SYNTHESIS AND ANTIPROLIFERATIVE AND ANTIVIRAL ACTIVITY OF 2'-DEOXY-2'-FLUOROARABINOFURANOSYL ANALOGS OF THE NUCLEOSIDE ANTIBIOTICS TOYOCAMYCIN AND SANGIVAMYCIN

The glycosylation of 3,4-dicyano-2-[(ethoxymethylene)amino]py (7) with 2-deoxy-2-fluoro-alpha-D-erythro-pentofuranosyl bromide (2) furnished an anomeric mixture of nucleosides (8a,b). This mixture was separated , and the individual anomers were treated with methanolic ammonia to e ffect a concomitant deblocking and ring closure. This furnished both a nomers of 2'-deoxy-2'-fluoro-ara-toyocamycin (9a,b). The cyano moiety of 9b was converted to the carboxamide moiety to furnish 2'-deoxy-2'-f luoro-ara-sangivamycin (10) and to the thiocarboxamide moiety to furni sh 2'-deoxy-2'-fluoro-ara-thiosangivamycin (11). The target compounds 10 and 11 showed similar antiproliferative activity against L1210 cell s in vitro, with IC50's Of 3 and 5 mu M. Antiviral evaluation revealed a somewhat different pattern of activity. All analogs, both alpha and beta anomers, were active against human cytomegalovirus (HCMV), albei t the beta anomers were most active. The beta anomers also were active against herpes simplex virus type 1 (HSV-1) and human immunodeficienc y virus (HIV). Compound 10 was most active in the series, ca. 10-fold more potent than 11; IC50's for 10 ranged from 4 to 25 nM for HCMV, HI V, and varicella tester virus (VZV) and from 30 to 500 nM for HSV-1. E ven though compound 10 was cytotoxic, which will probably preclude its use as an antiviral drug (IC50's = 0.2-5.5 mu M), the difference betw een cytotoxicity and activity against HCMV, HIV, and VZV was sufficien t to indicate specific activity against-a viral target.