Mini-Reviews in Medicinal Chemistry, Volume 5, No. 3, 2005
Contents
Enzyme Electrodes for Medical Sensors Pp. 231-239
Anja
Mueller
Anti-Inflammatory Effects of Intravenous
Anesthetics on Endotoxemia
Pp. 241-245
Current Status and Future Possibilities of
Nitric Oxide-Donor Drugs: Focus on S-Nitrosothiols Pp. 247-254
H.H.
Al-Sa’doni and A. Ferro
Polyoxotungstates Reduce the b-Lactam Resistance of Methicillin-Resistant Staphylococcus
aureus Pp. 255-268
Yutaka
Tajima
The Brown Adipose Cell: A Unique Model for
Understanding the Molecular Mechanism of Insulin Resistance Pp. 269-278
Angela
M. Valverde and Manuel Benito
Transglutaminases as Targets for
Pharmacological Inhibition
Pp. 279-292
Jolanta M. Wodzinska
Albumin Nanoparticles for the Intravitreal
Delivery of Anticytomegaloviral Drugs Pp. 293-305
J.M. Irache, M. Merodio, A. Arnedo, M.A. Camapanero, M. Mirshahi and S. Espuelas
Taxol Anticancer Activity and DNA Binding Pp. 307-311
H.
Malonga, J.F. Neault, S. Diamantoglou and H.A. Tajmir-Riahi
Antiangiogenesis by Chemotherapeutic Agents Pp. 313-317
Domenico Ribatti, Angelo Vacca, Francesca Merchionne and Marco Presta
Novel Antitumor Agents: Marine Sponge
Alkaloids, their Synthetic Analogs and Derivatives Pp. 319-336
Valery M. Dembitsky, Tatyana A. Gloriozova and Vladimir V. Poroikov
Abstracts
[Back to top] Enzyme Electrodes for Medical Sensors
Anja
Mueller
Enzyme electrodes for
biosensors are discussed. Different methods to increase electron transfer
between enzymes and electrodes are described. Results of encasing the enzymes
in conducting polymers as well as in hydrogels are presented. The environment
of the enzyme in the biosensor is compared to the natural
environment of
enzymes.
[Back to top] Anti-Inflammatory Effects of Intravenous
Anesthetics on Endotoxemia
Takumi
Taniguchi, and Ken Yamamoto
Endotoxemia and
endotoxin shock are common problems in the intensive care unit and carry a very
high mortality rate. Endotoxemia increases production of endogenous cytokines,
including tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), IL-6,
and IL-8. Not only endotoxin but also cytokines have been implicated as
important factors in the pathophysiology of endotoxic shock and the development
of cardiovascular dysfunction in endotoxemia. Recently, it has been shown both in
vitro and in vivo that several intravenous anesthetics have
anti-inflammatory effects. Thiopental and ketamine inhibit the
endotoxin-induced TNF-alpha, IL-1 and IL-8 responses and increase IL-10 release
in vitro. Ketamine prevent the pro-inflammatory cytokine (TNF-alpha,
IL-1, and IL-6) responses to endotoxemia in vivo. Moreover, thiopental
and ketamine suppress the activation of nuclear factor-kappa B induced by
endotoxin. Propofol have been proven its anti-inflammatory effects on
endotoxemia both in vitro and in vivo, but several studies have
shown that propofol does not have any anti-inflammatory effects and
deteriorates the inflammatory response to endotoxemia. This article reviews the
anti-inflammatory effects of intravenous anesthetics on endotoxemia and
endotoxic shock.
[Back to top] Current Status and Future Possibilities of
Nitric Oxide-Donor Drugs: Focus on S-Nitrosothiols
H.H.
Al-Sa’doni, and A. Ferro
Drugs which
release nitric oxide (NO) have great therapeutic potential. The organic
nitrates and sodium nitroprusside have been used in cardiovascular therapeutics
for many years, but several drawbacks limit their usefulness. In this review,
we consider novel and potential future developments in NO-donor drugs, and the
possible clinical usefulness of such compounds.
[Back to top] Polyoxotungstates Reduce the b-Lactam Resistance of Methicillin-Resistant Staphylococcus
aureus
Yutaka Tajima
Bacterial strains
isolated from clinical specimens have become more and more resistant to many
antimicrobials. This is because we have consumed large amounts of strong
antimicrobials over long periods of time and thus bacterial cells are able to
survive by altering the target(s) of antimicrobial agents. A good example of
this phenomenon is methicillin-resistant Staphylococcus aureus (MRSA).
One of the cell wallsynthesizing enzymes (known as PBP2') of this pathogen has
low affinity to b-lactams, and therefore the bacterial cells
continue to grow even under high concentrations of the agents. However, this
drug resistance does not seem to be total. They seem to have some weak spots
and several substances are known to sensitize strains of MRSA to b-lactams. This review discusses the ability
of polyoxotungstates (POTs) to sensitize MRSA to b-lactams
by reducing the expression of PBP2'. It is also possible that the sensitization
is a type of stress response of MRSA to POTs. This idea may provide a hint for
the development of a new antimicrobial agent.
[Back to top] The Brown Adipose Cell: A Unique Model for
Understanding the Molecular Mechanism of Insulin Resistance
Angela
M. Valverde and Manuel Benito
Type 2 diabetes mellitus (NIDDM) is a complex
metabolic disease that occurs when insulin secretion can no longer compensate
insulin resistance in peripheral tissues. At the molecular level, insulin
resistance correlates with impaired insulin signaling. This review provides new
insights into the molecular mechanisms of insulin action and resistance in
brown adipose tissue (BAT) and pinpoints the role of BAT in the control of
glucose homeostasis.
[Back to top] Transglutaminases as Targets for
Pharmacological Inhibition
Transglutaminases
(TGases), a family of enzymes that catalyze the formation of e-(g-glutamyl)lysine
isopeptide linkage, play an important physiological role in hemostasis, wound
healing, assembly and remodeling of the extracellular matrix, cell signaling
and apoptosis. Although many members of this class of enzymes have been known
for decades, their role in various physiological and pathological processes is
still a subject of substantial research and debate. Convincing evidence exists
that TGases are involved in formation of cytotoxic proteinatious aggregates in
Alzheimer’s, Huntington’s and other neurodegenerative diseases. However, it is
not clear if elevated levels of TGases play a causative or protective role in
several of these processes. Increased or defective TGase activity is a factor
in cortical cataract formation, lamellar ichtyosis and fibrosis. TGase creates
epitopes for the production of autoantibodies in celiac disease and possibly
other autoimmune diseases. Another TGase, Factor XIIIa, is involved in the
etiology of vascular diseases. Modulation of TGase activity through its
selective inhibition may have therapeutic benefit in a wide variety of
diseases. This paper will examine TGases as targets for the development of new
therapeutics and review the progress in discovery of selective inhibitors of
these enzymes.
[Back to top] Albumin Nanoparticles for the Intravitreal
Delivery of Anticytomegaloviral Drugs
J.M.
Irache, M. Merodio, A. Arnedo, M.A. Camapanero, M. Mirshahi and S. Espuelas
Albumin
nanoparticles (NP) were proved to be effective and safe carriers for delivering
anticytomegaloviral compounds in the vitreous. NP improved the antiviral
activity of both ganciclovir and the phosphodiester oligonucleotide analog to
formivirsen. NP appeared to be fusogenic carriers able to target the nucleus of
cells. In addition, these drug carriers were well tolerated when administered
by the intravitreal route and did not induce autoimmune reactions.
[Back to top] Taxol Anticancer Activity and DNA Binding
H.
Malonga, J.F. Neault, S. Diamantoglou and H.A. Tajmir-Riahi
The interaction of
taxol with DNA has major biological importance since it is shown the presence
of higher concentration of taxol in the nucleus, than in the human lung tumor
cell. Therefore, in this report we examine the interaction of taxol with
calf-thymus DNA in aqueous solution at physiological pH, using constant DNA
concentration (25 or 1.25 mM phosphate) and various taxol/DNA (phosphate)
ratios 1/200 to 1/2. Capillary electrophoresis and Fourier transform infrared
(FTIR) difference spectroscopic methods are used to characterize the nature of
drug-DNA interaction and to determine the taxol binding site, the binding
constant, sequence selectivity, helix stability and biopolymer secondary structure
in the taxol-DNA complexes in vitro.
Structural
analysis showed that taxol is an external DNA binder with no affinity towards
DNA intercalation. The major target of taxol is A-T, G-C bases and the backbone
PO2 groups. Two bindings were observed for taxol-DNA complexes with
K1= 1.4 x 104 M-1
and K2=3.5 X 103 M-1. The taxol-DNA
interaction is associated with a partial helix stabilization and no major
alterations of B-DNA structures.
[Back to top] Antiangiogenesis by Chemotherapeutic Agents
Domenico
Ribatti, Angelo Vacca, Francesca Merchionne and Marco Presta
Many tumors are
not curable because current treatments primarily target the tumor cells.
Intratumoral endothelial cells, on the other hand, proliferate rapidly and are
sensitive to the cytotoxic effects of chemotherapeutic agents. This review
summarizes the literature concerning the antiangiogenic effects of these agents
when administered alone or in combination with other angiogenesis inhibitors.
[Back to top] Novel Antitumor Agents: Marine Sponge
Alkaloids, their Synthetic Analogs and Derivatives
Valery
M. Dembitsky, Tatyana A. Gloriozova and Vladimir V. Poroikov
Present review
describes research on novel natural antitumor agents isolated from marine
sponges. More than 90 novel cytotoxic antitumor compounds and their synthetic
analogs have shown confirmed activity in vitro tumor cell lines bioassay
and are of current interest to NCI for further in vivo evaluation. A
great problem, to use directly the reservoir of marine organisms for therapy is
the very low availability and the isolation of only very small amounts of the
biologically active substances from the natural materials. Thus, the synthetic
chemistry is required to develop high yield synthetic methods, which are able
to produce sufficient marine alkaloids for a broad biological screening. This
review will present some of the aspects of the medicinal chemistry developed
recently to introduce such modifications. The structures, origins, synthesis
and biological activity of a selection of N-heterocyclic marine sponge
alkaloids are reviewed. The emphasis is on compounds poised as potential
anticancer drugs: pyrroles, pyrazines, imidazole, and other structural
families. With computer program PASS some additional biological activities are
also predicted, which point toward new possible applications of these
compounds. This review emphasizes the role of marine sponge alkaloids as an
important source of leads for drug discovery.