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Current
Bioactive Compounds
Current Bioactive Compounds
Volume 2, Number 2, June 2006
Contents
Photodynamic Inactivation of Bacteria Pp. 127-142
Edgardo N. Durantini
[Abstract]
Molecules from Nature: Modulating the Expression of
Estrogen Receptor Genes in Breast Cancer Cells Pp.
143-150
Mahmud Tareq Hassan Khan and Arjumand Ather
[Abstract]
Recent Progress of Medicinal Chemistry Research on
Peroxisome Proliferator-Activated Receptor (PPAR) Ligands
for the Treatment of Metabolic Syndrome Pp.
151 159
Hiroyuki Miyachi
[Abstract]
COX -2 Enzyme and its Inhibitors Pp.
161-178
P. M. Sivakumar and Mukesh Doble
[Abstract]
Bioactive Compounds
Anti-Cancer/Anti-Tumor Pp. 179
Anti-Diabetic Pp. 195
Anti-Inflammatory/Analgesic Pp.
201
Anti-Malarial Pp. 205
Anti-Microbial Pp. 208
Anti-Oxidant Pp. 212
Insecticidal Pp. 214
Anti-Parasite Pp. 215
Anti-Viral 215
Cardiovascular-Related Pp. 221
Cholesterol-Lowering Pp. 224
Central Nervous System-Related Pp. 225
Immunomodulator Pp. 230
Enzyme Inhibitors Pp. 233
Anti-Obesity Pp. 236
Other Activities Pp.237
Abstracts
[Back to top]
Photodynamic Inactivation of Bacteria
Edgardo N. Durantini
The emergence of antibiotic resistance amongst pathogenic
bacteria has led to a major research effort to find alternative
antibacterial therapies. A new promising approach to treat
bacterial infections is called bacterial photodynamic inactivation
(PDI). This is based in the administration of a photosensitizer,
which is preferentially accumulated in the microbial cells.
The subsequent irradiation with visible light, in the presence
of oxygen, specifically produces cell damages that inactivate
the microorganisms. Two oxidative mechanisms can occur after
photoactivation of the photosensitizer. In the type I photochemical
reaction, the photosensitizer interacts with a biomolecule
to produce free radicals, while in the type II mechanism,
singlet molecular oxygen, O2(1Δg),
is produced as the main species responsible for cell inactivation.
Previous investigation showed that porphyrin derivatives can
photosensitize the inactivation of various microbial pathogens.
In general, the studies show that Gram-positive bacteria are
efficiently photoinactivated by a variety of sensitizers,
whereas Gram-negative bacteria are usually resistant to the
action of negatively charged or neutral agents. The resistance
of Gram-negative bacteria to the action of photoactivated
sensitizers has been ascribed to the presence of highly organized
outer membrane, which hinders the interaction of the photosensitizer
with the cytoplasmic membrane and intercepts the photogenerated
reactive species. Cationic sensitizers have shown to photoinduce
direct inactivation of Gram-negative bacteria without the
presence of an additional permeabilization agent. The positive
charges on the photosensitizer molecule appear to promote
a tight electrostatic interaction with negatively charged
sites at the outer surface of the Gram-negative bacteria,
increasing the efficiency of the photoinactivation processes.
The mainly advantages of PDI are that bacteria can be eradicated
in very short time, resistance development in the target bacteria
is improbable and damage to adjacent host tissues and disruption
of normal microflora can be avoided. This approach is useful
to photoinactivate bacteria in a liquid medium and also immobilized
on a surface, which allows establishing conditions for the
treatment of pathogenic microorganisms growing as localized
foci of infection.
[Back to top]
Molecules from Nature: Modulating the Expression
of Estrogen Receptor Genes in Breast Cancer Cells
Mahmud Tareq Hassan Khan and Arjumand Ather
Estrogen receptors (ERα
and ERβ)
belong to the nuclear receptor superfamily. They mediate the
effects of estrogens by binding (as homodimers or heterodimers)
either directly to DNA at their estrogen-response elements
(EREs) or by protein-protein interactions with other transcription
factors (i.e., AP-1, NF-κβ)
bound to their cognate DNA sequences, thus regulating the
transcription of estrogen-responsive genes [1].
The ER mediates estrogenic activity in a variety of organs,
including those in the reproductive, cardiovascular, immune
and central nervous systems. Estrogen provides neuroprotection
against neurodegenerative diseases, including Parkinson's
disease. Its effects may stem from interactions with neurons,
astrocytes and microglia. Human breast cancer cell lines expressing
the (ERα),
all-trans-retinoic acid (ATRA) receptor α
(RARα)
and cellular retinoic acid binding protein II (CRABPII) genes
are sensitive to ATRA-mediated growth inhibition, as well.
Several naturally found polyphenols like, flavonoids, phytoestrogens,
etc., interact with the ERα
and ERβ,
exhibit estrogenic/antiestrogenic activities, and may play
protective roles in cancer, inflammation, heart disease and
osteoporosis, etc., and other disease conditions. These molecules
are considered “natural” selective estrogen receptor
modulators (SERMs) and their use as an alternative for hormone
therapy during menopause has recently expanded [2].
This review reports about some important and promising molecules
from natural resources, which modulate the ER expression and
ultimately cause modulations in breast cancer and related
clinical problems. The results discussed in this review are
some from the works from our group and also from other groups
around the globe.
[Back to top]
Recent Progress of Medicinal Chemistry Research
on Peroxisome Proliferator-Activated Receptor (PPAR) Ligands
for the Treatment of Metabolic Syndrome
Hiroyuki Miyachi
Improvements in our understanding of the functions of the
nuclear receptor peroxisome proliferator-activated receptor
(PPAR) subtypes as master regulators of lipid, lipoprotein,
and glucose homeostasis, and the rapid development of parallel
screening assay methods to evaluate transactivation and/or
binding activity toward individual PPAR subtypes, have provided
an opportunity to develop novel PPAR agonists with characteristic
subtype selectivity. Such agonists are candidates for the
treatment of metabolic syndrome, which includes type II diabetes,
dyslipidemia, obesity, and hypertension. This review focuses
on the recent literature dealing with medicinal-chemical strategies
to identify PPARδ-selective
agonists and PPARδ/α
dual agonists. Recent progress of studies on selective modulators
of PPARγM
(SPPARγM)
is also briefly reviewed.
[Back to top]
COX -2 Enzyme and its Inhibitors
P. M. Sivakumar and Mukesh Doble
Cyclooxygenases (COX) are involved in the biosynthesis of
prostaglandins from arachidonic acid (AA). At least three
cyclooxygenase enzymes were believed to be present and the
first two are constitutive (COX-1) and inducible (COX-2) in
nature, while little information is available about the third
enzyme. Classical NSAIDs are in use for a very long time which
are known to inhibit both the COX enzymes and, they are used
in treating inflammatory, thrombosis and analgesia. Inhibition
of both the isoforms leads to side effects, while selective
inhibition of COX-2, leads to therapeutically beneficial effect.
Structurally different group of compounds called ‘coxibs’
have been synthesized with increased selectivity towards COX-2
enzyme and as expected have reduced gastrointestinal toxicity.
Further studies showed that selective COX-2 inhibitors could
be useful in the treatment of colon cancer, angiogenesis,
and Alzheimer’s disease. Recently due to their cardiovascular
risk, COX-2 inhibitors namely ‘rofecoxib’ and
‘valdecoxib’ have been withdrawn from the market
while the mechanism behind this side effect is unknown. Till
now aspirin is the only NSAID with cardiovascular safety and
is known to inhibit COX-1, which is absent with drugs like
naproxen. So a detailed mechanistic understanding of the inhibition
of COX-1 and COX-2 is imperative for better drug design with
minimal side effect. In this review various structures that
have been synthesized and natural products that have been
tested towards COX -2 activity are discussed in detail. Also
attempts are made to integrate structural requirements for
coxibs and their interaction with the active site of both
COX-1 and COX-2 enzymes.
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