Current Medicinal Chemistry - Volume 12, Issue 18, 2005

The vesicular glutamate transporter (VGLUT) is responsible for the uptake of the excitatory amino acid, L-glutamate, into synaptic vesicles. VGLUT activity is coupled to an electrochemical gradient driven by a vacuolar ATPase and stimulated by low Cl - . VGLUT has relatively low affinity (Km = 1-3 mM) for glutamate and is pharmacologically and structurally distinct from the Na+-dependent, excitatory amino acid transporters (EAATs) found on the plasma membrane. Because glutamatergic neurotransmission begins with vesicular release, compounds that block the uptake of glutamate into the vesicle may reduce excitotoxic events. Several classes of competitive VGLUT inhibitors have emerged including amino acids and amino acid analogs, fatty acids, azo dyes, quinolines and alkaloids. The potency with which these agents inhibit VGLUT varies from millimolar (amino acids) to nanomolar (azo dyes) concentrations. These inhibitors represent highly diverse structures and have collectively begun to reveal key pharmacophore elements that may elucidate the key interactions important to binding VGLUT. Using known inhibitor structures and preliminary molecular modeling, a VGLUT pharmacophore is presented that will aid in the design of new, highly potent and selective agents.

Recently, the spectrum of molecular imaging devices such as positron emission tomography (PET) was further expanded by the now clinically available combined imaging modalities such as PET-CT and the preclinically used small animal PET scanners. These are powerful tools that can bridge the gap between preclinical and clinical evaluation studies of new radiotracers for molecular imaging of healthy and diseased states in vivo. The β-adrenoceptor (β-AR) radioligands discussed in this review represent a class of molecular probes for the non-invasive in vivo assessment of β-AR density eg. in the heart with PET. The β-AR radioligands (S)- [11C]CGP 12177 (1) or (S)-[11C]CGP 12388 (2) are currently investigated in clinical studies with PET. Additionally, subtype-selective b1-AR radioligands are used in preclinical research which show potential for the diagnostics of the "β1-AR organ" as such the heart can be defined. Non-invasive quantification of β-ARs could facilitate the accurate choice and control of therapeutic interventions. Here we summarize the state-ofthe- art of the radiochemistry of radioactive β-AR radioligands.

Research in the field of bioinorganic chemistry has been stimulated by the worldwide success of the anticancer drug cisplatin. 40 years after the first report about its biological activity, carboplatin and oxaliplatin are in routine clinical use today, whereas nedaplatin, lobaplatin, and heptaplatin (SKI2053R) are only approved in Japan, China, and South Korea, respectively. Up to now, about 35 platinum complexes entered clinical trials in order to circumvent the side-effects and the problem of tumor resistance to cisplatin. Additionally, improvement of tumor selectivity as well as the need for a broader spectrum of indications are the motivations for tremendous efforts in the development of novel anticancer platinum-based drugs. New synthetic strategies and innovative analytical approaches provide a basis for a deeper understanding of the pharmacological profile of cisplatin and analogues (biodistribution, clearance, detoxification, sideeffects, tumor specificity, cellular uptake, acquired or intrinsic resistance, platinum-DNA adduct removal by the cellular machinery) and give rise to a rational design of promising anticancer platinum coordination compounds. This article reviews the recent development of preclinical platinum complexes with interesting in vitro and in vivo tumor inhibiting properties. It focuses also on innovative synthetic strategies leading to novel classes of platinum complexes. A small part of the review is dedicated to new analytical approaches which have been supplied to or emerged in this field of research.

This contribution reviews the synthesis of a range of experimental drugs designed for and aiming at antiviral chemotherapy of severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV)-induced human disease conditions. The selection of 25 test materials includes eleven trioxa-adamantane-triols (TATs) [BN, IBNCA, ABNCA, VANBA, ethylVANBA, euBN, euVANBA, ansaBN, Ehrlich BN, [6]prismaneBN, nitrodiBN], trivially termed bananins, one trioxa-adamantan-ol (TAO) THYMOBA, one bis-bananin pi-bananin (piBN), one triazaadamantane delta-bananin (deltaBN), seven potential nucleic acid-binding drugs (XBQC, INDO, PivINDO, AZTRION, AZADO, AZOCYS, AZOGALL), one potential antiviral interferon-inducer and distant nucleoside analog diazon, one potential HIV protein Vif antagonist AZODIAZON, one folic acid-diazon condensate DIAZONOFOL, and one special nucleoside analog (fructoinosine/fructovir). Four of the eleven bananins (BN, IBNCA, VANBA, euBN) were already demonstrated to constitute effective inhibitors of SARS-CoV NSP10/nsp13 RNA/DNA helicase/NTPase protein ATPase enzymatic function. Bananin (BN) was an effective inhibitor of both SARS-CoV RNA/DNA helicase nucleic acid unwinding function and SARS-CoV (Coronaviridae, Coronavirus) RNA-viral replication in cell culture. In summary, at least one selected compound of the synthesized test materials represents an interesting drug candidate for treatment of SARS-CoV-induced human disease (SARS). Viewed in aspects of organic chemistry [6]prismaneBN and nitrodiBN are the first true hexaprismane derivatives synthesized, and all reported compounds are entirely new.

Copper ions, either alone or in copper complexes, have been used to disinfect liquids, solids and human tissue for centuries. Today copper is used as a water purifier, algaecide, fungicide, nematocide, molluscicide as well as an antibacterial and anti-fouling agent. Copper also displays potent anti-viral activity. This article reviews (i) the biocidal properties of copper; (ii) the possible mechanisms by which copper is toxic to microorganisms; and (iii) the systems by which many microorganisms resist high concentrations of heavy metals, with an emphasis on copper.