Bheemarao G. Ugarkar

Pradefovir: a prodrug that targets adefovir to the liver for the treatment of hepatitis B.

Adefovir dipivoxil, a marketed drug for the treatment of hepatitis B, is dosed at submaximally efficacious doses because of renal toxicity. In an effort to improve the therapeutic index of adefovir, 1-aryl-1,3-propanyl prodrugs were synthesized with the rationale that this selectively liver-activated prodrug class would enhance liver levels of the active metabolite adefovir diphosphate (ADV-DP) and/or decrease kidney exposure. The lead prodrug (14, MB06866, pradefovir), identified from a variety of in vitro and in vivo assays, exhibited good oral bioavailability (F = 42%, mesylate salt, rat) and rate of prodrug conversion to ADV-DP. Tissue distribution studies in the rat using radiolabeled materials showed that cyclic 1-aryl-1,3-propanyl prodrugs enhance the delivery of adefovir and its metabolites to the liver, with pradefovir exhibiting a 12-fold improvement in the liver/kidney ratio over adefovir dipivoxil.

DESIGN, SYNTHESIS AND ANTICONVULSANT ACTIVITY OF THE POTENT ADENOSINE KINASE INHIBITOR GP3269

Abstract The pyrrolopyrimidine nucleoside GP3269 (12) was shown to be a potent and selective inhibitor of human adenosine kinase (IC50 = 11 nM) and to exhibit anticonvulsant activity in rats after oral administration. Synthesis of GP3269 was accomplished in 4 steps from 4-chloro-5-iodopyrrolopyrimidine (9) and the protected 5-deoxy-1-α-chlororibose (8) using a base-catalyzed nucleoside coupling reaction and the Suzuki reaction to replace the 5-iodo substituent with phenyl.

Synthesis of 1-methyl-3-β-d-ribofuranosylpyrazolo[4, 3,-D]-pyrimidin-7(6h)-selone and Certain Related Nucleosides and Nucleotides

Abstract 1-Methy1-3-β-D-ribofuranosylpyrazolo[4, 3-d]pyrimidin-7(6H)-selone (6) and the corresponding thione analog (5) have been synthesized for the first time from l-methyl-3-(2, 3, 5-tri-O-acetyl-β-D]-ribo-furanosyl)pyrazolo[4, 3-d]pyrimidin-7(6H)-one (12). Thiation and deace-tylation of 12 gave 5. Compound 6 was prepared from 12 via the chloro intermediate (13) and selenourea followed by deacetylation. A convenient, high yield procedure for the preparation of 1-methylformycin B (4) from 1-methylformycin (7) is described. Phosphorylation of 7 provided 1-methylformycin 5′-phosphate (17). Compounds 6 and 17 were found to be potent inhibitors of growth of L1210 and P388 leukemia.

Stereoselective synthesis of 4-C-methyl-2,3,5-tri-O-benzyl-d-ribofuranose and 4-C-methyl-2,3,5-tri-O-benzyl-l-lyxofuranose

Abstract Sugar intermediates 4- C -methyl-2,3,5-tri- O -benzyl- d -ribofuranose ( 8b ) and 4- C -methyl-2,3,5-tri- O -benzyl- l -lyxofuranose ( 8a ) were synthesized by addition of alkylithium reagents to pentanones 3a , b . The nucleophilic additions proceeded with good stereoselectivity and good yields to give the titled compounds in four steps from perbenzylated methyl d -ribofuranoside and methyl 5′-deoxy- d -ribofuranoside.