Mini-Reviews in Medicinal Chemistry, Volume 4, No. 1, 2004
Contents
Metal
Compounds in Medicinal Chemistry
Executive
Editor: Dinorah Gambino
Trace Elements Supplementation: Recent
Advances and Perspectives
Pp.1-9
Enrique
J. Baran
Chemical and Biological Considerations in the
Treatment of Metal Intoxications by Chelating Agents Pp.11-21
Ole
Andersen
Metal Complexes as Chemotherapeutic Agents
Against Tropical Diseases: Trypanosomiasis, Malaria and Leishmaniasis Pp.23-30
Roberto
A. Sanchez-Delgado and Atilio Anzellotti
The Wide Pharmacological Versatility of
Semicarbazones, Thiosemicarbazones and Their Metal Complexes Pp.31-39
Heloisa
Beraldo and Dinorah Gambino
Pharmacokinetic Study and Trial for
Preparation of Enteric-Coated Capsule Containing Insulinomimetic Vanadyl
Compounds: Implications for Clinical Use Pp.41-48
Hiromu
Sakurai, Jun Fugono and Hiroyuki Yasui
Antitumor Titanium Compounds Pp.49-60
Francesco
Caruso and Miriam Rossi
Rhenium-188 and Copper-67
Radiopharmaceuticals for the Treatment of Bladder Cancer Pp.61-68
Malcolm
Frier
b-Lactams in the New Millennium. Part-I:
Monobactams and Carbapenems
Pp.69-92
G.S.
Singh
b-Lactams in the New Millennium. Part-II:
Cephems, Oxacephems, Penams and Sulbactam Pp.93-109
G.S.
Singh
Abstracts
[Back to top] Trace Elements Supplementation: Recent
Advances and Perspectives
Enrique
J. Baran
Supplementation of
essential trace elements has become an increasingly important field of research
in modern pharmacology. The present review presents general aspects related to
the essentiality of inorganic systems in living organisms, followed by a
detailed discussion of the supplementation of iron, copper, zinc, chromium, selenium,
magnesium and some other minor trace elements. Some recent advances in this
field as well as future challenges and perspectives are also discussed.
[Back to top] Chemical and Biological Considerations in the
Treatment of Metal Intoxications by Chelating Agents
Ole
Andersen
Effective
chelation treatment of metal intoxications requires that the pharmacokinetics
of the administered chelator in fact leads to chelation of the toxic metal,
preferably forming a less toxic species which is effectively excreted. This
depends on physical and chemical characteristics of metals and chelators as
e.g. ionic diameter, ring size and deformability, hardness/softness of electron
donors and acceptors, administration route, bioavailability, metabolism, organ
and intra/extra cellular compartmentalization, and excretion. In vivo chelation
is unlikely to reach equilibrium determined by the standard stability constant,
as rate effects and ligand exchange reactions as well as the pharmacokinetics
of the chelator considerably influence complex formation. Hydrophilic chelators
enhance renal metal excretion, but mainly their extracellular distribution
limit their effect to mainly extracellular metal pools. Lipophilic chelators
can decrease intracellular stores, but may redistribute toxic metals to e.g.
the brain. In chronic metal induced disease, necessitating life-long chelation,
toxicity and side effects of the chelator may limit the treatment. The metal
selectivity of chelators is important, due to the risk of essential metals
depletion. Dimercaptosuccinic acid and dimercaptopropionic sulfonate are
presently gaining increased acceptance among clinicians, undoubtedly improving
the management of human metal intoxications including lead, arsenic and mercury
compounds. Still, development of new safer chelators suited for long-term oral
administration for chelation of metal deposits, mainly iron, is an important
challenge to the future research.
[Back to top] Metal Complexes as Chemotherapeutic Agents
Against Tropical Diseases: Trypanosomiasis, Malaria and Leishmaniasis
Roberto
A. Sanchez-Delgado and Atilio Anzellotti
Parasitic diseases
represent a major world health problem with very limited therapeutic options, most
of the available treatments being decades old and suffering from limited
efficacy and/or undesirable collateral effects. The use of metal complexes as
chemotherapeutic agents against these ailments appears as a very attractive
alternative. Although the design of metal complexes with good therapeutic index
is still rather empirical, a number of potential metal-based antiparasitic
drugs have become available. In this review, advances in the use of metal
complexes for the treatment of trypanosomiasis, malaria, and leishmaniasis as
important representatives of the general area of tropical diseases is
described.
[Back to top] The Wide Pharmacological Versatility of
Semicarbazones, Thiosemicarbazones and Their Metal Complexes
Heloisa Beraldo and Dinorah Gambino
The more
significant bioactivities of a variety of semicarbazones (anti-protozoa,
anticonvulsant) and thiosemicarbazones (antibacterial, antifungal, antitumoral,
antiviral) and their metal complexes are reviewed together with proposed
mechanisms of action and structure-activity relationships. Clinical or
potential pharmacological applications of these versatile compounds are
discussed.
[Back to top] Pharmacokinetic Study and Trial for Preparation
of Enteric-Coated Capsule Containing Insulinomimetic Vanadyl Compounds:
Implications for Clinical Use
Hiromu
Sakurai, Jun Fugono and Hiroyuki Yasui
To treat patients
suffering from diabetes mellitus, we developed several types of orally active
vanadyl complexes to replace painful insulin injections, and prepared them in
the form of enteric-coated capsules containing vanadium compounds.
Pharmacokinetic analysis demonstrated that these capsules enhance the
bioavailability of pharmacologically active vanadyl species.
[Back to top] Antitumor Titanium Compounds
Francesco
Caruso and Miriam Rossi
Most anticancer
titanium compounds act against tumors in the gastrointestinal tract. Activity
towards breast, lung and skin (melanoma) cancers is shown by some as well.
Among their appealing properties is that they do not show common side effects
of widely used cytostatic agents such as emesis, alopecia or bone marrow
impairment. These features make titanium compounds interesting for combined
therapy and further study. This review focuses on two drugs that reached
clinical trials, namely, titanocene dichloride and budotitane. We try to
integrate the biological fate of the related Ti–cyclopentadienyl and
Ti–â-diketonato families of drugs, delineating the structure-activity
relationship. We also discuss novel related species with increased solubility
for improved drug delivery and some potentially useful polynuclear compounds.
[Back to top] Rhenium-188 and Copper-67
Radiopharmaceuticals for the Treatment of Bladder Cancer
Malcolm
Frier
The favourable
nuclear properties of copper-67 and rhenium-188 for therapeutic application are
described, together with methods for the chemical synthesis of a number of
derivatives. Survival from invasive bladder cancer has changed little over the
past 20 years. The intravesicular administration of Cu-67 or Re-188
radiopharmaceuticals in the treatment of bladder cancer offers some promise for
improvement in this situation.
[Back to top] b-Lactams in the New Millennium. Part-I:
Monobactams and Carbapenems
G.S.
Singh
â-lactam
ring-containing compounds such as penicillins, ampicillin, amoxicillin,
cephalosporins and carbapenem are among the most famous antibiotics. This
article reviews the recent developments in the study of such compounds. The
introductory paragraph, which highlights the significance of the subject and
cites most of the leading references of the previous century, is followed by an
overview of â-lactams and some novel methodologies for the synthesis of bi-,
tri- and polycyclic derivatives. The rest of the sections deal with design,
synthesis and biological activity of monobactams and carbapenems. Many of them
have potential antibacterial activity, even against some resistant strains, and
enzyme inhibitory activity.
[Back to top] b-Lactams in the New Millennium. Part-II:
Cephems, Oxacephems, Penams and Sulbactam
G.S.
Singh
â-lactam ring-containing
compounds such as penicillins, ampicillin, amoxicillin, cephalosporins and
carbapenems are among the most famous antibiotics. This article reviews the
recent developments in study of cephems, oxacephems, penams and sulbactam. Many
of the compounds reviewed have potential antibacterial activity, even against
resistant strains such as MRSA, and enzyme inhibitory activity.