Rh-Catalyzed Twofold Conjugate Addition of 2-Arylimidazo[1,2-a]pyridines to p-Quinols To Access Bridged Scaffolds with Three Contiguous Stereocenters.

A Rh(III)-catalyzed annulation of 2-arylimidazo[1,2-a]pyridines with p-quinols has been realized, leading to bridged heterocycles with three contiguous stereocenters via a twofold conjugate addition. The cascade reaction is diastereoselective and proceeds through a sequential Rh-catalyzed ortho C(sp2)-H functionalization of the aryl group of imidazo[1,2-a]pyridine with p-quinol followed by an intramolecular conjugate addition to provide a series of diverse, novel bridged heterocycles.

Design, synthesis and biological evaluation of novel pyrazolochalcones as potential modulators of PI3K/Akt/mTOR pathway and inducers of apoptosis in breast cancer cells.

Cancer has been established as the "Emperor of all maladies". In recent years, medicinal chemistry has focused on identifying novel anti-cancer compounds; though discovery of these compounds appears to be a herculean task. In present study, we synthesized forty pyrazolochalcone conjugates and explored their cytotoxic activity against a panel of sixty cancer cell lines. Fifteen conjugates of the series showed excellent growth inhibition (13b-e, 13h-j, 14c-d, 15 a, 15 c-d, 16b, 16d and 18f; GI50 for MCF-7: 0.4-20 µM). Conjugates 13b, 13c, 13d, 16b and 14d were also evaluated for their cytotoxic activity in human breast cancer cell line (MCF-7). The promising candidates induced cell cycle arrest, mitochondrial membrane depolarization and apoptosis in MCF-7 cells at a 2 µM concentration. Furthermore, inhibition of PI3K/Akt/mTOR pathway-regulators such as PI3K, p-PI3K, p-AKT, and mTOR were observed; as well as upregulation of p-GSK3ß and tumor-suppressor protein, PTEN. Our study indicates that pyrazolochalcone conjugates could serve as potential leads in the development of tailored cancer therapeutics.

Design, synthesis and biological evaluations of chirally pure 1,2,3,4-tertrahydroisoquinoline analogs as anti-cancer agents.

A series of fifteen chiral 1,2,3,4-tetrahydroisoquinoline (THIQ) derivatives have been synthesized and their antiproliferative properties have been studied. The in vitro screening was performed against five cancer cell lines; MCF-7 (breast cancer), A549 (lung cancer), DU-145 (prostate cancer), Hela (cervical cancer) and HepG2 (liver cancer). Most of the compounds showed promising activity with IC50 Values ranging from 0.72 to 92.6 µM. Among them, compounds 9a and 9b have shown significant activity against human prostate cancer cell line, i.e., DU-145 with IC50 value 0.72 and 1.23 µM respectively. To investigate the mechanism of action, detailed biological studies of compounds 9a and 9b were carried out on the human prostate cancer cell line, DU-145. Flow cytometric analysis revealed that these compounds induced cell cycle arrest at G2/M phase. Tubulin polymerization assay and immunofluorescence analysis results suggested that these compounds effectively inhibit microtubule assembly formation in DU-145. The apoptosis inducing properties were evaluated by DNA fragmentation analysis, Caspase-3 activity assay, Annexin V-FITC assay and Western blot analysis of proapoptotic protein, Bax and antiapoptotic protein Bcl-2.

Asymmetric Michael addition of ketones to nitroolefins: pyrrolidinyl-oxazole-carboxamides as new efficient organocatalysts.

Chiral pyrrolidinyl-oxazole-carboxamides were synthesized and used as efficient new organocatalysts for the asymmetric Michael addition of ketones with nitroalkenes under solvent-free conditions. Gratifyingly, the corresponding Michael adducts were obtained in higher yields (up to 99%) and excellent stereoselectivities (up to >99/1 dr and 99% ee). Transition state models have been proposed to account for the high enantio- and diastereoselectivity of these Michael addition reactions and also the energetics have been investigated using density functional methods. These results support the preferential formation of syn-products by the approach of trans-ß-nitrostyrene through the re-face of anti-enamine.