Dinesh R. Garud

Isoselenocyanates: A Powerful Tool for the Synthesis of Selenium-Containing Heterocycles

Selenium-containing heterocyclic compounds have been well recognized, not only because of their remarkable reactivities and chemical properties, but also because of their diverse pharmaceutical applications. In this context, isoselenocyanates have been emerged as a powerful tool for the synthesis of selenium-containing heterocycles, since they are easy to prepare and store and are safe to handle. In this review the recent advances in the development of synthesis methods for selenium-containing heterocycles from isoselenocyanates are presented and discussed.

Synthesis of 3-selena-1-dethiacephems and selenazepines via iodocyclization.

A convenient approach to synthesize novel selenium-beta-lactams, 3-selena-1-dethiacephems and selenazepines, was accomplished via the regioselective iodocyclization reaction. The substituent of allenyl moieties dramatically influenced the regiochemical outcome in the iodocyclization of allene-selenourea derivatives.

Selenium-Containing Heterocycles Using Selenoamides, Selenoureas, Selenazadienes, and Isoselenocyanates

In recent years, considerable attention has been devoted to the synthesis of selenium-containing heterocycles because of their interesting reactivities and potential pharmaceutical applications. The significant starting materials for the selenium-containing heterocycles synthesis are selenoamides, selenoureas, selenazadienes, and isoselenocyanates. This review article introduces the developed synthetic methods mainly on our findings.

Identification of organoselenium compounds that possess chemopreventive properties in human prostate cancer LNCaP cells

The process of cancer development consists of three sequential stages termed initiation, promotion, and progression. Oxidative stress damages DNA and introduces mutations into oncogenes or tumor suppressor genes, thus contributing to cancer development. Cancer chemoprevention is defined to prevent or delay the development of cancer by the use of natural or synthetic substances. In the present study, we synthesized a series of organoselenium compounds and evaluated their possible chemopreventive properties in human prostate cancer LNCaP cells. Among 42 organoselenium compounds tested, two compounds, 3-selena-1-dethiacephem 13 and 3-selena-1-dethiacephem 14 strongly activated the Nrf2/ARE (antioxidant response element) signaling and thus markedly increased expression of heme oxygenase-1 (HO-1), a phase II antioxidant enzyme. Translocation of Nrf2 to the nucleus preceded HO-1 protein induction by two compounds. The intracellular ROS level was strongly reduced immediately after treatment with these compounds, showing that they are potent antioxidants. Finally, both compounds inhibited cell growth via cell cycle arrest. Our findings suggest that compounds 13 and 14 could not only attenuate oxidative stress through Nrf2/ARE activation and direct ROS scavenging but also inhibit cell growth. Thus, these compounds possess the potential as pharmacological agents for chemoprevention of human prostate cancer.

Inhibition of Heparan Sulfate and Chondroitin Sulfate Proteoglycan Biosynthesis

Proteoglycans (PGs) are composed of a protein moiety and a complex glycosaminoglycan (GAG) polysaccharide moiety. GAG chains are responsible for various biological activities. GAG chains are covalently attached to serine residues of the core protein. The first step in PG biosynthesis is xylosylation of certain serine residues of the core protein. A specific linker tetrasaccharide is then assembled and serves as an acceptor for elongation of GAG chains. If the production of endogenous GAG chains is selectively inhibited, one could determine the role of these endogenous molecules in physiological and developmental functions in a spatiotemporal manner. Biosynthesis of PGs is often blocked with the aid of nonspecific agents such as chlorate, a bleaching agent, and brefeldin A, a fungal metabolite, to elucidate the biological roles of GAG chains. Unfortunately, these agents are highly lethal to model organisms. Xylosides are known to prime GAG chains. Therefore, we hypothesized that modified xylose analogs may able to inhibit the biosynthesis of PGs. To test this, we synthesized a library of novel 4-deoxy-4-fluoroxylosides with various aglycones using click chemistry and examined each for its ability to inhibit heparan sulfate and chondroitin sulfate using Chinese hamster ovary cells as a model cellular system.

One-Pot Synthesis of 2-Imino-1,3-selenazolidines by Reaction of Isoselenocyanates with Propargylamine

One-pot synthesis of 2-imino-5-methylene-l,3-selenazolidines has been achieved by reactions of alkylisoselenocyanates with propargylamines in high yields. 1 H NMR and NOESY experiments were used to explain the selenium coupling with hydrogen of carbon-carbon double bond.

4-Deoxy-4-fluoro-xyloside derivatives as inhibitors of glycosaminoglycan biosynthesis

Various 4-deoxy-4-fluoro-xylosides were prepared using click chemistry for evaluating their potential utility as inhibitors of glycosaminoglycan biosynthesis. 2,3-Di-O-benzoyl-4-deoxy-4-fluoro-β-D-xylopyranosylazide, obtained from L-arabinopyranose by six steps, was treated with a wide variety of azide-reactive triple bond-containing hydrophobic agents in the presence of Cu(2+) salt/ascorbic acid, a step known as click chemistry. After click chemistry, benzoylated derivatives were deprotected under Zemplén conditions to obtain 4-deoxy-4-fluoro-xyloside derivatives. A mixture of α:β-isomers of twelve derivatives were then separated on a reverse phase C18 column using HPLC and the resulting twenty four 4-deoxy-4-fluoro-xylosides were evaluated for their ability to inhibit glycosaminoglycan biosynthesis in endothelial cells. We identified two xyloside derivatives that selectively inhibit heparan sulfate and chondroitin sulfate/derman sulfate biosynthesis without affecting cell viability. These novel derivatives can potentially be used to define the biological actions of proteoglycans in model organisms and also as therapeutic agents to combat various human diseases in which glycosaminoglycans participate.

Synthetic approaches to selenacephams and selenacephems via a cleavage of diselenide and selenium anion

The bis-2-(trimethylsilyl)ethyl diselenide was prepared and used as a selenating reagent for the insertion of the 2-(trimethylsilyl)ethylseleno group at the C-4 position of the azetidinones. Bis-4-(azetidin-2-one) diselenides were used for the first time as a key intermediate for the synthesis of selenium-containing β-lactams i.e. selenacephams and selenacephems.

SELENIUM-CONTAINING BICYCLIC β-LACTAMS

The first β-lactam ring system was synthesized by H. Staudinger in 1907, but β-lactams as a class of compounds became attractive only after it was established that penicillin contained a β-lactam unit as the structural feature. Over the years, countless numbers of penicillin derivatives and a variety of new β-lactam ring systems have been prepared, tested, and introduced. As a class of β-lactam derivatives, selenium-containing bicyclic β-lactams have received only a limited attention. In this review the advances in the development of synthesis methods for selenium-containing bicyclic β-lactams are presented and discussed.

One-pot synthesis of 2-imino-1,3-oxaselenolanes by reaction of isoselenocyanates with 2-bromoethanol

- One-pot synthesis of 2-imino-l,3-oxaselenolanes has been achieved by reactions of isoselenocyanates with 2-bromoethanol in good to excellent yields. The structure of the 2-imino-l,3-oxaselenolanes was confirmed by spectroscopic and X-ray analysis. The thermal rearrangement of 2-imino-l,3-oxaselenolanes to l,3-selenazolidin-2-one is observed for the first time.