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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 15, Number 11, 2008
Contents
Comprehensive Review of Cancer Chemopreventive Agents
Evaluated in Experimental Carcinogenesis Models and Clinical
Trials Pp. 1044-1071
Rajesh Naithani, Loredana C. Huma, Robert M.
Moriarty, David L. McCormick and Rajendra G. Mehta
[Abstract]
Cytotoxic Nucleoside Analogues: Different Strategies
to Improve their Clinical Efficacy Pp. 1072-1082
C.M. Galmarini, F. Popowycz and B. Joseph
[Abstract]
The Current Status of the NNRTI Family of Antiretrovirals
Used in the HAART Regime Against HIV Infection Pp.
1083-1095
Sílvia Martins, Maria João Ramos
and Pedro Alexandrino Fernandes
[Abstract]
Algal Lectins for Potential Prevention of HIV
Transmission Pp.1096-1104
Yuqin Li, Xuewu Zhang, Gu Chen, Dong Wei and Feng
Chen
[Abstract]
Role of the Innate Immune System in Autoimmune
Inflammatory Demyelination Pp. 1105-1115
Kate O’Brien, Denise C. Fitzgerald, Karmeswaree
Naiken, Kishore R. Alugupalli, A.M. Rostami and Bruno
Gran
[Abstract]
Bacterial Protein Toxins: Current and Potential
Clinical Use Pp. 1116-1125
A. Fabbri, S. Travaglione, L. Falzano and C. Fiorentini
[Abstract]
BK Channel Modulators: A Comprehensive Overview
Pp. 1126-1146
Antonio Nardi and Søren-Peter Olesen
[Abstract]
Abstracts
[Back to top]
Comprehensive Review of Cancer Chemopreventive Agents Evaluated
in Experimental Carcinogenesis Models and Clinical Trials
Rajesh Naithani, Loredana C. Huma, Robert M.
Moriarty, David L. McCormick and Rajendra G. Mehta
Cancer chemoprevention refers to the use of pharmacological
agents to inhibit, delay or reverse the multi-step process
of carcinogenesis. The last two decades in particular have
witnessed explosive growth in this emerging field of cancer
chemoprevention. Extensive efforts to evaluate possible application
of various chemopreventive agents, in individuals at high
risk of neoplastic development have been carried out. Epidemiological
studies suggest a protective role of several agents in reducing
the risk of cancer. The protective action of all these agents
is explained as a combination of various proposed mechanisms
involving anti-oxidant, anti-inflammatory, immunomodulatory
action, apoptosis induction, molecular association with carcinogen,
cell cycle arrest, cell differentiation induction, antimicrobial
effect, and anti- angiogenesis etc. Large numbers of candidate
substances such as phytochemicals and their synthetic derivatives
have been identified by a combination of in vitro
and in vivo studies in a wide range of biological
assays. However, a comprehensive description of these chemopreventive
agents has not been extensively reviewed. In this review we
discuss cancer chemopreventive agents in relation to their
source, efficacy in cancer chemopreventive action in vivo
and epidemiological data. The experimental carcinogenesis
studies in different biological models, in addition to the
contribution from our laboratory are summarized.
[Back to top]
Cytotoxic Nucleoside Analogues: Different Strategies
to Improve their Clinical Efficacy
C.M. Galmarini, F. Popowycz and B. Joseph
Cytotoxic nucleoside analogues are clinically important anticancer
drugs. These agents behave as antimetabolites, compete with
physiologic nucleosides, and, consequently, interact with
a large number of intracellular targets to induce cytotoxicity.
Nucleoside analogues share some general common characteristics,
namely in terms of requiring transport by specific membrane
transporters and intracellular metabolism. However these compounds
differ in regard to the preferential interaction with certain
targets which may explain why some compounds are more effective
against rapidly proliferating tumours and others on neoplasia
with a more protracted evolution. Purine and pyrimidine analogues
are widely used not only as antileukaemic agents, but also
as cytotoxic agents to treat solid tumours. However, the clinical
use of these compounds is limited by important side-effects
and primary or acquired drug resistance. Thus, there is an
unmet medical need for the development of new antimetabolites
and for technologies allowing a more suitable and effective
administration of nucleoside analogues for the treatment of
cancer patients. Here, we will review literature data concerning
the recent development of novel purine nucleoside analogues
(clofarabine, nelarabine and forodesine) and pyrimidine nucleoside
analogues (troxacitabine, sapacitabine, CP-4055, 3’-C-ethynylcytidine
and 5 azapyrimidines) that are in evaluation at the clinical
level.
[Back to top]
The Current Status of the NNRTI Family of Antiretrovirals
Used in the HAART Regime Against HIV Infection
Sílvia Martins, Maria João Ramos
and Pedro Alexandrino Fernandes
Acquired immunodeficiency syndrome (AIDS) remains, after 25
years of its discovery, as one of the major threats to human
life. Reverse Transcriptase is an essential enzyme for virus
replication, and therefore constitutes a major target in HIV-1
therapy.
Among the different types of drugs targeting RT, the nonnucleoside
reverse transcriptase inhibitors (NNRTIs) act by binding in
an induced-fit allosteric pocket. In this review, we explore
the several NNRTIs’ structures and binding interactions,
as well as their mechanisms of action. The conformational
changes that they cause in RT and their effects on the topology
of the active site are discussed.
The emergence of mutant, resistant viruses is analysed, focussing
on the mutations responsible for the loss of antiviral efficacy
of NNRTIs. Explanations for the role of those mutations are
presented. Emergent drugs in the pipeline, together with the
underlying strategies for drug development, are also analysed.
[Back to top]
Algal Lectins for Potential Prevention of HIV Transmission
Yuqin Li, Xuewu Zhang, Gu Chen, Dong Wei and Feng
Chen
A number of lectins that bind high-mannose carbohydrates on
the surface of the envelopes of virus has been found to have
antiviral activity. In particular, some algal lectins such
as Cyanovirin-N, Microcystis viridis lectin, Scytovirin,
Griffithsin and Oscillatoria agardhii agglutinin,
exhibit high anti-HIV activity, and provide an alternative
route to prevention of HIV transmission. This review focuses
on the structural property, antiviral activity and possible
mechanism of these lectins, and future challenges for potential
prophylactic or therapeutic applications are also discussed.
[Back to top]
Role of the Innate Immune System in Autoimmune Inflammatory
Demyelination
Kate O’Brien, Denise C. Fitzgerald, Karmeswaree
Naiken, Kishore R. Alugupalli, A.M. Rostami and Bruno
Gran
Considerable research has been devoted to the role of the
adaptive immune system in the pathogenesis of autoimmune inflammatory
demyelination (AID). AID is thought to occur spontaneously
in patients with multiple sclerosis (MS), a common cause of
neurological disability. AID is also observed in the best
characterized animal model of MS, experimental autoimmune
encephalomyelitis (EAE). The adaptive immune system recognizes
and responds to antigens via highly specific T-cell
receptors. Myelin-reactive T-cells may initiate pathological
immune responses that lead to central nervous system damage
in MS and EAE. By contrast, the innate immune system recognizes
evolutionarily conserved structures that are common to invading
pathogens with high efficiency for rapid recognition and elimination
of viruses, bacteria, and fungi. This recognition is mediated
by pattern-recognition receptors such as Toll-like receptors
(TLRs) expressed on cells of the innate immune system (dendritic
cells and CNS-resident cells, such as microglia) that have
the potential to activate autoimmune responses by inducing
the production of inflammatory cytokines and chemokines. Conversely,
the innate immune system can also regulate autoimmune inflammation
by inducing the production of immunoregulatory molecules such
as type I interferons, which are currently used in the treatment
of MS. We review the evidence that TLRs can exacerbate or
regulate AID and discuss the therapeutic potential of targeting
either process.
[Back to top]
Bacterial Protein Toxins: Current and Potential Clinical
Use
A. Fabbri, S. Travaglione, L. Falzano and C. Fiorentini
Natural toxins are the product of a long-term evolution, and
act on essential mechanisms in the most crucial and vital
processes of living organisms. They can attack components
of the protein synthesis machinery, actin polymerization,
signal transduction pathways, intracellular trafficking of
vesicles as well as immune and inflammatory responses. For
this reason, toxins have increasingly being used as valuable
tools for analysis of cellular physiology, and in the recent
years, some of them are used medicinally for the treatment
of human diseases.
This review is devoted to protein toxins of bacterial origin,
specifically those toxins that are currently used in therapy
or those under study for their potential clinical applications.
Bacterial protein toxins are all characterized by a specific
mechanism of action that involves the central molecular pathways
in the eukaryotic cell. Knowledge of their properties could
be used for medical purposes.
[Back to top]
BK Channel Modulators: A Comprehensive Overview
Antonio Nardi and Søren-Peter Olesen
The large Ca2+-activated
K+ channel (BK channel) reflects
per excellence the dilemma of the molecular target driven
drug discovery process. Significant experimental evidence
suggests that the BK channels play a pivotal and specific
role in many pathophysiological conditions supporting the
notion that the channel represents an innovative and promising
drug target. However, after more than ten years of intense
research effort both in academia and industry, scientists
have yet to witness the approval of a single BK channel modulator
for clinical use. On the contrary, three BK openers that were
progressed to clinical development have recently been discontinued
(NS8, BMS204352 and TA1702) and, at the present time, only
one drug candidate targeting BK channels (andolast) remains
in the early phases of clinical development. Since biological
studies keep strengthening the concept of BK channels as a
potentially attractive target, the design and synthesis of
potent and selective BK modulators continue based on novel
chemical ideas. A comprehensive overview of BK channel modulators
is therefore timely and important to the current medicinal
chemist for review, summary, and classification of the multitude
of chemical entities claimed to be BK-modulating agents. Such
chemical entities are, herein, classified by both origin and
chemical structure in 1) Endogenous BK channel modulators
and structural analogues 2) Naturally-occurring BK channel
inhibitors and blockers 3) Synthetic BK channel inhibitors
and blockers 4) Marketed and/or investigational drugs with
BK-modulating side properties and structural analogues 5)
Naturally-occurring BK channel openers and structural analogues
6) Synthetic BK channel openers. This review is intended to
provide readers with current opinion on the BK channel as
a drug target, the chemical structures of BK channel modulators,
the structural and chemical features involved in the BK channel
modulating activity and, where and when possible, with highlights
of structure–activity relationships.
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