Synthesis and biological evaluation of carbocyclic analogs of lyxofuranosides of 2-amino-6-substituted purines and 2-amino-6-substituted-8-azapurines

Abstract

Carbocyclic analogues of lyxofuranosides of 2-amino-6-substituted-purines and 2-amino-6-substituted-8-azapurines were synthesized from (+/-)-(1 alpha, 2 alpha, 3 alpha, 5 alpha)-3-amino-5- (hydroxymethyl)-1,2-cyclopentanediol (2) and 2-amino-4,6-dichloropyrimidine (3). The 2-amino-6-chloropurine (8 and 11), the 2,6-diaminopurine (10 and 13), as well as the guanine (9) and 8-azaguanine (12) derivatives were all constructed from the key intermediate (+/-)-(1 alpha, 2 alpha, 3 alpha, 5 alpha)- 3-[(2,5-diamino-6-chloro-4-pyrimidinyl)amino]-5-(hydroxymethyl)-1,2- cyclopentanediol (7) by using established methodology. Compounds 8-13 were evaluated for both antitumor and antiviral activity. None of these materials exhibited appreciable activity against P-388 mouse leukemia cells in vitro. All of these analogues were investigated for activity versus herpes simplex virus type 1 (HSV-1) and influenza virus (IV-A), as well as the human immunodeficiency virus (HIV). Against HSV-1, only compound 9, the carbocyclic analogue of the lyxofuranoside of guanine, exhibited significant activity, yielding a virus rating (VR) of 2.1. The corresponding 2,6-diamino compound (10) demonstrated marginal activity, VR = 0.6, against that virus. The test compounds failed to exhibit inhibition of either IV-A or HIV. Additionally, 9 was tested against human cytomegalovirus (HCMV) and was found to display definite activity at concentrations as low as 32 microM.