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Mini-Reviews
in Medicinal Chemistry
ISSN: 1389-5575
Mini-Reviews in Medicinal
Chemistry
Volume 6, Number 3, March 2006
Contents
Interactions of Chemicals and Metal Ions with Proteins and
Role for Immune Responses Pp. 247-255
Stefan F. Martin, Irmgard Merfort and Hermann-Josef Thierse
[Abstract]
New Insights into Endocannabinoid Degradation
and its Therapeutic Potential Pp. 257-268
M. Bari, N. Battista, F. Fezza, V. Gasperi and M. Maccarrone
[Abstract]
Structural Requirements of Acetylcholinesterase
Reactivators Pp. 269-277
Kamil Kuca, Daniel Jun and Kamil Musilek
[Abstract]
Microcystin Produces Disparate Effects
on Liver Cells in a Dose Dependent Manner Pp.
279-285
Lars Herfindal and Frode Selheim
[Abstract]
Modifying Toll-like Receptor 9 Signaling
for Therapeutic Use Pp. 287-291
Rabindra N. Bhattacharjee and Shizuo Akira
[Abstract]
Unusual Amino Acids: Synthesis and
Introduction into Naturally Occurring Peptides and Biologically
Active Analogues Pp. 293-304
G. Cardillo, L. Gentilucci and A. Tolomelli
[Abstract]
Screening Methods for Antioxidants-A
Review Pp.305-312
Indu Pal Kaur and Thiraviam Geetha
[Abstract]
Cardiovascular Disease in Diabetes
Pp.313-318
Sho-ichi Yamagishi, Kazuo Nakamura, Takanori Matsui, Katsuhiko
Takenaka, Yuko Jinnouchi and Tsutomu Imaizumi
[Abstract]
Recent Advances in the Stereocontrolled Synthesis
of Antisense Phosphorothioates Pp.319-330
Yixin Lu
[Abstract]
Effects of the Natural Isoflavonoid Genistein on Growth, Signaling
Pathways and Gene Expression of Matrix Macromolecules by Breast
Cancer Cells Pp. 331-337
O. Ch. Kousidou, G.N. Tzanakakis and N.K. Karamanos
[Abstract]
Rho-Kinase as a Drug Target for the Treatment of Airway Hyperresponsiveness
in Asthma Pp.339-348
Reinoud Gosens, Dedmer Schaafsma, S. Adriaan Nelemans
and Andrew J. Halayko
[Abstract]
Anti-hyperglycemic Potential of Natural Products Pp.349-356
T. Matsui, I.A. Ogunwande, K.J.M. Abesundara and K.
Matsumoto
[Abstract]
Peroxisome Proliferator-Activated Receptors and the Control
of Fatty Acid Oxidation in Cardiac Hypertrophy Pp.357-363
Anna Planavila, Ricardo Rodríguez Calvo and
Manuel Vázquez-Carrera
[Abstract]
Abstracts
[Back to top]
Interactions of Chemicals and Metal Ions with Proteins
and Role for Immune Responses
Stefan F. Martin, Irmgard Merfort and Hermann-Josef Thierse
Chemicals and metal ions often induce allergic contact dermatitis.
We review here recent advances in the development of in
vitro assays for prediction of skin sensitizing potency
based on chemical and biological reactivity as well as in
the identification of physiological binding partners and immunological
pathomechanisms of chemical and metal ion induced disease.
[Back to top]
New Insights into Endocannabinoid Degradation
and its Therapeutic Potential
M. Bari, N. Battista, F. Fezza, V. Gasperi and M. Maccarrone
Endocannabinoids are amides, esters and ethers of long chain
polyunsaturated fatty acids, which act as new lipidic mediators.
Anandamide (N-arachidonoylethanolamine; AEA) and
2-arachidonoylglycerol (2-AG) are the main endogenous agonists
of cannabinoid receptors, able to mimic several pharmacological
effects of (-)-Δ9-tetrahydrocannabinol (THC),
the active principle of Cannabis sativa preparations
like hashish and marijuana. The activity of AEA and 2-AG at
their receptors is limited by cellular uptake through an anandamide
membrane transporter (AMT), followed by intracellular degradation.
A fatty acid amide hydrolase (FAAH) is the main AEA hydrolase,
whereas a monoacylglycerol lipase (MAGL) is critical in degrading
2-AG. Here, we will review growing evidence that demonstrates
that these hydrolases are pivotal regulators of the endogenous
levels of AEA and 2-AG in vivo, overall
suggesting that specific inhibitors of AMT, FAAH or MAGL may
serve as attractive therapeutic targets for the treatment
of human disorders.
Recently, the N-acylphosphatidylethanolamine-specific
phospholipase D (NAPE-PLD), which synthesizes AEA from N-arachidonoylphosphatidylethanolamine
(NArPE), and the diacylglycerol lipase (DAGL), which generates
2-AG from diacylglycerol (DAG) substrates, have been characterized.
The role of these synthetic routes in maintaining the endocannabinoid
tone in vivo will be discussed. Finally, the effects
of inhibitors of endocannabinoid degradation in animal models
of human disease will be reviewed, with an emphasis on their
ongoing applications in anxiety, cancer and neurodegenerative
disorders.
[Back to top]
Structural Requirements of Acetylcholinesterase
Reactivators
Kamil Kuca, Daniel Jun and Kamil Musilek
Nerve agents (sarin, soman, cyclosarin, tabun and VX agent)
and pesticides (paraoxon, chlorpyrifos, TEPP) represent extremely
toxic group of organophosphorus compounds (OPCs). These compounds
inhibit enzyme acetylcholinesterase (AChE, EC 3.1.1.7) via
its phosphorylation or phosphonylation at the serine hydroxy
group in its active site. Afterwards, AChE is not able to
serve its physiological function and intoxicated organism
is died due to overstimulation of cholinergic nervous system.
The current standard treatment of poisoning with highly toxic
OPCs usually consists of the combined administration of anticholinergic
drugs (preferably atropine) and AChE reactivators (called
"oximes"). Anticholinergic drugs block effects of
accumulated neurotransmitter acetylcholine at nicotinic and
muscarinic receptor sites, while oximes reactivate AChE inhibited
by OPCs.
Unfortunately, none from the currently used oximes is sufficiently
effective against all known nerve agents and pesticides. Therefore,
to find new oximes able to sufficiently reactivate inhibited
AChE (regardless of the type of OPCs) is still very important
task for medicinal chemistry with the aim to improve the efficacy
of antidotal treatment of the acute poisonings mentioned.
In this paper, the relationship between chemical structure
of AChE reactivators and their ability to reactivate AChE
inhibited by several nerve agents and pesticides is summarized.
It is shown that there are several structural fragments possibly
involving in the structure of proposed AChE reactivators.
Finally, an attempt of a future course of new AChE reactivators
development is discussed.
[Back to top]
Microcystin Produces Disparate Effects on
Liver Cells in a Dose Dependent Manner
Lars Herfindal and Frode Selheim
In this review we present recent studies on the effects of
the protein phosphatase inhibitor microcystin on mammalian
cells. Whereas high concentrations of microcystin promote
liver cell death induced by ROS signalling without the involvement
of typical apoptotic proteins, intermediate doses activate
classic apoptotic pathways. Low concentrations however, increase
liver cell survival and proliferation, and can cause primary
liver cancer.
[Back to top]
Modifying Toll-like Receptor 9 Signaling
for Therapeutic Use
Rabindra N. Bhattacharjee and Shizuo Akira
Toll-like receptor (TLR) 9 recognizes synthetic oligodeoxynucleotides
(ODN) containing unmethylated deoxycytidyl-deoxyguanosine
(CpG) motifs and mimics the immunostimulatory activity of
bacterial DNA. Both innate and adaptive immune systems are
activated through TLR9 signaling and thus its synthetic agonists
or inhibitors have potential significance as a target for
therapeutic use in immunological disorders. Interestingly,
TLR9 found in the dendritic cells and B cells produce differential
outcome in response to structurally distinct CpG-ODNs. While
one class of CpG-ODN activates B cells and produce immunoglobulin,
other can either redirect plasmacytoid dendritic (pDC) cells
to secrete high level of IFNα
or myeloid dendritic cells (mDC) to produce Th1-like cytokines
and chemokines necessary for asthma control. This review focuses
on potential use of various synthetic CpG to modify TLR9 signaling
for therapeutic treatment of multiple diseases including cancer,
asthma, allergy and systemic lupus erythematosus (SLE).
[Back to top]
Unusual Amino Acids: Synthesis and Introduction
into Naturally Occurring Peptides and Biologically Active
Analogues
G. Cardillo, L. Gentilucci and A. Tolomelli
This review covers our recent advances in the synthesis of
unusual amino acids in optically pure form, and their introduction
into naturally occurring peptides with specific biological
properties, or into modified bioactive peptides, aiming to
obtain analogues displaying enhanced performances in term
of activity, bioavailability and resistance to enzymatic hydrolysis
[Back to top]
Screening Methods for Antioxidants-A Review
Indu Pal Kaur and Thiraviam Geetha
Various environmental, physical and chemical stresses on
cells may induce either an overproduction of ROS (Reactive
Oxygen Species) or a deficiency of antioxidant enzymes. ROS
are responsible for various cellular anomalies like protein
damage, deactivation of enzymes, alteration of DNA and lipid
peroxidation which in turn leads to pathological conditions
like carcinogenesis, reperfusion injury, rheumatoid arthritis,
diabetes etc. The regular intake of antioxidants seems to
limit or prevent the dangerous effects caused by ROS. Thus,
to maintain cellular health, it is important to have a specific
and effective antioxidant that scavenges multiple types of
free radicals so that it can be used in multiple diseases.
Different in vitro and in vivo test systems
are available in the literature to assess the free radical
scavenging activity of various compounds. Based on the efficiency
of free radical scavenging, the compounds are classified into
strong, moderate and weak antioxidants. The following review
explains the brief procedure and the principle behind various
methods available in the literature, which can be used to
determine the scavenging of different types of free radicals.
[Back to top]
Cardiovascular Disease in Diabetes
Sho-ichi Yamagishi, Kazuo Nakamura, Takanori Matsui, Katsuhiko
Takenaka, Yuko Jinnouchi and Tsutomu Imaizumi
Diabetes is associated with a marked increase in the risk
of atherosclerotic vascular disorders, including coronary,
cerebrovascular, and peripheral artery disease. Cardiovascular
disease (CVD) could account for disabilities and high mortality
rates in patients with diabetes. In this paper, we review
the molecular mechanisms for accelerated atherosclerosis in
diabetes, especially focusing on postprandial hyperglycemia,
advanced glycation end products (AGEs) and the renin-angiotensin
system. We also discuss here the potential therapeutic strategy
that specifically targets CVD in patients with diabetes.
[Back to top]
Recent Advances in the Stereocontrolled Synthesis
of Antisense Phosphorothioates
Yixin Lu
Antisense technology has advanced substantially in the past
few decades and now is a well-established therapeutic approach
in medicinal chemistry, and it may prove to be a valuable
tool in the treatment of a wide range of diseases. Phosphorothioate
oligonucleotides are among the most important and promising
antisense agents. However, the key drawback lies in their
polydiastereomerism, which manifests itself in the different
chemical and biological properties of the diastereomeric species.
Methodologies towards the stereocontrolled synthesis of antisense
phosphorothioate oligonucleotides have been well investigated
in recent years. In this review, the progress in this field
is summarized.
[Back to top]
Effects of the Natural Isoflavonoid Genistein on Growth,
Signaling Pathways and Gene Expression of Matrix Macromolecules
by Breast Cancer Cells
O. Ch. Kousidou, G.N. Tzanakakis and N.K. Karamanos
Genistein is a well known protein tyrosine kinase inhibitor.
It is structurally similar to 17β-estradiol
and exerts antiestrogenic effects. It also affects the signal
transduction components Akt, FAK, ErbB-2 and Bcl-2. Key enzymes
implicated in cancer invasion are also affected by genistein.
A critical evaluation of the effects of genistein on breast
cancer growth, signaling and gene expression is presented
in this review.
[Back to top]
Rho-Kinase as a Drug Target for the Treatment of Airway
Hyperresponsiveness in Asthma
Reinoud Gosens, Dedmer Schaafsma, S. Adriaan Nelemans
and Andrew J. Halayko
In asthma, inflammatory and structural cells contribute to
increased bronchoconstriction acutely and more chronically
to airway remodelling. Current asthma therapy doesn’t
inhibit these features satisfactorily. This review discusses
Rho-kinase as a potential drug target, since increasing evidence
suggests a central role for this pathway in acute and chronic
airway hyperresponsiveness.
[Back to top]
Anti-hyperglycemic Potential of Natural Products
T. Matsui, I.A. Ogunwande, K.J.M. Abesundara and K.
Matsumoto
In order to evaluate the anti-hyperglycemic effect of natural
compounds via the inhibition of α-glucosidase
(AGH), the potential inhibitory effect of anthocyanins, caffeic
acid analogs, and caffeoylquinic acid analogs have been reviewed.
A new AGH assay system to mimic the membrane-bound AGH at
the small intestine was proposed and evaluated.
[Back to top]
Peroxisome Proliferator-Activated Receptors and the
Control of Fatty Acid Oxidation in Cardiac Hypertrophy
Anna Planavila, Ricardo Rodríguez Calvo and
Manuel Vázquez-Carrera
Cardiac hypertrophy is a response of the heart to a wide
range of extrinsic stimuli, such as arterial hypertension,
valvular heart disease, myocardial infarction, and cardiomyopathy.
Although this process is initially compensatory for an increase
workload, its prolongation frequently results in congestive
heart failure, arrhythmia, and sudden death. Cardiac hypertrophy
is associated with an increase in glucose utilization and
a decrease in fatty acid oxidation. It is unclear at present,
however, which consequences might result from impaired oxidation
of fatty acids in the heart, but several studies have demonstrated
that substrate utilization is important in the pathogenesis
of cardiac hypertrophy. Here we will focus on the effects
of cardiac hypertrophy on the activity of Peroxisome proliferator-activated
receptors (PPARs), ligand-activated transcription factors
that regulate the expression of genes involved in fatty acid
uptake and oxidation, lipid metabolism and inflammation. Interestingly,
activation of the Nuclear Factor (NF)-κB
signaling pathway, which is one of the most important signal
transduction pathways involved in the hypertrophic growth
of the myocardium, may suppress the activity of the PPARs,
affording a link between cardiac hypertrophy and the fall
in fatty acid oxidation in the hypertrophied heart. As a result,
inhibition of NF-κB
activation during cardiac hypertrophy may also ameliorate
cardiac fatty acid oxidation, achieving a better improvement
in the prevention or inhibition of this pathological process.
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