Medicinal Chemistry Reviews - Online (Discontinued) - Volume 2, Issue 5, 2005

Lipases are the most used enzymes as biocatalyst in the resolution of chiral compounds. To improve the results, many different techniques have been proposed (protein engineering, random mutagenesis with selection pressure, screening in the nature, etc). However, bearing in mind that enzymes are commonly utilised in the industry in an immobilised form, a simple strategy has recently been reported to permitting greatly improvement in the results using lipases. The strategy is based in the dramatic conformational changes of lipases during catalysis and the use of a library of immobilisation protocols that may permit to immobilise the lipases via different orientations, with different rigidity levels or generating different environments. This may be combined with the experimental conditions to significantly alter the results. In this review, we include some examples, with lipases from different sources and different compounds, where the enantiomeric ratio has been moved from almost negligible value to more than 100 just by this very simple strategy, the so-called "conformational engineering of lipases".

Phospholipases A2 belong to a large family of enzymes involved in the generation of several second messengers that play an important role in signal transduction processes associated with normal brain function. The phospholipase A2 family includes secretory phospholipase A2, cytosolic phospholipase A2, calcium-independent phospholipase A2, and plasmalogen-selective phospholipase A2. The systemic administration of kainic acid to rats results in seizures and subsequent degeneration of specific neurons in the hippocampus and striatum. The kainic acid-induced neurodegeneration is accompanied by upregulation of PLA2 activity and immunoreactivity. Stimulation of PLA2 activity results in the degradation of phospholipids in neuronal membranes with the generation of arachidonic acid and lysophospholipids. These products are further metabolized to potent inflammatory mediators such as eicosanoids and platelet activating factor. Although an inflammatory response can be induced by many different means, phospholipase A2-generated inflammatory mediators are closely associated with the pathogenesis of inflammation and oxidative stress in neurodegenerative diseases. Peroxidation of arachidonic acid, a PLA2 reaction product, also results in generation of 4-hydroxy-2,3-nonenal (4- HNE), an α, β-aldehyde with neurotoxic properties. In kainic acid-mediated neurotoxicity, the treatment of brain slices with antimalarial drugs, quinacrine, chloroquine, hydroxychloroquine, and quinine, inhibits neurodegeneration and reduces PLA2 and 4-HNE immunoreactivities. This suggests that antimalarial drugs can be used as neuroprotectants and anti-inflammatory agents in neurodegenerative diseases. In vitro and in vivo studies indicate that antimalarial drugs can also be used for the treatment of prion diseases, ischemic injury, and experimental Parkinson disease (PD). These drugs maintain blood pressure, decrease infarct size, reduce inflammation, and inhibit neurodegeneration in focal and global models of cerebral ischemia and protect dopaminergic neurons from neurodegeneration in experimental PD. Initial attempts to treat Creutzfeldt-Jakob disease (CJD) with quinacrine in humans indicate that this antimalarial drug may have some transient beneficial effects in advanced CJD patients. Antimalarial drugs have no beneficial effects in Alzheimer disease.

Tuberculosis (TB) remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis, and infects approximately 32 % of the world's human population. It is estimated that 8.2 million new TB cases occurred worldwide in the year 2000, with approximately 1.8 million deaths in the same year, and more than 95 % of those were in developing countries. The interruption of centuries of decline in case rates of TB occurred, in most cases, in the late 1980s and involved the USA and some European countries due to increased poverty in urban settings and the immigration from TB high-burden countries. Thus, no sustainable control of TB epidemics can be reached in any country without properly addressing the global epidemic. The reemergence of TB as a potential public health threat, the high susceptibility of human immunodeficiency virus-infected persons to the disease, and the proliferation of multi-drug-resistant (MDR) strains have created much scientific interest in developing new antimycobacterial agents to both treat M. tuberculosis strains resistant to existing drugs, and shorten the duration of short-course treatment to improve patient compliance. Bacterial cell-wall biosynthesis is a proven target for new antibacterial drugs. Mycolic acids, which are key components of the mycobacterial cell wall, are α- alkyl, β-hydroxy fatty acids, with a species-dependent saturated "short" arm of 20-26 carbon atoms and a "long" meromycolic acid arm of 50-60 carbon atoms. The latter arm is functionalized at regular intervals by cyclopropyl, α-methyl ketone, or α-methyl methylethers groups, and, as shown more recently, by unsaturations. The mycolic acid biosynthetic pathway has been proposed to involve five distinct stages: (i) synthesis of C20 to C26 straightchain saturated fatty acids to provide the α-alkyl branch; (ii) synthesis of the meromycolic acid chain to provide the main carbon backbone, (iii) modification of this backbone to introduce other functional groups; (iv) the final Claisen-type condensation step followed by reduction; and (v) various mycolyltransferase processes to cellular lipids. The drugs shown to inhibit mycolic acid biosynthesis are isoniazid, ethionamide, isoxyl, thiolactomycin, and triclosan. Pyrazinamide was thought to inhibit fatty acid synthase type I, thereby reducing the synthesis of precursor of mycolic acids. However, current experimental evidence indicates that it has no defined target of action. The main focus of our contribution is on new data describing the mode of action of antitubercular drugs that inhibit mycolic acid biosynthesis, and description of inhibitors of fatty acid synthase type II enzymes as potential lead compounds that may allow the development of new antitubercular agents.

Wide range of dose-limiting toxicities and tumor resistance to drug are significant limitations of the successful use of cis-diamminedichloroplatinum (cisplatin). For a long time it was believed that generally trans-isomers of platinum containing complexes are devoid of biological activity. Data accumulated by the structure-activity relationship studies up to date, confirm that trans-platinum(II) and trans-platinum(IV) complexes often exhibit enhanced activity in cisplatin resistant cell lines in comparison to their cis-analogs, indicating that trans-platinum compounds follow some different pattern of antitumor activity in comparison to their cis-isomers. Trans-platinum complexes that have been tested to date and have shown to possess attractive antitumor properties represent diverse group of compounds, and can be classified according to the structure and the nature of nonleaving (amine) ligand as following: trans-ammine(amine) platinum(IV) complexes, trans-platinum(II) complexes with planar ligands, trans-platinum(II) complexes with heterocyclic amine ligands, trans-platinum(II) complexes with iminoether ligands, trans-platinum(II) complexes with asymmetric aliphatic amine ligands, bifunctional binuclear and trinuclear trans-platinum(II) complexes. Potential of trans-platinum complexes to follow some different mechanisms of cell killing in comparison to cis-DDP and thus circumvent cis-DDP resistance, raises interest for their further preclinical evaluation.

Pentacyclic triterpenes have been found in many plants and can be isolated from any parts of the plant. Triterpene derivatives were shown to have biological activities including anti-HIV-1 and anti-cancer. The modes of action of the anti-HIV-1 triterpenes have been reported to be associated with virus entry, reverse transcription, virus assembly, and maturation. This review will focus on the mechanisms of action of anti-HIV triterpenes and the structural features that contribute to their anti-HIV-1 activity. Two classes of triterpenes are particularly potent and highly selective: one inhibits HIV-1 entry and the other interferes with HIV-1 maturation. Significant progresses have been made in identifying the mechanisms of action for these two classes of anti-HIV-1 triterpenes. The anti-HIV-1 entry activity is associated with a side chain at position 28 and the anti- HIV-1 maturation activity is associated with the pharmacophore at position 3. Compounds containing both of the pharmacophores at 3 and 28 positions can potently inhibit HIV-1 through their anti-HIV-1 entry and maturation activities. Although the detail mechanisms of action remains unclear, the anti-entry triterpenes target HIV-1 envelope glycoprotein, and the anti-maturation triterpenes affect the processing of the HIV-1 gag protein, CA-SP1.

Immunosuppressive therapy can be used to prevent graft rejection and to treat autoimmune diseases. Recent advances in the understanding of this immune response have focused on the development of new immunosuppressive medications and new approaches to induction of immunological tolerance and reduction of late graft losses. In this overview, preclinical and clinical studies of the new immunosuppressive agents and their analogs are reviewed from the discovery of cyclosporine. More recently, certain classical immunosuppressants tacrolimus and sirolimus were well used to prevent acute rejection of transplanted organs and to ensure long-term survival of the allografts. However, some immunosuppressants have specific and significant toxic effects, so that drug combination therapy has been of great interest in addition to the introduction of novel small molecule agents, including mycophenolate mofetil; sirolimus analogs, SDZ RAD; 15-deoxyspergualin (DSG) and its analogs, FTY720; malononitrilamide analogs, FK778 and leflunimide; Sanglifehrins A; PG490-88; FK330 and 4-amino-analog of tetrahydrobiopterin of nitric oxide synthase inhibitors; genistein, baohuoside- 1 and apigenin of flavonoid family; Prostaglandin E2; CYP3A4, CYP3A5, and P-glycoprotein; vitamin E analogs, α-tocopheryl (PEG-1000) succinate (TPGS). A newer immunomodulation concept and their new drugs will also be described.