|
Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 13, Number 7, 2006
Contents
Inhibitors of HIV Infection via the Cellular
CD4 Receptor Pp. 731-743
Kurt Vermeire, Dominique Schols and Thomas W. Bell
[Abstract]
Natural Products Inhibiting the Ubiquitin-Proteasome Proteolytic
Pp. 745-754
Pathway, A Target for Drug Development Sachiko Tsukamoto
and Hideyoshi Yokosawa
[Abstract]
Sphingolipids in Anticancer Therapy Pp. 755-770
José M. Padrón
[Abstract]
Tangier Disease Four Decades of Research: A Reflection of
the Importance of HDL Pp. 771-782
G.D. Kolovou, D.P. Mikhailidis, K.K. Anagnostopoulou, S.S.
Daskalopoulou and D.V. Cokkinos
[Abstract]
Current Strategies for Modulating Lymphangiogenesis
Signalling Pathways in Human Disease Pp. 783-792
S.A. Stacker, R.A. Hughes, R.A. Williams and M.G. Achen
[Abstract]
Role of Transmembrane Domain/Transmembrane Domain
Interfaces of P-Glycoprotein (ABCB1) in Solute Transport.
Convergent Information from Photoaffinity Labeling, Site Directed
Mutagenesis and in Silico Importance Prediction
Pp. 793-805
Peter Chiba, Ivana Mihalek, Gerhard F. Ecker, Stephan
Kopp and Olivier Lichtarge
[Abstract]
The Effect of Isoquinoline Alkaloids on Opiate Withdrawal
Pp. 807-812
A. Capasso, S. Piacente, N. De Tommasi, L. Rastrelli and
C.Pizza
[Abstract]
Steroidal Conjugates and Their Pharmacological Applications
Pp. 813-847
Deepak B. Salunke, Braja G. Hazra and Vandana S. Pore
[Abstract]
Abstracts
[Back to top]
Inhibitors of HIV Infection via
the Cellular CD4 Receptor
Kurt Vermeire, Dominique Schols and Thomas W. Bell
Recent advances in our understanding of cellular and molecular
mechanisms of viral penetration of the target cell have provided
the basis for novel chemotherapy and prophylaxis of HIV-1
infections. This knowledge has been successfully applied to
the development of inhibitors that target discrete steps of
the entry process. Interesting approaches for prevention of
HIV-1 entry include the use of small-molecule inhibitors,
natural ligands and/or monoclonal antibodies that interfere
with gp120/CD4 interaction. Other compounds acting by novel
mechanisms have recently been identified as anti-HIV agents
and seem worthy of further preclinical development. Of particular
interest in this regard are cyclotriazadisulfonamide (CADA)
compounds, which down-modulate the cellular receptor, CD4.
A series of analogues of 9-benzyl-3-methylene-1,5-di-p-toluenesulfonyl-1,5,9-triazacyclododecane
(CADA) has been synthesized and tested for CD4 down-modulation
and anti-HIV activity. Some derivatives proved to be highly
effective in decreasing cellular CD4 and in acting as HIV
entry inhibitors. Three-dimensional quantitative structure-activity
relationship (3D-QSAR) studies correlating molecular features
with potency have been used to produce a computational model.
This model can be used to design more potent CD4 down-modulating
drugs for HIV therapy and prophylaxis. This review summarizes
the results of recent studies relating to inhibitors of HIV
infection via CD4 and discusses the therapeutic potential
of targeting this cellular receptor. Special attention is
given to our own work on small-molecule HIV entry inhibitors
endowed with CD4 down-modulating properties.
[Back to top]
Natural Products Inhibiting the Ubiquitin-Proteasome
Proteolytic
Pathway, A Target for Drug Development Sachiko Tsukamoto
and Hideyoshi Yokosawa
The ubiquitin-proteasome proteolytic pathway plays a major
role in selective protein degradation and regulates various
cellular events including cell cycle progression, transcription,
DNA repair, signal transduction, and immune response. Ubiquitin,
a highly conserved small protein in eukaryotes, attaches to
a target protein prior to degradation. The polyubiquitin chain
tagged to the target protein is recognized by the 26S proteasome,
a high-molecular-mass protease subunit complex, and the protein
portion is degraded by the 26S proteasome. The potential of
specific proteasome inhibitors, which act as anti-cancer agents,
is now under intensive investigation, and bortezomib (PS-341),
a proteasome inhibitor, has been recently approved by FDA
for multiple myeloma treatment. Since ubiquitination of proteins
requires the sequential action of three enzymes, ubiquitin-activating
enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein
ligase (E3), and polyubiquitination is a prerequisite for
proteasome-mediated protein degradation, inhibitors of E1,
E2, and E3 are reasonably thought to be drug candidates for
treatment of diseases related to ubiquitination. Recently,
various compounds inhibiting the ubiquitin-proteasome pathway
have been isolated from natural resources. We also succeeded
in isolating inhibitors against the proteasome and E1 enzyme
from marine natural resources. In this review, we summarize
the structures and biological activities of natural products
that inhibit the ubiquitin-proteasome proteolytic pathway.
[Back to top]
Sphingolipids in Anticancer Therapy
José M. Padrón
Sphingolipids constitute a broad class of compounds with
many biological functions. The sphingolipid metabolites ceramide
and sphingosine are potent apoptosis inducers and produce
cell cycle arrest, whereas sphingosine-1-phosphate promotes
cellular growth and differentiation. Herein, the effects of
sphingolipids and their analogs on diverse signaling pathways
implicated in the apoptotic process are highlighted. The relatively
simple chemical structure of these compounds has led to several
strategies for their total synthesis. Those methods have contributed
to the development and biological study of several analogs
that present diverse degree of modification from the original
structure. This article catalogues many of the recently developed
synthetic analogs that act on diverse aspects of sphingolipid
metabolism. A description of known enzyme inhibitors of the
sphigolipids pathway is also given. Finally, diverse new sphingolipid-like
antitumor agents isolated from marine sources are presented.
This contribution opens the way for future development of
new sphingolipid analogs that might be useful in cancer chemotherapy.
[Back to top]
Tangier Disease Four Decades of Research: A Reflection
of the Importance of HDL
G.D. Kolovou, D.P. Mikhailidis, K.K. Anagnostopoulou, S.S.
Daskalopoulou and D.V. Cokkinos
Reduced circulating levels of high density lipoprotein cholesterol
(HDL-C) are a frequent lipoprotein disorder in coronary heart
disease patients and can be caused by either genetic and/or
environmental factors (sedentary lifestyle, diabetes mellitus,
smoking, obesity or a diet enriched in carbohydrates). Extremely
low serum HDL-C levels occur in patients with Tangier disease
(TD), which is caused by mutations in the adenosine triphosphate
(ATP)-binding cassette transporter A1 (ABCA1). Clinical manifestations
are related to the storage of cholesteryl esters in reticuloendothelial
tissues and to peripheral neuropathy.
This review focuses on the genetic and lipid abnormalities
of TD, the consequence of these on clinical outcome and the
possible treatment options. These abnormalities reflect the
importance of HDL in the pathogenesis of vascular disease.
[Back to top]
Current Strategies for Modulating Lymphangiogenesis
Signalling Pathways in Human Disease
S.A. Stacker, R.A. Hughes, R.A. Williams and M.G. Achen
The recent discovery that members of the vascular endothelial
growth factor (VEGF) family of secreted glycoproteins can
mediate lymphatic vessel growth (lymphangiogenesis) via
cell surface receptor tyrosine kinases expressed on endothelial
cells has opened the way for therapeutic intervention for
pathologies involving dysregulated lymphatic vessel function.
At least two members of this family, VEGF-C and VEGF-D, have
been shown to induce lymphangiogenesis in vivo. Lymphatic
vessels and their specific growth factors have been directly
implicated in a number of significant human pathologies. In
cancer, VEGF-C and VEGF-D appear to correlate with tumor metastasis
and poor patient outcome in a range of prevalent human cancers.
Experimental studies have demonstrated that expression of
the lymphangiogenic growth factors in tumor models induces
increased lymphangiogenesis and results in spread of tumor
cells via the lymphatics. In contrast, conditions
such as lymphedema, where lymphatic vessels fail to clear
fluid from interstitial spaces, are opportunities for which
the application of growth factors to generate new lymphatic
vessels may be a viable therapeutic option. The list of molecules
that control lymphangiogenesis is now expanding, allowing
more opportunities for the development of drugs with which
to manipulate the relevant signalling pathways. Modulating
these pathways and other molecules with specificity to the
lymphatic endothelium could offer alternative treatments for
a number of important clinical conditions.
[Back to top]
Role of Transmembrane Domain/Transmembrane Domain
Interfaces of P-Glycoprotein (ABCB1) in Solute Transport.
Convergent Information from Photoaffinity Labeling, Site Directed
Mutagenesis and in Silico Importance Prediction
Peter Chiba, Ivana Mihalek, Gerhard F. Ecker, Stephan
Kopp and Olivier Lichtarge
Human P-glycoprotein (P-gp, ABCB1) plays an important role
in the development of resistance to anticancer therapy. This
ABC-transporter (ATP-binding cassette transporter) intercepts
drugs at the level of the plasma membrane and effluxes them
before they are able to reach their intracellular target structures.
Inhibition of P-gp by low molecular weight compounds has been
advocated as a concept for resensitization of cells to anticancer
agents and several clinical studies in oncological patients
have advanced to phase III. Even more importantly, P-glycoprotein
also represents an antitarget. Its expression in cells lining
the intestinal tract, the canalicular side of hepatocytes,
renal tubuli and the blood brain barrier lead to interference
with pharmacokinetics of compounds that are recognized as
pump substrates. An early prediction of ADMET (Absorption-Distribution-Metabolism-Excretion-Toxicity)
properties is important during drug development, since interference
of a compound with P-gp might compromise its future development
into a drug. Despite considerable efforts, the mechanism by
which P-gp binds and transports its solutes remains unclear.
Generation of homology models of the protein allowed integration
of data obtained by photoaffinity labeling, in silico
prediction of functional importance by evolutionary tracing
and site directed mutagenesis. An integral view of data indicates
that these three lines of evidence converge to indicate two
pseudosymmetric P-gp drug binding pockets located at the two
transmembrane domain interfaces.
[Back to top]
The Effect of Isoquinoline Alkaloids on Opiate Withdrawal
A. Capasso, S. Piacente, N. De Tommasi, L. Rastrelli and
C.Pizza
Our interest has been centered on isoquinoline alkaloids
obtained from Argemone mexicana (Papaveraceae), Aristolochia
constricta (Aristolochiaceae) and the opium alkaloid,
papaverine. In this respect, the effect of these isoquinoline
alkaloids was investigated on contractions induced by naloxone
of isolated guinea pig ileum acutely exposed to morphine in
vitro. The activity of these alkaloids was compared to
the control compound, papaverine. Furthermore, the effect
of these isoquinoline alkaloids was also determined on naloxone-precipitated
withdrawal in isolated guinea pig ileum exposed to DAMGO (highly
selective mu opioid receptor agonist) and U50-488H (highly
selective kappa opioid receptor agonist) to test whether the
possible interaction of isoquinoline alkaloids on opioid withdrawal
involves mu- and/or kappa-opioid receptors. Isoquinoline alkaloids
from A. mexicana (from 5x10-6 to 1x10-4
M), from A. constricta (1x10-5-5x10-5-1x10-4
M) as well as papaverine treatment (1x10-7-5x10-6-1x10-6
M) before or after the opioid agonists were able of both preventing
and reversing the naloxone-induced contraction after exposure
to mu (morphine and DAMGO) or kappa (U50-488H) opiate receptor
agonists in a concentration-dependent manner. Both acetylcholine
response and electrical stimulation were also reduced by isoquinoline
alkaloids and papaverine treatment as well as the final opiate
withdrawal was still reduced.
The results of the present study indicate that isoquinoline
alkaloids as well as papaverine were able to produce significant
influence on the opiate withdrawal in vitro and these
compounds were able to exert their effects both at mu and
kappa opioid agonists.
[Back to top]
Steroidal Conjugates and Their Pharmacological Applications
Deepak B. Salunke, Braja G. Hazra and Vandana S. Pore
Nature continues to be the main source of inspiration for
synthetic chemists in their quest to make novel conjugates,
which can have different physical, biological and medicinal
properties. Nature makes these conjugates from mixed biosynthesis
and some of these chimeras are found to exhibit unusual biological
properties. During the past two decades design of such entities
has been receiving increasing attention. Among the hybrid
natural products, hybrids of steroid frameworks have attracted
great attention due to the significant biological properties
and numerous therapeutic effects of steroids. The developments
made over the past few years in the isolation, design and
synthesis of steroidal conjugates and their pharmacological
applications are discussed in this review.
|
