Venkitasamy Kesavan

An organocatalytic diastereo- and enantioselective synthesis of 2,2′-disubstituted benzofuran-3-ones bearing adjacent quaternary and tertiary stereocenters has been achieved through Michael addition of 2-substituted benzofuran-3-ones to 2-enoyl pyridines. Both the enantiomeric forms of the major diastereomer were obtained using l-proline derived squaramide and quinine derived bis squaramide with excellent yield (up to 98%) and stereoselectivities (up to 97:3 dr and 98% ee). The control experiment revealed that the presence and position of nitrogen atoms in the 2-enoylpyridine have played a crucial role in the stereochemical outcome of the product.

In this study, we have identified one microRNA, microRNA 493 (miR-493), which could simultaneously and directly regulate multiple genes downstream of the insulin-like growth factor 1 receptor (IGF1R) pathway, including IGF1R, by binding with complementary sequences in the 3' untranslated region (UTR) of mRNAs of IGF1R, insulin receptor substrate 1 (IRS1), and mitogen-activated protein kinase 1 (MAPK1), thereby potentiating their inhibitory function at multiple levels in development and progression of cancers. This binding was further confirmed by pulldown of miR with AGO-2 antibody. Further, results from head and neck samples showed that miR-493 levels were significantly downregulated in tumors, with a concomitant increase in the expression of IGF1R and key downstream effectors. Functional studies from miR-493 overexpression cells and nude-mouse models revealed the tumor suppressor functions of miR-493. Regulation studies revealed that Snail binds to the miR-493 promoter and represses it. We found the existence of a dynamic negative feedback loop in the regulation of IGF1R and miR-493 mediated via Snail. Our study showed that nicotine treatment significantly decreases the levels of miR-493-with a concomitant increase in the levels of Snail-an indication of progression of cells toward tumorigenesis, reestablishing the role of tobacco as a major risk factor for head and neck cancers and elucidating the mechanism behind nicotine-mediated tumorigenesis.

A highly enantioselective stereodivergent synthesis of 3-aminooxindole derivatives was accomplished via asymmetric Mannich reaction between 2-substituted benzofuran-3-one and isatin-derived ketimines. Both anti and syn-selective chiral 3,3-disubstituted amino oxindoles bearing two adjacent tetrasubstituted stereogenic centers with high yield and excellent enantioselectivities were obtained using readily available cinchona-alkaloid derived organocatalysts. The control experiment revealed that oxygen atom present in the benzofuran ring played an important role in switching diastereodivergence. The obtained Mannich product was further transformed into a biologically important 2,3-dihydrobenzofuran derivative having three contiguous stereocenters with no loss of enantioselectivity.

A new synthetic strategy to construct spirooxindole-naphthopyran scaffold has been demonstrated via Friedel-Crafts type/hemiketalization of oxindole α-ketoester with 2-naphthol. Under the established reaction condition, quaternary chiral center at C3-position of oxindole has been created with very good asymmetric induction up to 98 % for a broad range of substrates. DFT calculations, which account for the stereochemical outcome, were performed.

An asymmetric [3 + 2] formal cycloaddition reaction between oxindole α-keto esters and enals has been developed. This α,γ-regioselective reaction afforded multifunctional carbocyclic oxindoles via dienamine-enamine cascade reaction followed by isomerization. Furthermore, a highly enantioselective Diels-Alder reaction was demonstrated between 2,4-dienals and oxindole α-keto esters via trienamine intermediates. Chiral secondary amine catalyzed the both reactions under mild conditions and the cyclized products were isolated in moderate to good yields with good diastereoselectivities (>20:1 dr) and enantioselectivities (up to 99 %).

The catalytic efficiency of a bifunctional chiral thiourea derived from l-proline was evaluated in the asymmetric direct vinylogous Michael reaction of α,α-dicyanoolefins to β-nitrostyrenes with an electron-releasing or electron-withdrawing substituent in various positions. The corresponding adducts were isolated in good yields, with excellent diastereo- (>99%) and enantioselectivity (up to 95%). The Michael adducts were further functionalized to achieve the synthesis of polycyclic fused pyrrolidines with three contiguous stereocenters in good enantioselectivities.

Acyclic (l)-threoninol nucleic acid (aTNA) containing thymine, cytosine and adenine nucleobases were synthesized and shown to form surprisingly stable triplexes with complementary single stranded homopurine DNA or RNA targets. The triplex structures consist of two (l)-aTNA strands and one DNA or RNA, and these triplexes are significantly stronger than the corresponding DNA or RNA duplexes as shown in competition experiments. As a unique property the (l)-aTNAs exclusively form triplex structures with DNA and RNA and no duplex structures are observed by gel electrophoresis. The results were compared to the known enantiomer (d)-aTNA, which forms much weaker triplexes depending upon temperature and time. It was demonstrated that (l)-aTNA triplexes are able to stop primer extension on a DNA template, showing the potential of (l)-aTNA for antisense applications. This journal is

Copper(I) bromide catalyzed direct C-H arylation of cyclic enamides was achieved using diaryliodonium salts in the absence of base/additive at ambient temperature with high yields. A biologically active dihydro[a]benzocarbazole scaffold was synthesized using the established protocol. The scope of the current methodology was further extended for the synthesis of C4-, C7-aryl-substituted 1-naphthyl acetamides in good yields.

A new class of bifunctional tertiary amine thiourea was synthesized from l-proline. The reported thiourea is amenable to steric and electronic modifications at the stereogenic center bearing a thiourea moiety. Excellent enantioselectivity was obtained in the Michael addition of 2,4-pentanedione to various nitro olefins using the new organocatalyst. The construction of contiguous stereocenters via the Michael reaction of substituted 1,3-dicarbonyls to nitro olefins was also carried out with very good yield, enantioselectivity, and diastereoselectivity. © 2014 Elsevier Ltd. All rights reserved.

Diverse bispiro-3,4-dihydropyrans consisting of oxindole moieties with three contiguous chiral centers and vicinal quaternary stereocenters were synthesized with very good yields of up to 92% and excellent enantioselectivity of up to 99% ee by using a proline-derived thiourea organocatalyst.