| Mini-Reviews
in Medicinal Chemistry
ISSN: 1389-5575
Mini-Reviews in Medicinal
Chemistry
Volume 7, Number 5, May 2007
Contents
Chirality – A New Era of Therapeutics
Pp. 451-460
Y.K. Agrawal, H.G. Bhatt, H.G. Raval, P.M. Oza and P.J. Gogoi
[Abstract]
Treatment of Organophosphate Intoxication Using
Cholinesterase Reactivators: Facts and Fiction Pp.
461-466
Jiri Bajgar, Josef Fusek, Kamil Kuca, Lucie Bartosova
and Daniel Jun
[Abstract]
Pharmacological Therapy of Cushing’s Syndrome:
Drugs and Indications Pp. 467-480
Juan J. Díez and Pedro Iglesias
[Abstract]
Nitrogen-Containing Heterocyclic Quinones: a Class
of Potential Selective Antitumor Agents Pp. 481-489
Laura Garuti, Marinella Roberti and Daniela Pizzirani
[Abstract]
Rational Design of Vector and Antibiotic Peptides
Using Solid-State NMR Pp. 491-497
A.J. Mason, B. Bechinger and A. Kichler
[Abstract]
Computer-Assisted Methods in Chemical Toxicity Prediction
Pp. 499-507
C. Gopi Mohan, Tamanna Gandhi, Divita Garg and Ranajit
Shinde
[Abstract]
Intraperitoneal Chemotherapy as First-Line Treatment
in the Management of Epithelial Ovarian Cancer Pp.
509-517
S. Rekhraj, J. Kinross, S. Prabhudesai, A. Darzi and P.
Ziprin
[Abstract]
The AMP-Activated Protein Kinase: Role in Regulation
of Skeletal Muscle Metabolism and Insulin Sensitivity Pp.
519-526
Gregory R. Steinberg and Sebastian Beck Jørgensen
[Abstract]
Genetic Variant-Associated Endothelial Dysfunction
Behind Small-Vessel Cerebral Circulatory Disorders: A New
Pathomechanism Behind Common Cerebral Phenotypes
Pp. 527-530
Zoltán Szolnoki
[Abstract]
Emerging Drugs – Potential for Misuse in Sport
and Doping Control Detection Strategies Pp. 531-537
M. Thevis and W. Schänzer
[Abstract]
The Role of Exhaled Nitric Oxide in the Diagnosis,
Management and Treatment of Asthma Pp. 539-542
Steve Turner
[Abstract]
Molecular and Cellular Activities of Vitamin E Analogues
Pp. 543-558
Jean-Marc Zingg
[Abstract]
Abstracts
[Back to top]
Chirality – A New Era of Therapeutics
Y.K. Agrawal, H.G. Bhatt, H.G. Raval, P.M. Oza and P.J. Gogoi
To develop the newer pharmaceuticals and to spur the
strong growth, being a general property of ‘handedness’,
chirality plays a major role. The Easson-Stedman principle
shows the differences in the biological activity between enantiomers
resulted from selective reactivity of one enantiomer with
its receptor. It helps to improve the pharmacokinetic properties
and to remove undesirable side effects by virtue of the unique
activity of enantiomers. Racemic switching and marketing drug
combinations are used as tools for drug life-cycle management
and to redevelop racemic mixtures as single enantiomers.
[Back to top]
Treatment of Organophosphate Intoxication Using
Cholinesterase Reactivators: Facts and Fiction
Jiri Bajgar, Josef Fusek, Kamil Kuca, Lucie Bartosova
and Daniel Jun
Basic part of the current standard treatment of organophosphate
(OP) agent poisoning is administration of cholinesterase reactivators.
It includes different types of oximes with a similar basic
structure differing by the number of pyridinium rings and
by the position of the oxime group in the pyridinium ring.
Oximes hydrolytically cleave the organophosphates from acetylcholinesterase
(AChE), restoring enzymatic function. This reactivation of
AChE is dependent on the type of the agent and, on the reactivator
used. From the common oximes, mono- and bisquaternary pyridinium
oximes are more or less frequently used in clinical practice
such as pralidoxime, obidoxime, trimedoxime, and HI-6. Though
there are data on a good therapeutic effects of reactivators,
some attempts to undermine the role of reactivators as effective
antidotes against OP poisoning have been made. Some arguments
on the necessity of their administration following OP poisoning
are discussed with the aim to resolve the question on their
effective use, possible repeated administration in the treatment
of OP poisonig, their peripheral and central effects including
questions on their penetration through the blood brain barrier
as well as a possibility to achieve their effective concentration
for AChE reactivation in the brain. Reactivation of cholinesterases
in the peripheral and central nervous system is described
and it is underlined its importance for the survival or death
of the organism poisoned with OP. An universality of oximes
able to reactivate AChE inhibited by all OP is questioned
and trends (molecular modelling using neural network, structure-activity
relationship, combination of reactivation and anticholinergic
properties in one molecule) for future research are characterized.
[Back to top]
Pharmacological Therapy of Cushing’s Syndrome:
Drugs and Indications
Juan J. Díez and Pedro Iglesias
Objective: To review the main pharmacological
properties and clinical applications of the drugs used in
the medical therapy of Cushing’s syndrome.
Data Sources: Search for articles
were performed in the following dababases: MEDLINE, EMBASE,
Cochrane Database of systematic Reviews and The Cochrane Central
Register of Controlled Trials (CENTRAL). Search terms included
Cushing’s syndrome and drug therapy.
Data Synthesis: Available data suggest
that neuromodulatory compounds affect corticotropin (ACTH)
or ACTH-releasing hormone (CRH) synthesis and release. They
include serotonin antagonists, dopaminergic agonists, valproic
acid, reserpine, somatostatin analogs and thiazolidinediones.
These agents have been effective in a limited number of patients
with ACTH-dependent Cushing’s syndrome. Inhibitors of
steroidogenesis reduce cortisol production by blocking one
(metyrapone, trilostane) or several (aminoglutethimide, ketoconazole,
fluconazole, etomidate) enzymes involved in steroid biosynthesis.
Mitotane is a steroidogenesis inhibitor with adrenolitic properties.
Mifepriston'e blocks glucocorticoid receptor activation without
modifying cortisol synthesis.
Conclusion: Agents that inhibit
steroidogenesis are useful in all forms of Cushing’s
syndrome and are effective in about 70% of patients. Main
indications for drug therapy include preparation for surgery,
persistence or recurrence after surgery, while awaiting for
the effect of radiation therapy, occult ectopic ACTH syndrome,
severe hypercortisolism and malignancy related hypercortisolism.
[Back to top]
Nitrogen-Containing Heterocyclic Quinones: a Class
of Potential Selective Antitumor Agents
Laura Garuti, Marinella Roberti and Daniela Pizzirani
The development of prodrugs that are enzymatically activated
into anticancer agents is a promising perspective in cancer
therapy. Many nitrogen-containing quinoid heterocycles have
been reported to show antitumor effect. The principal interest
in these compounds lies on their potential to produce tumor-selective
toxicity. Selectivity occurs by difference in oxygen tension
between normal and tumor tissue and by levels of the required
activating enzymes.
In this review a summary of the most interesting heterocyclic
quinones is given together with their biological property.
SAR studies concerning the importance of some structural features
will be described.
[Back to top]
Rational Design of Vector and Antibiotic Peptides
Using Solid-State NMR
A.J. Mason, B. Bechinger and A. Kichler
The application of 2H solid-state
NMR in determining structure activity relationships and mechanism
of action of membrane active peptides is discussed. The enhancement
of the disruption of anionic lipids in the membrane by new
lead compounds is shown to be a key determinant of both DNA
vector and antimicrobial activity.
[Back to top]
Computer-Assisted Methods in Chemical Toxicity Prediction
C. Gopi Mohan, Tamanna Gandhi, Divita Garg and Ranajit
Shinde
In Silico predictive ADME/Tox screening of compounds
is one of the hottest areas in drug discovery. To provide
predictions of compound drug-like characteristics early in
modern drug-discovery decision making, computational technologies
have been widely accepted to develop rapid high throughput
in silico ADMET analysis. It is widely perceived
that the early screening of chemical entities can significantly
reduce the expensive costs associated with late stage failures
of drugs due to poor ADME/Tox properties. Drug toxic effects
are broadly defined to include toxicity, mutagenicity, carcinogenicity,
teratogenicity, neurotoxicity and immunotoxicity. Toxicity
prediction techniques and structure–activity relationships
relies on the accurate estimation and representation of physico-chemical
and toxicological properties. This review highlights some
of the freely and commercially available softwares for toxicity
predictions. The information content can be utilized as a
guide for the scientists involved in the drug discovery arena.
[Back to top]
Intraperitoneal Chemotherapy as First-Line Treatment
in the Management of Epithelial Ovarian Cancer
S. Rekhraj, J. Kinross, S. Prabhudesai, A. Darzi and P.
Ziprin
Recent evidence has suggested improved outcomes following
incorporation of intraperitoneal chemotherapy administration
with intravenous systemic chemotherapy as first-line treatment
of small volume residual epithelial ovarian cancer. This review
focuses on the mechanism of actions of the chemotherapeutic
drugs and reviews the possible reasons for the superior outcomes
of intraperitoneal chemotherapy.
[Back to top]
The AMP-Activated Protein Kinase: Role in Regulation
of Skeletal Muscle Metabolism and Insulin Sensitivity
Gregory R. Steinberg and Sebastian Beck Jørgensen
Over the past decade, an epidemic of obesity has developed
throughout the Western World. In recent years, significant
interest has focused on the role of the AMP-activated protein
kinase (AMPK) as a potential therapeutic target for the treatment
of obesity and type 2 diabetes and is such the focus of this
review. Specifically, the potential role of AMPK in skeletal
muscle metabolism as it relates to the insulin sensitizing
effects of exercise and the hormones, leptin, adiponectin,
ciliary neurotrophic factor and interleukin-6 are discussed.
We caution that despite the convincing associations between
the activation of AMPK signalling and the restoration of insulin
sensitivity, future studies in genetic models of AMPK deficiency
or constitutive activation within skeletal muscle are needed
to evaluate the quantitative role of AMPK and to validate
whether strategies designed to activate skeletal muscle AMPK
may be important for regulating whole-body insulin sensitivity.
[Back to top]
Genetic Variant-Associated Endothelial Dysfunction
Behind Small-Vessel Cerebral Circulatory Disorders: A New
Pathomechanism Behind Common Cerebral Phenotypes
Zoltán Szolnoki
An increasing body of evidence suggests that different genetic
factors, such as angiotensin-converting enzyme (ACE) I/D ,
angiotensin II type-1 receptor (AT1R) A1166C, methylenetetrahydrofolate
reductase (MTHFR) C677T and ENOS G894T variants are associated
with an endothelial dysfunction (ED). EDs are relatively new
phenomena that are presumed to contribute to vasoregulatory
malfunctions at the small-vessel level. Ever more clinical
observations indicate that the above genetic variants are
also associated with cerebral small-vessel disorders. This
article reviews the knowledge available on the roles of ED-
associated genetic variants in cerebral circulatory disorders,
and suggests that EDs can be causative factors for different
common cerebral pathologies such as leukoaraiosis or/and small-vessel
infarcts. Newly-developed drugs involving phosphodiesterase
type-5 inhibitors, which improve the endothelial functions,
may comprise a new approach to the treatment and prevention
of small-vessel cerebral circulatory disorders.
[Back to top]
Emerging Drugs – Potential for Misuse in Sport
and Doping Control Detection Strategies
M. Thevis and W. Schänzer
Preventive doping research includes the development of methods
for the detection of new or emerging drugs to be implemented
in routine screening analysis. Candidates with great potential
for misuse in elite sports include selective androgen receptor
modulators, growth hormone secretagogues, hypoxia-inducible
factor stabilizers and erythropoietin mimetics.
[Back to top]
The Role of Exhaled Nitric Oxide in the Diagnosis,
Management and Treatment of Asthma
Steve Turner
Asthma is a chronic respiratory condition affecting many adults
and children. An association between asthma and raised gaseous
nitric oxide in the exhaled breath was first reported in 1993.
In the absence of an objective test for diagnosing and monitoring
asthma, a vigorous research effort has subsequently sought
to determine the nature of the relationship between exhaled
nitric oxide (ENO) and asthma and to determine the clinical
utility of ENO measurements in asthmatics. Many methodological
issues relating to ENO measurements have also been addressed.
The evidence indicates that ENO originates from a number of
sources and the "excess" ENO in asthmatics is mostly
derived from the lower respiratory epithelium where ENO probably
reflects eosinophilic airway inflammation. Clinical studies
have revealed that ENO may be useful in the diagnosis of atopic
asthma but not non-atopic asthma. Longitudinal measurements
of ENO have been found to correlate with asthma symptoms,
including relapse of symptoms after cessation of corticosteroids
treatment. In summary, over a relatively short time ENO has
become recognised as a useful objective tool for diagnosing
and monitoring asthma. More clinical studies will be required
in order for ENO to become fully established in the diagnosis
and management of asthma.
[Back to top]
Molecular and Cellular Activities of Vitamin E Analogues
Jean-Marc Zingg
Natural vitamin E comprises 8 different analogues,
the α-,
β-,
γ-,
and δ-tocopherols
and the α-,
β-,
γ-,
and δ-tocotrienols.
However, only α-tocopherol
is selectively enriched by the liver; the other vitamin E
analogues and also excess α-tocopherol
are converted to several metabolites and eliminated. Recently,
a novel phosphorylated form of tocopherol, α-tocopheryl
phosphate, was shown to occur naturally in animal and human
tissues as well as in foods. Several synthetic vitamin E derivatives
have been synthesized that are either converted by esterases
to the natural form, or exert novel or vitamin E related biological
activities. During the last years, specific cellular effects
for each individual vitamin E analogue have been described
that are the consequence of modulating signal transduction
and gene expression. These effects possibly reflect specific
interactions of each of the vitamin E analogues with enzymes,
structural proteins, lipids and transcription factors. In
this review, the different natural vitamin E analogues and
synthetic derivatives are compiled in relation to their major
molecular and cellular activities.
|
