Cyclopentene carbocyclic nucleosides related to the antitumor nucleoside clitocine and their conversion to 8‐Aza‐neplanocin analogues. Synthesis and antiviral activity

Abstract Synthesis of the cyclopentene carbocyclic analogue of the naturally occurring nucleoside clitocine ( 1 ) is reported. Starting with racemic cyclopentenylamine ( 10 ), the heterocyclic moieties of the clitocine analogue 4 and related 1,6‐dihydro‐6‐oxo, 5 , and 2‐amino‐1,6‐dihydro‐6‐oxo, 6 , analogues were constructed. These compounds were respectively converted to 8‐aza‐neplanocin A (7) , 8‐aza‐neplanocin D ( 8 , the inosine analogue), and the corresponding 8‐aza‐guanosine analogue 9 after reduction of the nitro group followed by nitrous acid cyclization. Extensive antiviral evaluation revealed that only 8‐aza‐neplanocin A ( 7 ) had enough antiviral activity to warrant further studies. This compound showed weak antiviral activity against HSV‐1, HSV‐20 and the thymidine kinase deficient (TK‐) HSV‐1. However, it displayed good antiviral activity against human cytomegalovirus (HCMV) at a concentration of 0.40–2.50 μg/ml, well below the cytotoxicity threshold. This activity profile is consistent with a mechanism of action involving the inhibition of the enzyme adenosylhomo‐cysteine hydrolase.