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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 13, Number 12, 2006
Contents
Lipid Bilayer Fragments and Disks in Drug Delivery Pp.
1359-1370
Ana Maria Carmona-Ribeiro
[Abstract]
Protein Transduction: Cell Penetrating Peptides and Their
Therapeutic Applications Pp. 1371-1387
Kylie M. Wagstaff and David A. Jans
[Abstract]
Intervention of Toll-like Receptor-Mediated Human Innate
Immunity and Inflammation by Synthetic Compounds and Naturally
Occurring Products Pp. 1389-1395
Stephen Fasciano and Liwu Li
[Abstract]
Premature Ovarian Failure (POF) Syndrome: Towards the Molecular
Clinical Analysis of its Genetic Complexity Pp.
1397-1410
W. Fassnacht, A. Mempel, T. Strowitzki and P.H.
Vogt
[Abstract]
Synthesis, Biological Evaluation and 3D-QSAR of 1,3,5
Trisubstituted-4,5-Dihydro-(1H)-Pyrazole Derivatives
as Potent and Highly Selective Monoamine Oxidase A Inhibitors
Pp. 1411-1428
Franco Chimenti, Adriana Bolasco, Fedele Manna, Daniela Secci,
Paola Chimenti, Arianna Granese, Olivia Befani, Paola Turini,
Roberto Cirilli , Francesco La Torre, Stefano Alcaro, Francesco
Ortuso and Thierry Langer
[Abstract]
Antiobesity Therapy: Emerging Drugs and Targets Pp.
1429-1460
Saibal Kumar Das and Ranjan Chakrabarti
[Abstract]
Advance in Antitumor Agents Targeting Glutathione-S
Transferase Pp. 1461-1471
Guisen Zhao and Xiaobing Wang
[Abstract]
Intrabody-Based Approaches to Cancer Therapy: Status
and Prospects Pp. 1473-1480
Brent R. Williams and Zhenping Zhu
[Abstract]
Abstracts
[Back to top]
Lipid Bilayer Fragments and Disks in Drug Delivery
Ana Maria Carmona-Ribeiro
Certain lipids can be dispersed as colloidally stable
bilayer fragments (BF) or disks with interesting properties
for solubilization and delivery of hydrophobic or amphiphilic
drugs. They were first observed and characterized as such
in the nineties but remained silent in the literature regarding
applications for drug delivery. Only recently their potential
for delivery of hydrophobic drugs started to be realized.
This review deals with electrostatically or sterically stabilized
bilayer fragments which provided excellent solubilization
sites for antifungal drugs, acted as drugs themselves against
bacteria or fungus, could be loaded with amphiphilic drugs
or produced lipid-covered drug particles to be delivered as
a synergistic formulation in vivo.
[Back to top]
Protein Transduction: Cell Penetrating Peptides and
Their Therapeutic Applications
Kylie M. Wagstaff and David A. Jans
Cell penetrating proteins or peptides (CPPs) have
the ability to cross the plasma membranes of mammalian cells
in an apparently energy- and receptor-independent fashion.
Although there is much debate over the mechanism by which
this “protein transduction” occurs, the ability
of CPPs to translocate rapidly into cells is being exploited
to deliver a broad range of therapeutics including proteins,
DNA, antibodies, oligonucleotides, imaging agents and liposomes
in a variety of situations and biological systems. The current
review looks at the delivery of many such molecules by various
CPPs, and their potential therapeutic application in a wide
range of areas. CPP ability to deliver different cargoes in
a relatively efficient and non-invasive manner has implications
as far reaching as drug delivery, gene transfer, DNA vaccination
and beyond. Although many questions remain to be answered
and limitations on the use of CPPs exist, it is clear that
this emerging technology has much to offer in a clinical setting.
[Back to top]
Intervention of Toll-like Receptor-Mediated
Human Innate Immunity and Inflammation by Synthetic Compounds
and Naturally Occurring Products
Stephen Fasciano and Liwu Li
Human innate immunity plays a pivotal role in host
defense against various microbial challenges. Mediated by
a family of Toll-like-receptors (TLR) and associated intracellular
downstream signaling molecules, human innate immunity can
specifically recognize diverse microbial products and many
other non-microbial environmental cues. Beyond its role of
providing first line of defense, activation of innate immunity
signaling can lead to expression of diverse pro- and anti-
inflammatory mediators, which are critical for regulating
various cell and tissue metabolism. Alteration in innate immunity
signaling may therefore lead to infection and inflammatory
diseases such as atherosclerosis, diabetes, and cancer. TLR
receptors as well as intracellular signaling proteins can
serve as therapeutic targets for treating various inflammatory
diseases. Several synthetic ligands of TLR receptors such
as lipid A analogs, poly(I:C), loxoribine, oligodeoxynucleotides
have been shown to be effective in regulating innate immune
response. This review discusses the potential, challenge,
and recent progress of developing synthetic as well as naturally
occurring TLR ligands in regulating innate immunity and treating
inflammatory diseases.
[Back to top]
Premature Ovarian Failure (POF) Syndrome: Towards
the Molecular Clinical Analysis of its Genetic Complexity
W. Fassnacht, A. Mempel, T. Strowitzki and P.H.
Vogt
The Premature Ovarian Failure (POF) syndrome is a very heterogeneous
clinical disorder due probably to the complex genetic networks
controlling human folliculogenesis. Clinical subgroups of
POF patients whose aetiology of ovarian failure is based on
the same genetic factors are therefore difficult to establish.
Some experimental evidence suggests that these genes might
be clustered on the female sex chromosome in the POF1
and POF2 loci. This review is aimed to present an
overview of the actual structural changes of the X chromosome
causing POF, and to present a number of X and autosomal female
fertility genes which are probably key genes in human folliculogenesis
and are therefore prominent POF candidate genes. Towards the
molecular analysis of their functional contribution to the
genetic aetiology of POF in the clinic, an interdisciplinary
scheme for their diagnostic analysis is presented in a pilot
study focussed on chromosome analyses and the expression analysis
of some major POF candidate genes (DAZL, DBX, FOXL2, INHα,
GDF9, USP9X) in the leukocytes of 101 POF patients. It
starts with a comprehensive and significantly improved clinical
diagnostic program for this large and heterogenous patient
group.
[Back to top]
Synthesis, Biological Evaluation and 3D-QSAR of 1,3,5
Trisubstituted-4,5-Dihydro-(1H)-Pyrazole Derivatives
as Potent and Highly Selective Monoamine Oxidase A Inhibitors
Franco Chimenti, Adriana Bolasco, Fedele Manna, Daniela
Secci, Paola Chimenti, Arianna Granese, Olivia Befani, Paola
Turini, Roberto Cirilli , Francesco La Torre, Stefano Alcaro,
Francesco Ortuso and Thierry Langer
The present report provides a extended study of the chemistry,
the inhibitory activity against monoamino oxidases (MAO),
and molecular modeling including the 3D-QSAR hypothesis of
1,3,5-trisubstituted-4,5-dihydro-(1H)-pyrazole derivatives.
Four series of about eighty novel pyrazoline derivatives were
prepared and investigated for their ability to inhibit the
activity of the A and B isoforms of MAO selectively. Most
of the new synthesized compounds proved more reversible, potent,
and selective inhibitors of MAO-A than of MAO-B, and could
be taken into account to develop the search further in this
field, knowing that reversible and selective MAO-A inhibitors
are used as antidepressant and antianxiety drug. The 30 most
active compounds show inhibitory activity on MAO-A in the
8.6 x 10-8- 9.0 x 10-9M range. Moreover,
it should be pointed out that for most of them a high IC50
≥ 10-9M value is associated with a high A-selectivity
(Selectivity Index MAO-B/MAO-A in the 10,000 - 16,250 range).
Furthermore, due to the presence of a chiral centre at the
C5 position of the pyrazole moiety, we performed the semi-preparative
chromatographic enantioseparation of the most potent, selective,
and chiral compounds.
The separated enantiomers were then submitted to in vitro
biological evaluation, and from the results of these experiments
it has been possible to point out a difference in inhibiting
the two isoforms selectively between the racemic mixture and
the single enantiomers.
The molecular modeling work was carried out combining the
Glide docking approach with CoMFA with the aim to rationalize
the structure-activity relationships of each pyrazoline inhibitor
toward MAO-A and MAO-B isoforms and to derive a suitable selectivity
model.
[Back to top]
Antiobesity Therapy: Emerging Drugs and Targets
Saibal Kumar Das and Ranjan Chakrabarti
Obesity and its associated morbidities and mortalities are
the effects of imbalance between energy intake and expenditure.
The healthcare burden for the treatment of obesity is significantly
high, due to increased risk of secondary chronic diseases
such as hypertension and associated co-morbidities such as
diabetes and cardiovascular disease. Lack of physical activity,
high fat diets and sedentary life styles are major factors
contributing to obesity. However, genetic predisposition and
ethnicity are increasingly found to cause obesity. Till date,
approved therapeutics have addressed excess energy intake
by acting on central neural circuits that regulate feeding
or on peripheral mechanisms to reduce nutrient absorption
from the gut. These approaches have met with moderate success;
and recently with safety concerns, leaving an unmet medical
need for effective and safe pharmacotherapy for obesity thereby
posing a significant challenge to pharmaceutical industry.
Potential antiobesity drugs, which are being investigated
by different companies, can be classified in 4 broad categories:
1) Agents that primarily decrease appetite through central
action; 2) Agents that primarily increase metabolic rate or
affect metabolism through peripheral action; 3) Agents that
act on gastrointestinal tract; and 4) Agents that not only
affect obesity but also overall Metabolic Syndrome. The current
review will deal mainly with different molecules, which are
under development for the above-mentioned targets and also
their potential benefits and disadvantages.
[Back to top]
Advance in Antitumor Agents Targeting Glutathione-S
Transferase
Guisen Zhao and Xiaobing Wang
Glutathione-S-transferases (GSTs; EC 2.5.1.18),
a family of phase II detoxification enzymes, catalyze the
conjugation of glutathione with broad substrates including
chemotherapeutic agents, and are involved in cell protection
against apoptotic signals by inhibiting the stress-signaling
cascade mediated by ASK1 (Apoptosis signal-regulating kinase)-JNK
(c-Jun N-terminal kinase). As GSTs are overexpressed in some
malignant tumors, GSTs is a promising therapeutic target.
This article reviews the progress in the development of GSTs
inhibitors and GSTs activated prodrugs.
[Back to top]
Intrabody-Based Approaches to Cancer Therapy: Status
and Prospects
Brent R. Williams and Zhenping Zhu
Continuing developments from the study of cancer at the molecular
level are yielding increasing numbers of targets that may
be used for therapeutic intervention. Advances in the field
of antibody engineering over the past several decades have
given scientists the capability of directing the highly specific
interaction of antibodies with antigens inward, to the intracellular
compartments of living cells. These intracellular antibodies,
i.e., intrabodies, are being developed to bind to, neutralize,
or modify the function or localization of cancer-related targets
and thereby affect the malignant phenotype. This has resulted
in a promising new tool for the study and treatment of cancer.
Due to recent advances in the development of the antibody
engineering technologies, increasing numbers of intrabodies
are being exploited to a growing list of cancer-related, as
well as other disease targets. There are still, however, many
technical issues, particularly related to clinical applications
of the intrabodies, that must be addressed before the full
promise of this class of therapeutic agent is realized. This
review will focus on the recent progress in the generation
and use of intrabodies in the field of oncology. The technical
issues associated with their further development will also
be discussed.
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