Letters in Drug Design & Discovery - Volume 4, Issue 5, 2007

The investigation of metal-containing drugs over several decades has set out to improve upon the toxicity and efficacy of conventional chemotherapeutic agents. Promising pre-clinical and clinical data have fostered the broadening for the search of metal compounds in cancer treatment and combination therapy. Gallium is only second to platinum in terms of anti-tumor activity. Its subsequent investigation has been ongoing for nearly three decades, primarily in the form of salts, and more recently coordinated to organic ligands as coordination complexes. From its early investigation as a diagnostic agent to its anti-tumor potential, promising clinical results have shown a renewed interest in exploring gallium in a host of malignancies, especially lymphoma and bladder cancer. However, the detailed mechanisms of action of gallium compounds are not completely defined. Further understanding the underlying mechanisms along with optimizing the structural components of gallium complexes will further improve the therapeutic index of gallium.

Chiral derivatives of two cyclohexylethyl halopyridyl thiourea compounds (HI-509 and HI-510), two α -methyl benzyl halopyridyl compounds (HI-511 and HI-512), and a cyclohexyl ethyl thiazolyl thiourea compound (HI-513) were synthesized and evaluated for their anti-cancer activity. Preliminary screening indicated that the (S)- isomers displayed improved activity in comparison with (R)- enantiomers to inhibit tubulin polymerization and activate caspase- 3. In accordance with these results, the thiourea derivatives displayed potent anti-cancer activity against human B-lineage (Nalm-6) and T-lineage (Molt-3) acute lymphoblastic leukemia cell lines. Based on the results we conclude that the anti-leukemic activity of these compounds also depends on their chirality.

Synthesis of different N10-substituted-4-methyl acridones are described. The compounds are prepared with varying alkyl side chain length with propyl and butyl substitution and a tertiary amine group at the terminal end of the alkyl side chain. The structural requirement of in-vitro anti-cancer and reversal of drug resistance are studied. These compounds have been tested against the breast cancer cell lines MCF-7 and MCF- 7/Adr. The results show that compound 17 with four carbon spacer exhibited promising in-vitro anti-cancer and reversal of drug resistance in comparison to the other analogues. The studies show that the reversal of drug resistance is by P-gp inhibition.

In view of the significant side-effects of existing substances as well as of supportive therapies for the treatment of pulmonary edema, there is a renewed search for novel drugs that increase the uptake of sodium in type II alveolar epithelial cells, a phenomenon which is crucial for lung liquid clearance. We describe here the discovery and characterization of a Tumor Necrosis Factor (TNF)-derived peptide mimicking the lectin-like domain of the cytokine as a potential novel anti-edema agent.

New cisplatin analogue carrying a cholic acid, complex [PtCl(UDC)(en)] (en = ethylenediamine, UDC = Ursodeoxycholate) has been synthesized from [PtCl2(en)] and characterized. This novel complex shows increased cytotoxicity against a cisplatin-resistant ovarian tumor cell line (CH1cisR) as compared with the parent compound cisDDP. Moreover, while cisplatin only exerts its activity over the G2/M population, [PtCl(UDC)(en)] seems to induce apoptosis both in cycling and resting cells. Intrinsically fluorescence at room temperature was observed for this platinum complex with a quantum yield Φ = 0.11. In order to achieve dynamic pictures of the biological effects of cisplatin analogues, it would be very interesting to have intrinsically fluorescent compounds with cytotoxic activity, especially against drug-resistant cell-lines.

ERα17p is a synthetic peptide corresponding to a regulatory motif located within the autonomous AF-2a region of the estrogen receptor α (ERα). ERα17p binds to the receptor and enhances its transcriptional activity. Structural characteristics of this peptide suggest that it interferes with intra- and/or interprotein interactions involving ERα.

HIV-specific protease inhibitors are fundamental antiviral drugs for people with HIV/AIDS. Hologram quantitative structure-activity relationships (HQSAR) were conducted on a class of 82 protease inhibitors. The final model obtained was used to predict the potency of 17 test set compounds. The predicted values were in good agreement with the experimental results.

The present study examines the pharmacological profile of a new five indole derivatives 2a-e, ligands of the serotonin receptor evaluating the affinity for the serotoninergic, (5HT1A, 5HT2A and 5HT2C) receptors. The affinity of indole derivatives 2a-e (10-6-5x10-7-10-7 M) for receptors is defined as inhibition percentage of radioligand/receptor binding and measured as the radioactivity of remaining complex radioligand/receptor. The results of our experiments indicate that compounds 2a and 2e show high affinity for the 5-HT2A receptors; compounds 2b and 2c show high affinity for the 5-HT1A receptors and compound 2d shows high affinity for the 5-HT2C receptors. Results of computational chemistry suggest that the presence of a methoxyl group in 6 on the indole system is necessary for the serotoninergic activity.

To identify the important structural components of glutathione that induce sedative and hypnotic effects, intracerebroventricular (i.c.v.) injection of three glutathione-related dipeptides, i.e., glutamyl-cysteine (Glu-Cys), cysteinyl-glycine (Cys-Gly) and glutamyl-glycine (Glu-Gly) were given during an acute stress condition in neonatal chicks. These peptides attenuated distress vocalizations and spontaneous activity induced by social isolation. The increase in the time for sedation including sleep was also observed following the i.c.v. injection of dipeptides and then the time for active wakefulness decreased. Among the three peptides, Glu-Cys and Glu-Gly had a tendency to attenuate corticosterone release. In conclusion, dipeptides related to glutathione had a sedative and hypnotic effect, and did not vary in their action from each other.

The majority of current smokers in the U.S. also have at least one comorbid psychiatric illness. Looking at commons mechanisms of nicotine dependence and psychiatric disorders of hedonic regulation reveals nicotinic acetylcholine receptors and the glycine site on NMDA receptors as potential targets for pharmacological treatment of these disorders.

The synthesis of new triphenyltin derivatives with (N-substituted-pyrazol-3-yl) carboxylic acid fragments is described. The in vitro antibacterial activity of the new agents was evaluated against two fungal strains (Saccharomyces cerevisiae and Fusarium oxysporum f.sp albedinis) and against bacterial strains (Echerichia coli). A considerable activity was recorded with respect to the three studied micro-organisms. Structure activity relationship studies (SAR) reflect the effect of substituted pyrazolic fragment.