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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 13, Number 11, 2006
Contents
(Q)SAR Studies to Design New Human Choline Kinase Inhibitors
as Antiproliferative Drugs Pp. 1231-1248
J.M. Campos, R.M. Sánchez-Martín,
A. Conejo-García,A. Entrena, M.A. Gallo and A. Espinosa
[Abstract]
Human Umbilical Cord Blood Biology, Transplantation and Plasticity
Pp. 1249-1259
Gal Goldstein, Amos Toren and Arnon Nagler
[Abstract]
Recent Advances in Small Molecule Antagonists of the
Corticotropin-Releasing Factor Type-1 Receptor-Focus on Pharmacology
and Pharmacokinetics Pp. 1261-1282
C. Chen
[Abstract]
Receptor-Ligand Binding Sites and Virtual Screening Pp.
1283-1304
Channa K. Hattotuwagama, Matthew N. Davies and Darren R. Flower
[Abstract]
Inhibitors of HIV-1 Tat-Mediated Transactivation Pp.
1305-1315
S.N. Richter and G. Palù
[Abstract]
Nuclear Translocation During the Cross-Talk Between
Cellular Stress, Cell Cycle and Anticancer Agents
Pp. 1317-1320
E. Tiligada
[Abstract]
Current Advances in Antifungal Targets and Drug Development
Pp. 1321-1335
Sandeep Sundriyal, Rohit K. Sharma and Rahul Jain
[Abstract]
Platinum Group Antitumor Chemistry: Design and Development
of New Anticancer Drugs Complementary to Cisplatin Pp.
1337-1357
Adnan Salim Abu–Surrah and Mika Kettunen
[Abstract]
Abstracts
[Back to top]
(Q)SAR Studies to Design New Human
Choline Kinase Inhibitors as Antiproliferative Drugs
J.M. Campos, R.M. Sánchez-Martín,
A. Conejo-García,A. Entrena, M.A. Gallo and A. Espinosa
Most of the signal transduction pathways are mediated
by protein kinases regulating every aspect of cell function.
Mutations which deregulate their expression or their function
or both result in cancers. Therefore, protein kinase inhibitors
have become the focus of development of new therapies for
cancer. A comprehensive review of Choline kinase (ChoK) was
published by us in 2003. Since then, molecular information
of ChoK inhibitors has been accumulated. In this review, we
intend to summarize the new lines of evidence that will include
the design of the most active antiproliferative agents so
far described against ChoK. Studies have been aimed at the
establishment of structure-activity relationships and the
structural parameters that define ChoK inhibitory and antiproliferative
activities of a set of twenty-five acyclic biscationic pyridophane
and forty acyclic biscationic quinolinephane compounds. The
corresponding QSAR equation was obtained for the whole set
of bisquinolinium compounds for the antiproliferative activity,
taking into consideration the electronic parameter σR
of R4,
the molar refractivity (MR) of R8,
and the lipophilic parameters clog P and πlinker.
The most potent antiproliferative agent shows an IC50
= 0.45 μM,
predicted by the QSAR equation, whilst its experimental value
is IC50=
0.20 μM.
Finally, toxicity assays were performed for the most promising
compounds because of their interesting antiproliferative activities
[IC50
HT-29
= 0.70, 0.80, 1.50 and 1.90 μM]
and low toxicity [LD50
= 16.7, 12.5, > 25 and > 20 mg/kg of mouse]. These biological
activities justify further analysis for antitumoral assays
under in vivo conditions.
[Back to top]
Human Umbilical Cord Blood Biology, Transplantation
and Plasticity
Gal Goldstein, Amos Toren and Arnon Nagler
As the significance of hematopoietic stem cell transplantation
(HSCT) is constantly rising, the scarcity of matched donors
is proving to be a troubling issue. Cord blood (CB) is an
important source of stem cells (SC) for transplantation. It
has been used in the last two decades for approximately 4500
transplantations. Its collection, cryopreservation, banking
and thawing techniques pose unique challenges to clinicians
and researchers CB has abundant stem cell with impressive
proliferative capacity. On the other hand, CB's immunological
system has a naïve and more tolerant nature. Except for
the biological aspects, few ethical issues have become a concern
for transplantation teams who use CB. There are few advantages
of CB over bone marrow, especially the lower rates of acute
and chronic graft-versus-host disease (GVHD) after transplantation.
On the other hand, there are relatively high rates of early
treatment related mortality in cord blood transplantation
(CBT). This is related to the small nucleated cell (NC) dose
infused from each CB unit. The clinical experience in CBT,
especially in children, is encouraging. When using adequate
number of NC/kg, results in CBT for malignant and non-malignant
diseases are comparable to bone marrow transplantation (BMT).
In this article, a comprehensive review of the largest scale
studies is presented. There is a continuous search for an
optimal way to deal with delayed engraftment of CB and its
implication. The current investigational, and also first clinical
trials using diverse methods to overcome high rates of TRM
are reviewed. Almost twenty years after the first CBT was
preformed, many advocate for a routine parallel search, BM
and CB, for unrelated donor. Future uses of CB might also
be in the field of gene transfer and non hematopietic injured
tissues repair.
[Back to top]
Recent Advances in Small Molecule Antagonists
of the Corticotropin-Releasing Factor Type-1 Receptor-Focus
on Pharmacology and Pharmacokinetics
C. Chen
Corticotropin-releasing factor (CRF), a 41-amino
acid peptide, has been recognized as an important factor mediating
stress. Efforts to discover small molecule antagonists of
the CRF type-1 receptor (CRF1-R)
for potentially novel treatment of anxiety and depression
started in the early 1990’s. Although highly potent
in vitro and efficacious in animal models,
early reported compounds such as CP-154,526 and NBI-27914
are highly lipophilic and possess high plasma protein and
tissue binding, long elimination half life, and toxicity,
likely due in part to accumulation in tissues. Recently, several
laboratories have reported potent CRF1-R
antagonists with improved physicochemical properties. Compounds
such as DMP696, NBI-30775/R121919 and R278995/CRA0450 possess
at least one additional polar group in their structures and
are therefore less lipophilic than the earlier compounds,
while still maintaining high potency. For example, DMP696
has a Ki
value of 1.7 nM and a cLogP of 3.2, which is similar to CP-154,526
in potency but about 4-log units lower in partition coefficient.
Despite its high plasma protein binding (98.5% in rat), DMP696
occupies over 50% of brain CRF1-R
at a total plasma concentration above 100 nM, which is consistent
with the doses that produce anxiolytic effects in the rat
defense withdrawal test of anxiety. This article will review
small molecule CRF1-R
antagonists by focusing on their pharmacological and pharmacokinetic
properties. In addition, the pharmacology of small molecules
binding to the CRF1
receptor will be discussed. An orally available compound with
desirable properties in these categories will have a good
chance to be developed into a novel treatment for anxiety
and depression which may be devoid of the side effects of
existing antidepressant treatments.
[Back to top]
Receptor-Ligand Binding Sites and Virtual Screening
Channa K. Hattotuwagama, Matthew N. Davies and Darren R. Flower
Within the pharmaceutical industry, the ultimate source of
continuing profitability is the unremitting process of drug
discovery. To be profitable, drugs must be marketable: legally
novel, safe and relatively free of side effects, efficacious,
and ideally inexpensive to produce. While drug discovery was
once typified by a haphazard and empirical process, it is
now increasingly driven by both knowledge of the receptor-mediated
basis of disease and how drug molecules interact with receptors
and the wider physiome. Medicinal chemistry postulates that
to understand a congeneric ligand series, or set thereof,
is to understand the nature and requirements of a ligand binding
site. Likewise, structural molecular biology posits that to
understand a binding site is to understand the nature of ligands
bound therein. Reality sits somewhere between these extremes,
yet subsumes them both. Complementary to rules of ligand design,
arising through decades of medicinal chemistry, structural
biology and computational chemistry are able to elucidate
the nature of binding site-ligand interactions, facilitating,
at both pragmatic and conceptual levels, the drug discovery
process.
[Back to top]
Inhibitors of HIV-1 Tat-Mediated Transactivation
S.N. Richter and G. Palù
The transactivation responsive (TAR) RNA is the 5'-leader
sequence of the HIV-1 mRNA genome and interacts with the Tat
protein during transcription. Tat and the positive transcription
elongation factor (P-TEFb) complex bind to TAR to promote
efficient transcription of the full-length HIV genome. In
the absence of the TAR  Tat
P-TEFb interaction,
viral transcription is inefficient, which makes this RNA-protein
complex an important target for therapeutic intervention of
HIV replication. Inhibitors of HIV-1 transactivation mainly
target: 1) TAR RNA, 2) Tat protein and 3) Tat
P-TEFb complex. 1) Compounds against TAR RNA are the most
numerous: besides cationic peptides, which were initially
developed, recent advances in TAR binding inhibitors include
oligonucleotide based-agents and small molecules. Specific
research efforts are currently underway to increase cellular
uptake. 2) By targeting the Tat protein, both transactivation
and other Tat-mediated intra/extracellular functions are affected.
Various biopolymeric drugs are reported to effectively inhibit
Tat activity. In addition, Tat-targeted antibodies have recently
been developed. 3) Intracellular proteins have been discovered
to disrupt Tat
P-TEFb interaction, raising the chance of inhibiting HIV-1
transcription via novel mechanisms.
[Back to top]
Nuclear Translocation During the Cross-Talk Between
Cellular Stress, Cell Cycle and Anticancer Agents
E. Tiligada
The function of many endogenous molecules in all eukaryotic
cells depends on their subcellular localisation, being active
when localized in one cellular compartment and inactive in
another. Translocation or re-localization of mislocalized
components in the optimal subcellular site may contribute
to the development of novel cancer therapies and to the re-evaluation
of conventional treatment. For instance, various agents are
able to entrap cytoplasmic anti-apoptotic pathways to the
nucleus, thus activating apoptosis. Moreover, amongst the
factors identified so far, the optimal location of the tumor
suppressor p53 for promoting cell arrest and apoptosis seems
to be the nucleus, while the nuclear factor kappa B (NFκB)
is desirable to stay in the cytoplasm. Thus, the mechanisms
of nuclear translocation of endogenous signaling components,
like p53, NFκB
and various heat shock proteins (HSPs), may serve as targets
for pharmacological intervention, without excluding the possible
role of uptake and active transport into the nucleus of extracellular
proteins.
[Back to top]
Current Advances in Antifungal Targets and Drug Development
Sandeep Sundriyal, Rohit K. Sharma and Rahul Jain
Fungi are one of the most neglected pathogens apparent from
the fact that the Amphotericin B, a polyene antibiotic, discovered
way back in 1956 is still used as a ‘gold standard’
for antifungal therapy. Past two decades have witnessed a
dramatic rise in the incidences of life threatening systemic
fungal infections. This can be ascribed to the increase in
the number of immuno-compromised patients due to rise in HIV
infected population, cancer chemotherapy and indiscriminate
use of antibiotics. Majority of clinically used antifungals
suffer from various drawbacks in terms of toxicity, efficacy
and cost, and their frequent use has led to the emergence
of resistant strains. Hence, there is a great demand for novel
antifungals belonging to wide range of structural classes,
selectively acting on novel targets with fewer side effects.
This article aims at reviewing recent efforts made towards
discovering novel antifungal drug targets and investigational
molecules acting on them.
[Back to top]
Platinum Group Antitumor Chemistry: Design and Development
of New Anticancer Drugs Complementary to Cisplatin
Adnan Salim Abu–Surrah and Mika Kettunen
In the next two decades, the world is expected to see around
20 million cases of cancer. Moreover, the types of cancer
will vary considerably from country to other. Therefore, all
efforts will be needed to face such a vast diversity of problems.
With current annual sales of about $500 millions, the platinum(II)
complex known as cisplatin [cis-(NH3)2PtCl2]
is still one of the most effective drugs to treat testicular,
ovarian, bladder and neck cancers. Since it was launched in
1978 there has been a rapid expansion in research to find
new, more effective metal-based anticancer drugs and to study
their interactions with biological systems.
This study gives an up to date overview of the anticancer
chemistry of the platinum group elements platinum, palladium,
and nickel with an emphasis on the new strategies used in
the development of new antitumor agents. Methodologies for
application of bulky aromatic or aliphatic nitrogen ligands,
chiral organic moieties, chelates containing other donor atoms
than nitrogen, and biologically active ligands in the design
of agents analogous to cisplatin are presented. The review
also aims to highlight the class of the unconventional complexes
that violate the empirical structure-activity rules (SAR)
of platinum compounds and the common features and structural
differences between the most successful anticancer complexes
that are currently in human clinical trials.
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