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Current
Bioactive Compounds
Current Bioactive Compounds
Volume 2, Number 3, September 2006
Contents
Catalysis and Inhibition of HIV-1 Protease Pp.
243-261
Bruno Tamames, Pedro Alexandrino Fernandes and Maria João
Ramos
[Abstract]
Action of the Aqueous Extract of Sesamum Radiatum
Schum. & Tonn. (Pedaliaceae) on the Cardiovascular System
of Mammalians: Hypotensive Effect Pp. 263-267
Konan Brou André, Datté-Jacques Yao and
Offoumou Atté Michel
[Abstract]
Chemistry and Biology of Novel Microtubule-Destabilizing
Agents that Bind α-Tubulin
Pp. 269-299
Francisco Sarabia, Miguel García-Castro and Antonio
Sánchez-Ruiz
[Abstract]
Search for and Development of Active Vitamin D3
Analogs Pp. 301-315
Noboru Kubodera
[Abstract]
Bioactive Compounds
Anti-Cancer/Anti-Tumor Pp. 317
Anti-Diabetic Pp. 330
Anti-Viral Pp. 335
Anti-Inflammatory/Analgesic Pp.
345
Anti-Malarial Pp. 353
Anti-Microbial Pp. 357
Anti-Oxidant Pp. 362
Cardiovascular-Related Pp. 367
Central Nervous System-Related Pp. 373
Cholesterol-Lowering Pp. 382
Anti-Depressant Pp. 383
Anti-Obesity Pp. 384
Other Activities Pp.386
Abstracts
[Back to top]
Catalysis and Inhibition of HIV-1 Protease
Bruno Tamames, Pedro Alexandrino Fernandes and Maria João
Ramos
Since AIDS was first recognized in the early eighties,
more than 25 million people have died and tens of millions
of people have been infected with HIV. Presently more than
40 million men, women and children are living with HIV. In
the most affected countries, AIDS dramatically diminishes
life expectancy and economic potential, by killing people
in the prime of their lives, and undermines the future generations
by creating millions of orphans. Although HIV infection rates
are especially dramatic in Africa and South-eastern Asia,
in the most populous countries including China, Indonesia
and Russia, the disease is spreading rapidly.
Several targets have been identified in the search for a treatment
against HIV infection, but until now only three have been
successfully spotted. They correspond to two fundamental enzymes
for the virus life cycle (protease (PR) and reverse transcriptase
(RT)) and very recently to the event of membrane fusion between
the virus and the cell. FDA has approved a total of twenty
five antiretrovirals, nine of which targeting PR, fifteen
RT and one targeting virus entry. Additionally, albeit in
the early stages of clinical trials, there are also inhibitors
being developed against the viral enzyme integrase (IN).
This work deals with the inhibition of PR. This enzyme has
been considered as a paradigm of success in structure based
drug design, and there are more three-dimensional structures
resolved for PR than for any other enzyme. The catalytic mechanism
is briefly outlined. Subsequently, the rational development
of PR inhibitors is discussed, the existing data for the currently
in vitro and in vivo efficient compounds
are compiled, and the methodologies to improve their potency
and bioavailability are explained.
[Back to top]
Action of the Aqueous Extract of Sesamum
Radiatum Schum. & Tonn. (Pedaliaceae) on the Cardiovascular
System of Mammalians: Hypotensive Effect
Konan Brou André, Datté-Jacques Yao and
Offoumou Atté Michel
The effects of the aqueous extract of Sesamum radiatum
Schum & Tonn (ESera) were studied on the cardiovascular
system of mammalians. ESera administered intravenously (6
x 10-4 g/kg b.w. - 5.7 x 10-2 g/kg b.w.),
caused a decrease in the arterial blood arterial pressure
(hypotension) in a dose-dependent manner (ED50
= 1.3 x 10-2 g/kg b.w.). These effects induced
by ESera were reversed in the presence of atropine at a concentration
of 10-8 g/kg b.w. Our observations regarding the
isolated heart of rat showed that the extract induced both
negative inotropic and negative chronotropic effects. Similarly,
the experimentation based on the isolated aorta obtained from
guinea pig revealed that the extact decreased the basal tonus
of this smooth muscle. These results suggest that ESera could
act via cholinergic receptors. The effects of ESera could
result from both cardiodepression and vasorelaxation mechanism.
[Back to top]
Chemistry and Biology of Novel Microtubule-Destabilizing
Agents that Bind α-Tubulin
Francisco Sarabia, Miguel García-Castro and
Antonio Sánchez-Ruiz
Bioactive compounds capable of interacting with tubulins
and microtubules represent powerful weapons in cancer chemotherapy.
Most of these compounds, including the well-established chemotherapeutic
agents colchicine (1), podophyllotoxin (3),
vinblastine (4) and vincristine (5)
that interfere with the formation and growth of microtubules,
or Taxol (11) and the epothilones (12-13),
which promote tubulin polymerization and stabilize microtubules,
share an interaction with β-tubulin,
one of the two subunits of the globular heterodimeric protein
tubulin. In contrast, few compounds have been identified as
interacting with α-tubulin.
A select group of natural compounds are pironetin (18)
and the hemiasterlins, and the synthetic compounds cyanoacrylates
(21-22), dinitroanilines (23-25)
and tetrahydrofuranyl derivatives COBRA-0 (133)
and COBRA-1 (26). In addition to their interaction
with the α-tubulin
subunit, all these compounds share the capacity of destabilizing
microtubules. In the present review, we will discuss the most
relevant aspects of the biology and chemistry of these compounds,
with an emphasis on their antiproliferative properties and
potential as anticancer drugs.
[Back to top]
Search for and Development of Active Vitamin
D3 Analogs
Noboru Kubodera
Twenty-five years ago, alfacalcidol arrived on the scene
as a prodrug of the active form of vitamin D3,
calcitriol [1,25(OH)2D3] to remedy vitamin
D3 deficiency. With the concurrent reported discovery
of the differentiation-inducing effect of active vitamin D3,
its diverse physiological effects have become appreciated
and the research aiming to accentuate selected physiological
effects by analog synthesis has made a fresh development.
Our studies aimed particularly at separating the differentiation-inducing
effect/cell growth-inhibitory effect and the calcemic effect
of active vitamin D3 led to the development of
two characteristic analogs, OCT and ED-71. OCT, characterized
by its profound differentiation-inducing effect and modest
calcemic effect, is currently in practical use as an injectable
therapeutic agent for secondary hyperparathyroidism as well
as in clinical settings as an ointment for the treatment of
psoriasis vulgaris, an intractable skin disease. The other
analog, ED-71, possesses a profile inverse to that of OCT
and is now under phase III clinical development as an oral
preparation for treatment of osteoporosis. OCT and ED-71 are
considered second generation analogs developed from first
generation analogs, 1,25(OH)2D3 and
alfacalcidol used in vitamin D3 formulations. In
further investigation of analogs having grater activity and
biological differentiation than second generation analogs,
we adopted in vivo bone effects as a target effect
v. in vivo calcemic effects as a side effect using
ovariectomized rats. From these studies, we are currently
developing third generation analogs of 1,25(OH)2D3,
such as DD-281, which is also discussed in the review.
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