates (7, 8),
2-amino-3-cyano-4,5-diarylfurans (17-19) and 2-
amino-3-cyano-4,5-diphenylthiophene (20) via Friedländer condensation with
selected ketones. These compounds are competitive and, in a few cases,
non-competitive inhibitors for AChE, the most potent being compound (14),
though three-fold less active than tacrine. The BuChE inhibitory activity is
only significant in compounds 11 and 14, ten-fold less active than tacrine.
Furthermore, the products 12 and 13 are selective and moderate AChE inhibitors.
[Back to top] A Review of Natural and Modified Betulinic,
Ursolic and Echinocystic Acid Derivatives as Potential Antitumor and Anti-HIV Agents
I.
Baglin, A.-C. Mitaine-Offer, M. Nour, K. Tan, C. Cave and M.-A. Lacaille-Dubois
The aim of this
review is to update current knownledge on the betulinic, ursolic and
echinocystic acids and their natural and semisynthetic analogs, focussing on
their cytotoxic and anti-HIV activities. Then, the last results of the authors'
team on unusual semisynthetic derivatives of these triterpenoids will be
presented in order to establish structure/activity relationships.
[Back to top] Plant-Derived Triterpenoids as Potential
Antineoplastic Agents
W.N. Setzer and M.C. Setzer
Man has relied on
plants as a source of medicinal agents for centuries. Today, with the specter
of antibiotic resistance, emerging infectious diseases, and cancers,
phytochemicals continue to provide new structural leads for the
chemotherapeutic industry. A number of triterpenoids have shown promise as
antineoplastic agents. Members of the cycloartane, lupane, ursane, oleanane,
friedelane (especially quinone methides), dammarane, cucurbitacin, and limonoid
triterpenoids, have demonstrated anti-proliferative activity on various cancer
cell lines. This review covers the recent developments regarding
antineoplastic/cytotoxic triterpenoids, excluding saponins, from higher plants.
[Back to top] 7-Keto-D5-Steroids:
Key-Molecules Owning Particular Biological and Chemical Interest
E.S.
Arsenou, M.A. Fousteris, A.I. Koutsourea and S.S. Nikolaropoulos
7-keto-D.5-steroids have been suggested for the
treatment of several diseases. Their significant biological profile resulted in
the development of a great number of methods and reagents for the allylic
oxidation of .D5-steroids. These methods and the biological evaluation of the main
oxidizeD .5-steroids
are summarized.
[Back to top] Systemic Lupus Erythematosus and Other
Autoimmune Diseases from Endogenous and Exogenous Agents: Unifying Theme
of Oxidative Stress
Peter
Kovacic and Jason D. Jacintho
Extensive evidence
supports oxidative stress (OS) via endogenous and exogenous agents as an
important factor in induction of autoimmunity. OS arises from the immune system
and other endogenous sources. The literature contains support for OS
involvement of various drugs and other exogenous substances that produce the
condition. Studies reveal prevention or amelioration by antioxidants.
[Back to top] Selective ACAT Inhibitors as Promising
Antihyperlipidemic, Antiatherosclerotic and Anti-Alzheimer Drugs
M.P.
Giovannoni , V. Dal Piaz , C. Vergelli
and D. Barlocco
Inhibition of
ACAT, the enzyme which catalyses the intracellular formation of cholesteryl
esters, is a very attractive target for the treatment of hypercholesterolaemia
and atherosclerosis. However, in the past years many ACAT inhibitors gave
disappointing results in clinical trials showing very low efficacy. In
addition, their development was affected by the adrenotoxicity observed in many
compounds. The discovery of two isoforms of the enzyme, namely ACAT1 and ACAT2,
with different substrate specificity and different potential function, offers a
precious information for planning selective inhibitors with reduced secondary
effects. Today some potent, bioavailable and non adrenotoxic ACAT inhibitors
are under clinical evaluation. Amongst others, a very promising compound is
Avasimibe, presently in phase III clinical trials as anti-hyperlipidemic and
anti-atherosclerotic agent. Finally, ACAT inhibitors have recently been
proposed for the treatment of Alzheimer’s disease.
[Back to top] Cysteine Protease Inhibitors Containing Small
Rings
T.
Schirmeister and A. Klockow
Since the
discovery of E-64 in 1978 as potent cysteine protease inhibitor a variety of
inhibitors containing small rings as electrophilic building blocks responsible
for enzyme inhibition have been developed. In this review we summarize new
aspects concerning epoxysuccinyl peptides derived from E-64 and discuss
inhibition potency, selectivity and mechanisms of peptidic and peptidomimetic
inhibitors containing epoxide, aziridine, thiirane, cyclopropane, ß-lactam and
ß-lactone rings as electrophilic fragments.
[Back to top] DNA Topoisomerases as Targets for
Antiprotozoal Therapy
R.P.
Bakshi and T.A. Shapiro
Diseases caused by
parasitic protozoa present a health problem of immense magnitude, and there is
an urgent need for safe and effective new therapies. DNA topoisomerases are
clinically relevant targets for anticancer and anti-bacterial agents. Inhibitor
studies on parasite topoisomerases have revealed that these enzymes have great
promise as molecular targets for anti-parasitics, and have helped to dissect
the basic biology of DNA topoisomerases in these organisms. This review
provides a brief introduction to DNA topoisomerases and anti-topoisomerase
drugs, and an overview of studies on protozoal DNA topoisomerases and their
inhibitors.
[Back to top] Molecular Diversity of Hydroxamic Acids: Part
II. Potential Therapeutic Applications
Boliang
Lou and Kexin Yang
A hydroxamic acid
moiety has been demonstrated as the key structural element in many highly
potent and selective inhibitors against a variety of metalloprotease enzymes,
such as MMPs, TACE, HDAC, PDF, etc. Over the last several years, there has been
a rapid growth of literature and patent applications dealing with the
development of the hydroxamic acid-based inhibitors. This review highlights the
most recent examples to show their potential therapeutic applications.
[Back to top] Advances in Angiotensin Converting Enzyme
Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs)
K.M.K.
Swamy, Mei-Jung Lin and Chung-Ming Sun
Hypertension
remains one of the most unmet medical needs of this century. While many drugs
are available for treating hypertension, efforts are still insufficient to find
potent therapeutic agents since cause for hypertension in all patients is not
the same. Angiotensin-converting enzyme inhibitors (ACEIs) have emerged as an
important class of drugs in the treatment of hypertension, congestive heart
failure (CHF), protenuric renal disease, myocardial infarction and stroke. This
class of drugs blocks the conversion of angiotensin I to angiotensin II and
prevents bradykinin breakdown. However, the lack of specificity of ACEIs leads
to the frequent side effects like cough and angio-oedema. Recently developed,
specific non-peptide and orally active angiotensin receptor blockers (ARBs)
have become the prime therapeutics as they alone or coadministration with ACE
inhibitors can control the renin angiotensin disorders. This review explores
recent developments in the design, synthesis, and structural modifications of
ACE inhibitors as well as angiotensin receptor blockers.