Ram Chandra Mishra

Carbohydrate based Potential Chemotherapeutic Agents: Recent Developments and their Scope in Future Drug Discovery

In addition to being valuable source of energy, carbohydrates, one of the main dietary components, are integral parts of the cell. As extra- & intracellular molecules they act as cell surface receptor and also as signaling molecules playing predominant role in molecular recognition and many other cellular processes. The clear understanding of their role in the various important biological events has led to the demand for easy access of diverse glycoconjugates for their complete chemical and biological investigations. Several carbohydrate-based molecules both of synthetic and natural origin are known for their wide range of pharmacological activities and even many of them are clinically used to treat different ailments. Due to their structural diversity in terms of functional groups, ring size and linkages they are valuable scaffolds in drug discovery processes. Because of the hydrophilic nature of monosaccharides they offer good water solubility, optimum pharmacokinetics and decreased toxicity. These naturally occurring molecules have therefore been extensively used to access diverse library of compounds with great chemotherapeutic importance. This review highlights an overview of development of carbohydrate-based molecules from others and our lab which have shown promising biological activity against front line diseases.

CONJUGATE ADDITION OF AMINES TO SUGAR DERIVED OLEFINIC ESTERS: SYNTHESIS OF GLYCOSYLATED AMINO ESTERS AS DNA TOPOISOMERASE-II INHIBITORS

Conjugate addition of amines to olefinic esters derived from sugars leading to formation of glycosylated amino esters in a stereoselective manner is described. Some of the synthesized compounds possess DNA topoisomerase-II enzyme inhibitory activities at low concentrations.

Diastereoselective Synthesis and Antifungal Activity of Glycosyl Isoxazolines

Abstract Glycosyl nitrile oxides, generated in situ by reaction of glycosyl oximes (3a, 3b, 4) with N‐chlorosuccinimide and DBU, on 1,3‐dipolar cycloaddition with substituted alkenes resulted in glycosyl isoxazolines (5, 7–28) in diastereoselective manner. The extent of diastereoselection varies with the nature of substituents both in sugar and alkenes. The compounds synthesized were screened in vitro against many fungi wherein two of the compounds (12, 23) showed significant inhibition against Sporothrix schenckii, Trychophyton mentagrophytes, and Cryptococcus neoformans with MIC of 12.5 and 6.25 µg/mL, respectively. #CDRI Communication No.6460.

Diastereoselective Synthesis of Galactopyranosyl Amino Esters and Their Transformation into C‐Nucleosides

Abstract Galactopyranosylated olefinic ester (4) on conjugate addition of amines yielded stereoselectively galactopyranosylated amino esters (5–18) in fair to good yield. The selected amino esters (5, 6, 13, and 15–17) on reaction with isocyanates resulted in ureido galactopyranosyl amino esters (19–24) in very good yields. Lactamization of compounds 19–24 with DBU, 4 Å MS, and tetrabutylammonium bromide in refluxing toluene gave respective C‐galactopyranosyl dihydropyrimidine‐2,4‐diones (25–30) in respectable yields.

Tetrabutylammonium Hydrogensulphate Catalyzed Efficient Synthesis of Glycosyl(aryl) Dihydropyrimidinones

An efficient synthesis of glycosyl dihydropyrimidinones using a three-component reaction of a βketo ester, glycosyl aldehyde, urea (or thiourea), in the presence of tetrabutylammonium hydrogensulphate and diethylene glycol as eco-friendly solvent has been reported. The reaction has been extended to the synthesis of aryl dihydropyrimidinones also. The glycosyl dihydropyrimidinones were obtained in excellent yields in less time than the methods already reported.

SYNTHESIS AND DNA TOPOISOMERASE-II INHIBITORY ACTIVITY OF UNNATURAL NUCLEOSIDES

The synthesis and biological activities of a number of unnatural nucleosides (23–43) is described. Nucleosides have been synthesized by SnCl4-catalyzed condensation of amino sugar acetates and silylated modified pyrimidines. Few of the 2′-O -acetyl derivatives of the nucleosides were hydrolyzed to the respective hydroxy derivatives by treatment with methanol saturated with ammonia. The compounds were screened against Filarial DNA-topoisomerase-II but only one of the compounds (29) inhibited this enzyme at 40 µg/mL of reaction mixture.

GLUTATHIONE SYNTHESIS IN FILARIAL WORMS: AN ATTRACTIVE TARGET FOR THE DESIGN AND SYNTHESIS OF NEW ANTIFILARIALS

A library of 363 glycoconjugates and C-nucleosides synthesized by our earlier reported methods were screened for their effect on isolated filarial glutamate cysteine ligase (GCL) and glutathione reductase (GR). Many of the compounds from the library including one glycosyl urea and one nucleoside showed inhibition of more than 50% on GCL, and seven glycosylated amino esters, two sugars, one glycosyl urea, five glycosyl hydroxamates, one glycosyl hydrantoin, three nucleoside and one N-protected glycopeptide compounds showed inhibition of more than 50% on GR from S. cervi. The effect of the most promising ones have been looked on the counterparts from mammalian sources and difference in the susceptibility towards enzyme activity inhibition were noted.

A VERSATILE SYNTHESIS OF DIHYDROPYRIMIDINONE C-NUCLEOSIDES +

A versatile synthesis of N‐substituted dihydropyrimidinone C‐nucleosides (20–29) is described. Glycosyl amino esters (3–9), obtained by reductive alkylation of glycosyl amino esters 1 and 2, on condensation with different isocyanates afforded respective ureido derivatives (10–19) in good to quantitative yields. The latter on cyclative amidation with a combination of DBU/TBAB (tetrabutylammonium bromide)/4Å molecular sieve gave the corresponding nucleosides (20–29) in good yields.

Reductive amination of glycosyl aldoses: synthesis of n-glycosylated β-glycosyl amino alcohols and their enzyme inhibitory effect.

Abstract Reductive amination of glycosyl aldehydes (1a–c, 2) with glycosyl amino esters (3a–c, 4) in the presence of sodium borohydride gave diglycosylated amino esters (5–15) in good yield. N‐Glycosyl‐glycosylated amino esters were reduced to the respective diglycosyl amino alcohols (16–26) with LiAlH4 in good yield. All the synthesized compounds were studied for their inhibitory effect, if any, against hepatic glucose‐6‐phosphatase, glycogen phosphorylase, and intestinal brush border membrane α‐glucosidase; among these compounds 7, 21, and 25 have shown marked inhibition on these enzymes, respectively. #CDRI Communication No. 6605.