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Cyclopentene carbocyclic nucleosides related to the antitumor nucleoside clitocine and their conversion to 8‐Aza‐neplanocin analogues. Synthesis and antiviral activity
Author(s) -
Marquez Victor E.,
Lim Benjamin B.,
Driscoll John S.,
Snoek Robert,
Balzarini Jan,
Ikeda Satoru,
Andrei Graciela,
De Clercq Erick
Publication year - 1993
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570300536
Subject(s) - chemistry , stereochemistry , cyclopentene , nucleoside , nucleoside analogue , inosine , thymidine kinase , guanosine , enzyme , biochemistry , virus , virology , herpes simplex virus , biology , catalysis
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.