Letters in Drug Design & Discovery - Volume 12, Issue 2, 2015

A new series of phenothiazine and carbazole derivatives was synthesized and evaluated for their biological activity on human protein farnesyltransferase. The farnesyltransferase assays revealed that carbazole 4f was the best farnesyltransferase inhibitor in the current study (IC50 (human FTase) = 35.0 μM), providing that the presence of the carbazole unit is important in this family of compounds. Moreover, unexpected disulfide analogues were observed during coupling reactions of activated esters 12 and 13 with aminoethanethiol and mercaptoethanol, respectively. These dimers deserve further chemical and biological investigation in order to develop new chemical entities for anticancer research.

Ribonucleotide reductase is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides. We present for the first time a quantum-chemical study of the thermodynamics of reactions of naturally occurring potent inhibitors (trans-resveratrol, trans-piceatannol and hydroxyurea) of ribonucleotide reductase with tyrosine radical and cysteine radical, scavenging of which is crucial for the inhibition of the enzyme. Density functional theory has been applied to compute the Gibbs free enthalpy changes for these reactions in the gas phase and in the presence of water medium. Various reaction pathways have been analyzed. The results obtained prove that trans-resveratrol 4’-OH group is mainly responsible for effective reaction with these enzymatic free radicals. In water medium, the reactions studied are characterized by more negative values of the Gibbs free enthalpy changes than in vacuum. It was found that transresveratrol and trans-piceatannol may be efficient inhibitors of the enzyme (trans-piceatannol is more efficient than transresveratrol). Because inhibition of ribonucleotide reductase is essential for blockage of the cancer development pathways, the polyphenols studied may block diverse processes (including cancerogenesis) by inhibition of free radical reaction steps that occur during the catalytic action of this enzyme.

Mannich bases are pharmacologically important molecules having wide range of bioactivities. We previously synthesized and characterized a number of Mannich base derivatives of planar polycyclic/heterocyclic starting materials of which four of them [MB1 (3-(bis(2-chloroethyl)amino)-1-phenylpropan-1-one hydrochloride), MB2 (3-(bis(2- chloroethyl)amino)-1-(naphthalen-2-yl)propan-1-one hydrochloride), MB3 (3-(bis(2-chloroethyl)amino)-1-(phenanthren- 3-yl)propan-1-one hydrochloride) and MB4(3-morpholino-1-(pyren-1-yl)propan-1-one hydrochloride)] manifested antiproliferative effects in three cancer cell lines (PC3, HeLa, and MCF7) and one non-tumoral cell line (293 HEK). Because several reports covering anti-proliferation address DNA topoisomerases as the cellular targets, we undertook further assays using these four compounds with type I and type II topoisomerases to identify if their effects were mediated through topoisomerase reactions. Our results indicated that the three of these compounds (MB2, MB3 and MB4) target topoisomerase II without affecting type I topoisomerase. However, targeting type II enzyme did not generate considerable strand breaks, which in turn places the compounds MB2, MB3 and MB4 in potential topoisomerase II inhibitors, not poisons.

(E)-2-Arylmethylideneindolin-3-ol derivatives have been explored as new and potential anti-proliferative agents. Synthesis of these compounds was carried out by using a Pd/C-catalyzed alternative and one-pot method involving C-C coupling of 1-(2-(p-tosylamino)phenyl)prop-2-yn-1-ol with a range of iodoarenes followed by intramolecular hydroamination in the same pot. The reaction proceeded faster when performed under ultrasound irradiation. All these compounds showed selective growth inhibition of MDA-MB 231 cancer cells.

A series of hybrids of 3-hydroxy-indolin-2-one and 2,3-dihydroquinolin-4(1H) -one were synthesized and their anti-proliferative activities against two human cancer cell lines were initially evaluated. Compound 7g was selected for further study and demonstrated moderate anti-proliferative activities against four human cancer cell lines. Meanwhile, 7g had inhibitory effects on the growth of SGC-7901 cells in dosage-and time-dependent manners and the cancer cells appeared morphological changes. Moreover, 7g was more effective in the inhibition of xenografted tumor in vivo growth and mice treated with 7g showed more weight gain than 5-FU-treated mice over the treatment period, suggesting a lower toxic effect than 5-FU. After treatment with 7g, the tumor showed typical morphological changes as evaluated by H&E staining.

The prediction of contact maps in protein is a challenging topic for the determination of three-dimensional protein structures. In this paper, we introduce Forest of Decision Trees, a methodology for the prediction of protein contact maps based on (1) a divide-and-conquer approach to analyze the prediction problem; (2) a codification vector that combines the information obtained from the target amino acids neighborhood, and the sub-sequence between them; (3) an ensemble of classifiers that employs a hybrid of Genetic Algorithms and Decision Trees as base classifiers; and (4) a rulebased interpretation mechanism. The comparison against the top sequence-based methods in CASP10 showed that our predictor is very competitive, showing a high reliability. Their main advantage is its capability to generate a humancomprehensible rule-based interpretation mechanism, giving the specialist some clues to find an easier and interpretable solution for the protein-folding recognition and the prediction of unknown structures.

A small collection of eugenol- and curcumin-analog hydroxylated biphenyls was prepared by straightforward methods starting from natural 4-substituted-2-methoxyphenols and their antitumoral activity was evaluated in vitro. Two curcumin-biphenyl derivatives showed interesting growth inhibitory activities on different malignant melanoma cell lines with IC50 ranging from 13 to 1 μM. Preliminary molecular modeling studies were carried out to evaluate conformations and dihedral angles suitable for antiproliferative activity in hydroxylated biphenyls bearing a side aliphatic chain.

Several plant medicines are presented that have not been previously discussed in detail and are used in China and the USA for the management of Alzheimer’s disease. These plant medicines may provide new leads for drug therapy of this disease. Prevention of Alzheimer’s disease is presented as potentially the best way to manage the disease.

A series of bisphenol-C derivatives was synthesized by condensing bisphenol-C with benzylchloride, alkylchloroacetates and alkylchloroformates in the presence of anhyd. K2CO3 in THF using catalytic amount of PEG-600. The compounds were characterized by FTIR, 1HNMR, 13CNMR and MS; and assayed for their antibacterial activity against S. aureus MTCC-96, B. subtilis MTCC-441, E. coli MTCC-443, S. typhi MTCC-98 and antifungal activity against A. niger MTCC-282 and A. clavatus MTCC-1323 at different concentrations and compared with standard drugs. The minimum inhibition concentration (MIC) of the compounds was studied by micro broth dilution method. 1a-c, 1e-g and 2b-g showed moderate to comparable antibacterial activity against E. coli, S .typhi, B. subtillis and S. aureus. All of these compounds did not show antifungal activity. Increasing hydrophobic chain length, methyl side substituent and aromatic ring affected considerably antibacterial activity.

Alzheimer's disease (AD) is a multi factorial disease, related to the loss of neurons and synapses in cerebral cortex and subcortical structures, leading to degenerative changes and atrophy. Despite abundance of facts related to AD and its pathology, the only drugs used in the prevention and treatment are those from the cholinesterase inhibitors group. However, there is growing evidence that a non-classical therapeutic approach in the treatment of AD has beneficial effects. In this review we summarized recent literature data related to the non-classical drugs for the treatment of AD predominantly used in clinical testing, such as amyloid aggregation inhibitors, beta-sheet breakers, antioxidants, estrogens and immunotherapeutics.