Carbocyclic Analogs of Guanosine and 8-Azaguanosine

(±)-9-[trans-2,trans-3-Dihydroxy-cis-4-(hydroxymethyl)- cyclopentyl]guanine. the carbocyclic analog of guanosine, was synthesized by a five-step route beginning with (┴)-trans-3-amino-trans-5-(hydroxymethyl)-cis-l ,2-cyclopentanediol and 2-amino-4.6- dichloropyrimidine. Preparation and reduction of a 5-(p-chlorophenylazo)pyrimidine derivative introduced the prerequisite 5- amino substituent. Formation of the imidazole ring from this 5- amino derivative with triethyl orthoformate and acidic hydrolysis of the resulting mixture of 2-amino-6-chloropurine derivatives furnished the guanosine analog. The same 5-aminopyrimidine intermediate was diazotized to the 2-amino-6-chloro-8-azapurine, and the latter derivative was hydrolyzed to the carbocyclic analog of 8-azaguanosine. Neither of these analogs was cytotoxic to human epidermoid carcinoma cells in vitro. In tests using leukemia L-1210, the guanosine analog was quite toxic but was inactive at nontoxic doses; the 8-azaguanosine analog was not active in initial (single- dose) tests.