A b-lactam-azasugar hybrid as a competitive potent galactosidase inhibitor Ganesh Pandey, a, * Shrinivas G. Dumbre, a M. Islam Khan, b M. Shabab b and Vedavati G. Puranik c a Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pashan Road, Pune 411008, Maharashtra, India b Division of Biochemical Science, National Chemical Laboratory, Pashan Road, Pune 411008, Maharashtra, India c Division of Material Science, National Chemical Laboratory, Pashan Road, Pune 411008, Maharashtra, India Received 27 July 2006; revised 20 August 2006; accepted 1 September 2006 Available online 25 September 2006 Abstract—A b-lactam-azasugar hybrid (polyhydroxylated carbacephem) has been designed and synthesized as a potent glycosidase inhibitor. Ó 2006 Elsevier Ltd. All rights reserved. The design and synthesis of hybrid molecules, that is, structural motifs developed through domain assimila- tion of two or more different classes of biologically ac- tive compounds of natural and/or synthetic origin has attracted the attention of synthetic chemists in the past few years owing to the enhanced possibility of discover- ing new biologically active therapeutic agents. 1 In this context, several hybrid molecules of natural products such as steroids, taxoids, carbohydrates and peptides with counterparts such as b-lactams, C 60 -fullerenes, anthraquinones, enediyne and porphyrin have been synthesized and their properties evaluated. 2 Azasugar inhibitors of glycosidases and related enzymes are the subject of intense current research interest due to their potential clinical applications as anti-diabetic, 3 anti-cancer, 4 anti-HIV 5 and anti-influenza 6 agents. These low molecular weight entities are believed to exhi- bit their inhibitory activities due to their binding with glycosidases by mimicking the shape and charge of the postulated oxo-carbenium ion intermediate for the gly- cosidic bond cleavage reaction. 7 Some of the potent aza- sugar based glycosidase inhibitors (Fig. 1), such as 1, 8 2, 9 3, 10 4, 11 and 5 12 , which become positively charged on protonation due to the presence of basic amino, ami- dine and hydrazine moieties, are suggested to derive their inhibitory activities either by mimicking the charge or shape, or both, of the glycosidase transition state. In contrast, neutral glyconolactams, 13 such as 6 (K i = 85 lM, b-glucosidase), where the glycosidic oxygen is re- placed by a pseudo sp 2 ring nitrogen, was originally be- lieved to inhibit glycosidases by involving a tautomeric iminol form. However, Withers and co-workers 14 have suggested that glycosidase inhibition by 6 and similar other compounds such as 7 and 8 may in fact be caused by H-bonding of the lactam carbonyl moiety with the enzyme as the tautomerization energy for the amide– iminol conversion is of the order of 11 kcal mol 1 , 15 indicating the concentration of the corresponding iminol form in solution at any given time to be very low. 0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2006.09.005 Keywords: Glycosidase inhibitor; b-Lactam-azasugar; Hybrid mole- cules; b-Galactosidase. * Corresponding author. Tel.: +91 20 25902324; fax: +91 20 25902624; e-mail: gp.pandey@ncl.res.in NH HO HO OH OH N H X HO R OH OH N HO HO OH OH NH 2 1 2 X=CH 2 , R=H 3 X=CH 2 , R=OH 4 X=NH, R=H 5 NH HO HO OH OH O N O OH HO H HO OH O 6 N O O HO HO H HO 7 8 Figure 1. Structures of some potent glycosidase inhibitors. Tetrahedron Letters 47 (2006) 7923–7926