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Mini-Reviews
in Medicinal Chemistry
ISSN: 1389-5575
Mini-Reviews in Medicinal
Chemistry
Volume 8, Number 6, June 2008
Contents
Indolo[3,2-b]quinolines: Synthesis, Biological Evaluation
and Structure Activity-Relationships Pp. 538-554
Eyunni V.K. Suresh Kumar, Jagan R. Etukala and
Seth Y. Ablordeppey
[Abstract]
Trans-Plasma Membrane Electron Transport in Human
Blood Platelets Pp. 555-563
L. Avigliano, I. Savini, M.V. Catani and
D. Del Principe
[Abstract]
Aromatase Inhibitors: A New Reality for the Adjuvant
Endocrine Treatment of Early-Stage Breast Cancer in Postmenopausal
Women Pp. 564-574
M. Colozza, R. Califano, E. Minenza, P.
Dinh and E. Azambuja
[Abstract]
Saponins in Tumor Therapy Pp. 575-584
Christopher Bachran, Silke Bachran, Mark Sutherland,
Diana Bachran and Hendrik Fuchs
[Abstract]
A Novel Mercaptopyruvate Sulfurtransferase Thioredoxin
Dependent Redox-Sensing Molecular Switch: A Mechanism for
the Maintenance of Cellular Redox Equilibrium Pp.
585-589
Noriyuki Nagahara
[Abstract]
Activation and Regulation of Toll-like Receptor
9: CpGs and Beyond Pp. 590-600
Jason Kindrachuk, Jean Potter, Heather L. Wilson,
Philip Griebel, Lorne A. Babiuk and Scott Napper
[Abstract]
The Role of Retinoids in the Adult Nervous System
and their Therapeutic Potential Pp. 601-608
V.B. Christie, T.B. Marder, A. Whiting and
S.A. Przyborski
[Abstract]
Statins-Mediated Inhibition of Rho GTPases as
a Potential Tool in Anti-Tumor Therapy Pp. 609-618
Chiara Riganti, Elisabetta Aldieri, Sophie Doublier,
Amalia Bosia and Dario Ghigo
[Abstract]
Endothelial Lipase: A Key Player in HDL Metabolism
Modulates Inflammation and Atherosclerotic Risk Pp.
619-627
Pascual DeSantis, Trey Coleman, Stephan Schiekofer,
Peter P. Nawroth, Paul Schlimmer and Jochen G. Schneider
[Abstract]
Small Molecule Inhibitors of Lck: The Search for
Specificity within a Kinase Family Pp. 628-637
Malcolm A. Meyn III and Thomas E. Smithgall
[Abstract]
Abstracts
[Back to top]
Indolo[3,2-b]quinolines: Synthesis, Biological
Evaluation and Structure Activity-Relationships
Eyunni V.K. Suresh Kumar, Jagan R. Etukala and
Seth Y. Ablordeppey
The tetracyclic indolo[3,2-b]quinoline ring system constitutes
an important structural moiety in natural products exhibiting
numerous biological activities. In particular, indolo [3,
2-b]quinoline, commonly known as linear quindoline is of particular
interest, because of its rigid structure and scope of derivatization.
Although the core linear quindoline skeleton shows little
or no activity in several biological systems, introduction
of a methyl group on the N-5 atom leading to cryptolepine
induces remarkable activity against a broad spectrum of biological
targets. A number of analogs of quindoline and cryptolepine
have been synthesized, incorporating various functional groups
on the core quindoline skeleton leading to improved biological
activities. In this review, we describe various synthetic
methodologies leading to the quindoline scaffold, the biological
activities and the structure activity relationships (SAR)
of quindoline derivatives toward different disease states
to give a better picture of the importance of this moiety
in medicinal chemistry.
[Back to top]
Trans-Plasma Membrane Electron Transport in Human
Blood Platelets
L. Avigliano, I. Savini, M.V. Catani and
D. Del Principe
The plasma membrane redox (PMR) system is important for
cell metabolism and survival; it is also crucial for blood
coagulation and thrombosis. This review will give an update
on the PMR system, with a particular regard to platelets,
and on the role of antioxidant vitamins belonging to this
system.
[Back to top]
Aromatase Inhibitors: A New Reality for the Adjuvant
Endocrine Treatment of Early-Stage Breast Cancer in Postmenopausal
Women
M. Colozza, R. Califano, E. Minenza, P.
Dinh and E. Azambuja
Tamoxifen, a selective estrogen receptor modulator (SERM),
has been used for many decades as the “gold standard”
adjuvant treatment for patients with hormone-receptor-positive
early breast cancer. This drug, when administered for 5 years,
reduces the risk for recurrence, contralateral breast cancer
(BC) and death. The optimal duration of tamoxifen in the adjuvant
setting has not been established yet, but it has been demonstrated
that 5 years are better than shorter treatment while it is
still unclear if a prolongation of the treatment for more
than 5 years is worthwhile.
In the last few years, third generation aromatase inhibitors
(AIs), either steroidal (exemestane) or non-steroidal (anastrozole,
letrozole), have shown to be an effective alternative to tamoxifen
in postmenopausal patients with BC regardless of its stage.
These agents act by blocking the aromatase enzyme which converts
androgens into estrogens.
The goal of this article was to review the results of recent
randomized trials comparing AIs to tamoxifen in postmenopausal
women in the adjuvant setting. Two strategies have been utilized:
a direct upfront comparison in which both tamoxifen and AIs
were given for 5 years or an early switch in which AIs were
administered after 2-3 years of tamoxifen for 3-2 years or
vice versa. Both strategies have shown a superiority of AIs
over tamoxifen and a different safety profile but, the optimal
treatment modality has yet to be defined.
Moreover, in an attempt to further reduce patients’
risk of recurrence after the administration of tamoxifen for
5 years, three trials have evaluated the role of prolonging
the adjuvant treatment with AIs for 5 more years in comparison
to placebo (late switch). A significant improvement of disease-free
survival and of overall survival in the subgroup of nodepositive
patients, at least in one trial, has been observed with AIs.
Despite these important results several unanswered questions
remain and the results of ongoing trials will hopefully clarify
some of them.
[Back to top]
Saponins in Tumor Therapy
Christopher Bachran, Silke Bachran, Mark Sutherland,
Diana Bachran and Hendrik Fuchs
Saponins are plant glycosides with favorable anti-tumorigenic
properties. Several saponins inhibit tumor cell growth by
cell cycle arrest and apoptosis with IC50
values of up to 0.2 μM.
We discuss diverse groups of saponins (dioscins, saikosaponins,
julibrosides, soy saponins, ginseng saponins and avicins)
investigated in relation to tumor therapy and focus on cellular
and systemic mechanisms of tumor cell growth inhibition both
in vitro and in vivo. The review also describes
saponins in combination with conventional tumor treatment
strategies, which result in improved therapeutic success.
Some combinations of saponins and anti-tumorigenic drugs induce
synergistic effects with potentiated growth inhibition.
[Back to top]
A Novel Mercaptopyruvate Sulfurtransferase Thioredoxin
Dependent Redox-Sensing Molecular Switch: A Mechanism for
the Maintenance of Cellular Redox Equilibrium
Noriyuki Nagahara
An intermolecular disulfide bond serves as a thioredoxin-dependent
redox-sensing switch for the regulation of the enzymatic activity
of 3-mercaptopyruvate sulfurtransferase (MST, EC.2.8.1.2).
A cysteine residue on the surface of each subunit was oxidized
to form an intersubunit disulfide bond so as to decrease MST
activity, and thioredoxin-specific conversion of a dimer to
a monomer increased MST activity. Further, a low redox potential
sulfenate was reversibly formed at a catalytic site cysteine
so as to inhibit MST, and thioredoxin-dependent reduction
of the sulfenate restored the MST activity. Concludingly,
MST partly contributes to the maintenance of cellular redox
homeostasis via exerting control over cysteine catabolism.
[Back to top]
Activation and Regulation of Toll-like Receptor 9:
CpGs and Beyond
Jason Kindrachuk, Jean Potter, Heather L. Wilson,
Philip Griebel, Lorne A. Babiuk and Scott Napper
Toll-like receptor 9 has been the focus of considerable
research attention for the ability to modulate its activity,
and subsequent innate immune responses, through DNA-based
immunotherapeutics. Nucleic acids are attractive as therapeutics
for their low cost, chemical stability and ease of production.
While the ability for TLR9 to be differentially regulated
by nucleic acids of varying sequences and structures offers
flexibility for immunotherapeutic design, it also necessitates
a more comprehensive characterization of these agonists in
terms of how these structural parameters correlate with the
activation of unique cellular responses. Despite the utilization
of TLR9 agonists in human trials these issues have not been
adequately addressed. While a wealth of cell stimulation experiments
demonstrate the preferential ability for nucleic acids which
contain unmethylated cytosine-phosphate-guanine (CpG) motifs
to initiate innate immune responses this has not been supported
by binding investigations from which largely contradictory
information has emerged with respect to the ability of TLR9
to bind nucleic acids in a sequence-dependent fashion. Recent
models help to reconcile this apparent contradiction by suggesting
that while TLR9 activation is specific for CpG-containing
nucleic acids, the receptor binds, and is functionally influenced
by, nucleic acids in a sequence-independent fashion. We have
proposed a model in which the absolute concentration of nucleic
acids modulates the sensitivity of the receptor in a sequence-dependent
fashion while activation is specifically achieved by CpG-containing
ligands. In this review we reconsider the literature from
the perspective of this new appreciation of the functional
complexity of TLR9 ligand binding and higher-order regulation
with discussion of the implications for immunotherapeutic
targeting of TLR9.
[Back to top]
The Role of Retinoids in the Adult Nervous System
and their Therapeutic Potential
V.B. Christie, T.B. Marder, A. Whiting and
S.A. Przyborski
The mode of action of retinoids in relation to their
activity in the adult central nervous system and the potential
of synthetic retinoid analogues is reviewed. Investigation
into the activity of such molecules will further our understanding
of the retinoid pathway during nervous system development
and in various neurological disease states.
[Back to top]
Statins-Mediated Inhibition of Rho GTPases as a Potential
Tool in Anti-Tumor Therapy
Chiara Riganti, Elisabetta Aldieri, Sophie Doublier,
Amalia Bosia and Dario Ghigo
Rho GTPases, which control processes such as cell proliferation
and cytoskeleton remodeling, are often hyperexpressed in tumors.
Several members, such as RhoA/B/C, must be isoprenylated to
interact with their effectors. Statins, by inhibiting the
synthesis of prenyl groups, may affect RhoA/B/C activity and
represent a promising tool in anticancer therapy.
[Back to top]
Endothelial Lipase: A Key Player in HDL Metabolism
Modulates Inflammation and Atherosclerotic Risk
Pascual DeSantis, Trey Coleman, Stephan Schiekofer,
Peter P. Nawroth, Paul Schlimmer and Jochen G. Schneider
Endothelial Lipase (EL) is a newly identified member
of the triacylglycerol lipase family. Recent studies suggested
that EL may be an important determinant of HDL-metabolism
and inflammation acting at the level of the vessel wall. The
aim of this review is to summarize important facts derived
from experimental approaches and from epidemiologic human
studies to provide a comprehensive view on the role of EL
in inflammation and atherogenesis as well as target for potential
pharmaceutical interventions.
[Back to top]
Small Molecule Inhibitors of Lck: The Search for Specificity
within a Kinase Family
Malcolm A. Meyn III and Thomas E. Smithgall
The Src family of non-transmembrane protein kinases is
comprised of eleven homologous members in mammals. Together,
these kinases regulate a wide variety of cellular processes
including cell survival, proliferation, differentiation, and
motility. One member of this family, Lck, plays a pivotal
role in T-cell signaling. Inhibition of Lck with small molecules
has significant potential for therapeutic immunosuppression
and treatment of diseases such as rheumatoid arthritis and
asthma. Critical for successful clinical use of any Lck inhibitor
is high specificity for Lck as inhibition of other members
of the Src kinase family may result in unwanted side effects.
In this review we provide an overview of the various synthetic
compounds currently under investigation as Lck-specific inhibitors.
In addition we provide an analysis of the properties of these
compounds that account for the specificity required for the
inhibition of one of eleven highly similar kinases.
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