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Mini-Reviews
in Medicinal Chemistry
ISSN: 1389-5575
Mini-Reviews in Medicinal
Chemistry
Volume 6, Number 7, July 2006
Contents
Structural and Functional Properties of NAD Kinase, a Key
Enzyme in NADP Biosynthesis Pp. 739-746
Giulio Magni, Giuseppe Orsomando and Nadia Raffaelli
[Abstract]
Fused 1,4-Dihydropyridines as Potential Calcium
Modulatory Compounds Pp. 747-755
Cihat Safak and Rahime Simsek
[Abstract]
Function and Molecular Mechanism of Tumor-Targeted
Peptides for Delivering Therapeutic Genes and Chemical Drugs
Pp. 757-764
Ryan Craig and Shulin Li
[Abstract]
Myostatin: Biology and Clinical Relevance Pp.
765-770
Gilles Carnac, Stéphanie Ricaud, Barbara Vernus and
Anne Bonnieu
[Abstract]
Biological Therapies for Inflammatory Bowel Disease:
Research Drives Clinics Pp. 771-784
Silvio Danese, Stefano Semeraro, Alessandro Armuzzi, Alfredo
Papa and Antonio Gasbarrini
[Abstract]
New Inotropic Pharmacologic Strategies Targeting
the Failing Myocardium in the Newborn and Infant Pp.
785-792
Alex Veldman, Stefan Rupp and Dietmar Schranz
[Abstract]
Synthesis and in vitro Modeling and
Characterization of Self-Assembling Drug Conjugates for Targeted
Medicinal Application Pp. 793-803
D.K. Sarker
[Abstract]
Structural Properties of the NMDA Receptor and
the Design of Neuroprotective Therapies Pp. 805-815
A.M. Gerber and M.L. Vallano
[Abstract]
Chemical Communication–Do We Have a Quorum?
Pp. 817-825
Monika I. Konaklieva and Balbina J. Plotkin
[Abstract]
Cyclooxygenases in Cancer: Chemoprevention and
Sensitization to Conventional Therapies Pp. 827-833
Y.T. Jeon and Y.S. Song
[Abstract]
Angiotensin II Receptor Blocker: Possibility
of Antitumor Agent for Prostate Cancer Pp. 835-844
Hiroji Uemura, Hitoshi Ishiguro and Yoshinobu Kubota
[Abstract]
Abstracts
[Back to top]
Structural and Functional Properties of NAD Kinase,
a Key Enzyme in NADP Biosynthesis
Giulio Magni, Giuseppe Orsomando and Nadia Raffaelli
NAD kinase is an essential enzyme, which plays a key role
in cellular energy and signal transduction systems. In this
report, the recent studies on the features of bacterial and
human NAD kinases are summarized. They include detailed kinetic
and structural analyses and highlight important differences,
which could be exploited for the design of novel selective
antimicrobial drugs.
[Back to top]
Fused 1,4-Dihydropyridines as Potential Calcium Modulatory
Compounds
Cihat Safak and Rahime Simsek
1,4-Dihydropyridine (1,4-DHP) derivatives nifedipine of which
the prototype, are the most popular drugs having calcium antagonistic
activity. Fused 1,4-dihydropyridines (DHPs) have also exhibit
calcium modulatory activities. In this article, we emphasize
calcium channels and fused 1,4-DHP derivatives affecting calcium
channels. In addition, the basic considerations of synthesis,
metabolism, structure-activity relationships and the latest
developments on fused 1,4-DHP derivatives will be reviewed.
This review also has extended examples of fused 1,4-DHP derivatives
having cited activities synthesized by our group.
[Back to top]
Function and Molecular Mechanism of Tumor-Targeted
Peptides for Delivering Therapeutic Genes and Chemical Drugs
Ryan Craig and Shulin Li
Tumor-targeted chemo- or gene-therapies is a new form of treatment
which provides the benefits of reducing systemic toxicity,
increasing the tolerance, and enhancing therapeutic efficacy.
This review will discuss the discovery, function, application,
and mechanism by which the short peptides (5-9) work for tumor-targeted
gene or drug delivery.
[Back to top]
Myostatin: Biology and Clinical Relevance
Gilles Carnac, Stéphanie Ricaud, Barbara Vernus and
Anne Bonnieu
Myostatin is a negative regulator of muscle mass. Important
advances in our understanding of the complex biology of this
factor have revealed the therapeutic potential of antagonizing
the myostatin pathway. Here we present the rationale for evaluating
anti-myostatin therapies in human muscle-wasting disorders.
[Back to top]
Biological Therapies for Inflammatory Bowel Disease:
Research Drives Clinics
Silvio Danese, Stefano Semeraro, Alessandro Armuzzi, Alfredo
Papa and Antonio Gasbarrini
The better understanding of the mechanisms of inflammatory
bowel disease has driven our progress into the development
of new biological therapies targeting specific molecules.
Anti-TNF-α
biologic compounds have shown great efficacy particularly
in Crohn’s disease. Infliximab (an IgG1 mouse/human
chimeric monoclonal anti-TNF-<α
antibody fragment) is the most efficacious compound in induction
and maintenance therapy of active and fistulizing Crohn’s
disease, being at present the only biological compound approved
for therapy, but with the limit of the immunogenicity; CDP-571
(a humanized anti-TNF-α
antibody) and CDP-870 (a PEGylated anti-TNF-α
antibody) are less immunogenic, showed some efficacy in induction
therapy in Crohn’s disease but a rapid loss of response
in maintenance therapy. Etanercept and onercept (soluble human
recombinant TNF-α receptors fusion proteins) seem not
to be efficacious in Crohn’s disease demonstrating no
class-effect for anti-TNF-α
compounds. In preliminary study, adalimumab (an IgG1 humanized
monoclonal anti-TNF-α
antibody) offers good perspective of efficacy and safety also
in infliximab-resistant or allergic patients. Inhibition of
lymphocyte trafficking to the gut, through anti-adhesion molecules
specific therapies (natalizumab, MLN-02, alicaforsen), has
shown promising results: unfortunately, natalizumab, the most
effective drug of this class, has recently been suspected
to favour serious neurological complications. Other biologic
therapies are under evaluation but at present seem to be less
promising than infliximab; they consist of antiinflammatory
cytokines, inhibitors of proinflammatory cytokines, hormones
and growth factors: anti-IL12-antibody, interferon-α,
interferon-β,
G-CSF, GM-CSF, EGF, growth hormone, anti-interferon-γ,
anti-IL-18, anti-IL-2-receptor and anti-CD3 antibodies. The
evaluation of other biological drugs has been suspended for
severe side effects as happened for anti-CD40L antibody causing
thromboembolism and anti-CD4 antibody causing ly.mphopenia.
Other compounds as IL-10 and IL-11 have been proven to be
ineffective even if an oral formulation of IL-11 is under
evaluation. Among the MAP kinases inhibitors BIRB-796 and
RDP58 showed to be ineffective while CNI-1493 is under evaluation.
The effort in identifying specific patients features predicting
therapy response and the possible combination of different
biological therapies represent undoubtedly a very promising
perspective. Aim of this article is to review the biological
compounds and their efficacy in IBD.
[Back to top]
New Inotropic Pharmacologic Strategies Targeting the
Failing Myocardium in the Newborn and Infant
Alex Veldman, Stefan Rupp and Dietmar Schranz
Pharmacologic support of the failing neonatal heart to maintain
cardiac output, which is vital for sufficient end organ perfusion,
is a challenging task for the pediatric intensivist, especially
since strategies which have been proven to be effective in
adults cannot necessarily be extrapolated to neonates. The
unique biochemical properties and structure of the neonatal
heart, including the increased non-contractile tissue mass,
a lower responsiveness to beta adrenergic agents and the heart
rate dependent cardiac output with a limited ability to increase
stroke volume, favor some of the new inotropes of the Ca+
sensitizer family. Focusing on the after load reduction, inodilators
as phosphodiesterase inhibitors and human brain natriuretic
peptide offer treatment options for the neonatal myocardium.
Additionally, thyroxine and steroids have been investigated
in neonates with low cardiac output after surgery for congenital
heart disease. Gene therapy, in particular cardiac-selective
gene transfer, might offer perspectives for future support
for the neonatal heart. This text reviews some of the most
recent pharmacologic strategies targeting the failing myocardium
in the critically ill newborn and infant.
[Back to top]
Synthesis and in vitro Modeling and Characterization
of Self-Assembling Drug Conjugates for Targeted Medicinal
Application
D.K. Sarker
A number of conjugates tend to self-associate in a transient
or permanent fashion and this has formed the basis of considerable
intense scientific and commercial investigation over recent
years. This article considers a variety of strategic formulations,
their flaws and advantages. Working practices and groundbreaking
developmental activities within the sphere of self-assembling
drug conjugates are also reviewed.
[Back to top]
Structural Properties of the NMDA Receptor and the
Design of Neuroprotective Therapies
A.M. Gerber and M.L. Vallano
NMDA receptors are linked to neuronal loss in stroke and neurodegeneration
because their activation can trigger excitotoxic Ca2+
dysregulation. Accordingly, NMDA receptor antagonists are
neuroprotective, providing a rationale for their clinical
application. However, side effects often outweigh benefits.
Herein we highlight structural properties in receptors that
are used in drug development.
[Back to top]
Chemical Communication–Do We Have a Quorum?
Monika I. Konaklieva and Balbina J. Plotkin
There are two types of bacterial communication
systems, those in which the signal produced by bacteria is
directed only at other organisms, and those where the signal
is detected by others and self. The latter is involved in
adaptation to the environment. The adaptation signals are
autoinducers, the response is population density-dependent
and has been termed "quorum sensing". Our current
knowledge of bacterial signaling systems indicates that Gram
positive bacteria use small peptides for both types of signaling,
whereas Gram negative organisms use homoserine lactones as
autoinducers. Gram- negative bacteria internalize the signals
which act upon an intracellular receptor. Gram-positive bacteria
use the signals as ligands for an extracellular receptor of
a two-component signaling system. Inhibitors of quorum sensing
compounds for both Gram positive and Gram negative bacteria
are being explored. Signal inhibitors could be potentially
effective in impeding biofilm formation, which might prolong
the utility of the currently available antibiotics in this
era of antibiotic resistance. In this review, we will explore
both bacteria-host and bacteria-bacteria communication systems,
with an emphasis on inhibitors of these systems both natural
and synthetic.
[Back to top]
Cyclooxygenases in Cancer: Chemoprevention
and Sensitization to Conventional Therapies
Y.T. Jeon and Y.S. Song
We have focused on cyclooxygenase, the key enzyme in prostaglandin
synthesis, from our basic knowledge regarding the enzyme,
to its clinical application in the field of oncology. We will
present evidence that this enzyme is intimately associated
with carcinogenesis, invasion, metastasis, and the response
of tumors to current therapeutic modalities in a variety of
human malignancies. We will also discuss the applications
of cyclooxygenase inhibitors to chemoprevention and to the
sensitization of tumors to conventional anti-cancer therapies.
[Back to top]
Angiotensin II Receptor Blocker: Possibility of Antitumor
Agent for Prostate Cancer
Hiroji Uemura, Hitoshi Ishiguro and Yoshinobu Kubota
It is known that the renin-angiotensin system (RAS) plays
a fundamental role not only as a vasoconstrictor in controlling
blood pressure and electrolyte/fluid homeostasis, but also
as a mitogenic factor through the Ang-II type-1 (AT1) receptor
in smooth muscle cells and cardiac myocytes. Angiotensin II
(Ang-II) is indeed thought to be a growth factor, and Ang-II
receptor blockers (ARBs), a class of antihypertensive agent,
suppress signal transduction pathways mediated by several
growth factors or cytokines, through the AT1 receptor. There
is increasing evidence that the RAS is implicated in the development
of various cancers. We previously demonstrated that ARBs have
the potential to inhibit the growth of prostate cancer cells
and tumors through the AT1 receptor. This review highlights
the possibility of ARBs as novel agents for prostate cancer
as well as other cancers, and reviews the literature on this
area.
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