title: Synthesis and biological evaluation of carbocyclic analogues 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.
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, College of Pharmacy, Minneapolis 55455.
authors.forename: M L
authors.initials: ML
authors.lastname: Peterson
authors.forename: R
authors.initials: R
authors.lastname: Vince
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D000998:Antiviral Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D002522:Chlorocebus aethiops; D003587:Cytomegalovirus / Q000187:drug effects; D005663:Furans / Q000138:chemical synthesis* / Q000494:pharmacology; D006151:Guanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D007942:Leukemia, Experimental / Q000188:drug therapy; D051379:Mice; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D009975:Orthomyxoviridae / Q000187:drug effects; D011687:Purines / Q000138:chemical synthesis* / Q000494:pharmacology; D018139:Simplexvirus / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D005663:Furans; D009705:Nucleosides; D011687:Purines; D006151:Guanosine; C063536:2-amino-1,9-dihydro-9-(2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)-6H-purin-6-one; C063537:3-(2,6-diamino-9H-purin-9-yl)-5-(hydroxymethyl)-1,2-cyclopentanediol; D000241:Adenosine