THE IMPORTANCE OF THE 4'-HYDROXYL HYDROGEN FOR THE ANTITRYPANOSOMAL AND ANTIVIRAL PROPERTIES OF (-5'-NORARISTEROMYCIN AND 2 7-DEAZA ANALOGS())

(+)-5'-Noraristeromycin (1) has shown significant antiviral activity w hile its 7-deaza analogue 2 is an antitrypanosomal candidate. To deter mine the relevance of the 4'-hydroxyl hydrogen in these activities, a derivative of 1 (that is, 3) where the C-4' hydroxyl hydrogen has been replaced by a methyl group has been prepared beginning with palladium (0) mediated coupling of the sodium salt of N-6-benzoyladenine (9) an d (1S,4R)-4-methoxy-2-cyclopenten-1-yl acetate (5). The synthesis of c ompound 5 is described from 1S,4R)-1-[(tert-butyldimethylsilyl)oxyl-4- hydroxy- cyclopent-2-ene (6) in three steps. Analogous preparations of the 7-deaza and 8-aza-7-deaza derivatives of 3 related to 2 (that is, 4 and 12) are also reported. The new derivatives (3, 4, and 12) faile d to show improved antiviral activity. Compound 12 was the only deriva tive with some anti-trypanosomal activity, giving 40% inhibition of gr owth at 100 mu M against bloodstream forms of a Typanosoma brucei bruc ei isolate in a standard in vitro screen. This study indicated that th e C-4'-hydroxyl hydrogen plays a role in the medicinal properties of 1 and 2. (C) 1998 Elsevier Science Ltd. All rights reserved.