Current Medicinal Chemistry - Volume 9, Issue 20, 2002

Cell-mediated immune responses are important for the control of HIV replication in vivo. Cytotoxic CD8+ T cells (CTL) recognize and kill HIV-infected cells which display MHC class-I proteins. In addition to the recognition and killing of infected cells, CD8+T cells can interfere with stages of the HIV life-cycle. Chemokines produced by CD8+ T cells bind to their seven-transmembrane G protein-coupled receptors resulting in a block in the entry of HIV into macrophages and T cells. In addition, activated CD8+ T cells produce factors which strongly modulate HIV at the level of transcription. This review will focus primarily on the current knowledge of the multifactorial functions of CD8+ T cells in HIV infection. An understanding of the mechanisms involved in the CD8-mediated control of transcription may identify other factors with potential value in the treatment of HIV infection.

It is increasingly evident that the true biological origin of many metabolites originally isolated from certain marine macroorganisms is cyanobacterial. For example, several dolastatins, potent cytotoxic compounds originally derived from the sea hare Dolabella auricularia, have now been isolated from marine cyanobacteria of the genera Lyngbya and Symploca. This review discusses the isolation of dolastatins and close structural analogues from cyanobacteria. Biosynthetic signatures of metabolites isolated from sea hares, but which are most probably cyanobacterial in origin, are also presented. Finally, some more complex ecology involving movement of cyanobacterial metabolites through the marine food web is presented.

Chemical substance abuse has tormented mankind throughout history. A number of chemical approaches have been employed in an attempt to treat chemical addiction. Unfortunately, most of these have proven unsuccessful though several chemical entities have been shown to be moderately effective. The naturally occurring alkaloid ibogaine has been reported to interrupt the cravings for alcohol, cocaine and opiates. Other alkaloids from Tabernanthe iboga, such as ibogamine and tabernanthine, provide insight into the structure activity relationship at the different receptors believed to be involved in addiction. The synthetic iboga alkaloid congener, 18-MC, also shows potential as an anti-addictive agent without the hallucinogenic effects of ibogaine. Additionally, acamprosate, BP 897, GBR12909, lofexidine and memantine have shown promising results in the treatment of addiction. All of these leads provide a start for the medicinal chemist to design anti-addictive agents, since currently no drugs are approved in the U.S. for the treatment of addictions to cocaine, methamphetamine, other stimulants or PCP.

Correct QSAR analysis requires reliable measured or calculated logP values, being logP the most frequently utilized and most important physico-chemical parameter in such studies. Since the publication of theoretical fundamentals of logP prediction, many commercial software solutions are available. These programs are all based on experimental data of huge databases therefore the predicted logP values are mostly acceptable - especially for known structures and their derivatives. In this study we critically reviewed the published methods and compared the predictive power of commercial softwares (CLOGP, KOWWIN, SciLogP / ULTRA) to each other and to our recently developed automatic QS(P)AR program. We have selected a very diverse set of 625 known drugs (98%) and drug-like molecules with experimentally validated logP values. We have collected 78 reported “outliers” as well, which could not be predicted by the “traditional” methods. We used these data in the model buildings and validations. Finally, we used an external validation set of compounds missing from public databases. We emphasized the importance of data quality, descriptor calculation and selection, and presented a general, reliable descriptor selection and validation technique for such kind of studies. Our method is based on the strictest mathematical and statistical rules, fully automatic and after the initial settings there is no option for user intervention. Three approaches were applied: multiple linear regression, partial least squares analysis and artificial neural network. LogP predictions with a multiple linear regression model showed acceptable accuracy for new compounds therefore it can be used for “in-silico-screening” and / or planning virtual / combinatorial libraries.

Statins significantly reduce cardiovascular-related morbidity and mortality in patients with and without coronary artery disease. The potential of this drug class has yet to be fully explored. Accumulating evidence from basic research and clinical trials indicates that statins have pleiotropic effects that may largely account for the clinical benefits observed. Potential beneficial effects of these agents include enhancement of nitric oxide production in vasculature and the kidney. Statins have been shown to stabilize unstable plaques, improve vascular relaxation, and promote new vessel formation. Clinical trials and animal studies have shown that these agents reduce cardiovascular disease (CVD) risks and events, progression of nephropathy, development of diabetes, and fracture rates, these are benefits that go beyond lipid lowering alone. Potential beneficial effects are due to the positive impact on vascular and glomerular nitric oxide (NO) production and attenuation of vascular inflammation. Effects on bone, including fracture reduction, are thought to be mediated by direct action on bone formation. Moreover, potential reduction in the development of diabetes as observed in the West of Scotland Coronary Prevention Study (WOSCOPS) may relate to the improvement in insulin sensitivity. These actions are mediated, in part, by the effects on small G-proteins, modulation of signaling cascades, transcription, and gene expression. In particular, the inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the direct cellular effects of statins on the vascular wall. The clinical relevance of these effects is beginning to be recognized, and ongoing studies will be able to answer these many questions in the near future. Actions of statins on vascular, glomerular, bone, and insulin-sensitive tissue as well as effects of statins on cognitive function and oncoprotection will be discussed in this review.