The design and synthesis of a new anticancer drug based on a natural product lead compound: from neplanocin A to cyclopentenyl cytosine (CPE-C).
In 1979, an unusual, carbocyclic nucleoside was discovered in a Japanese fermentation broth and designated neplanocin A. This compound is an analog of adenosine possessing a cyclopentene-containing "sugar" glycon. Although neplanocin A was biologically active, it was quite toxic. It therefore became a lead compound for analog synthesis in an attempt to maximize antitumor and antiviral activity while minimizing toxicity. First, a total synthesis of naturally occurring (-)-neplanocin A was accomplished using a new, versatile cyclopentenone carbocyclic "sugar" intermediate. This intermediate was then used to synthesize some 20 purine and pyrimidine analogs of neplanocin A which were evaluated for their antitumor and antiviral properties. Among the purine analogs, 3-deazaneplanocin A, a powerful inhibitor of S-adenosylhomocysteine hydrolase, was found to have excellent antiviral activity both in vitro and in vivo. Cyclopentenyl cytosine (CPE-C) was found to be the most biologically active compound among the carbocyclic pyrimidine nucleosides. In addition to activity against over 20 viruses, this compound had excellent preclinical antitumor activity against both murine leukemias and human tumor xenografts. CPE-C is currently under clinical evaluation as an anticancer drug.
Driscoll
J S
JS
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Marquez
V E
VE
D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry; D000998:Antiviral Agents / Q000138:chemical synthesis*; D003562:Cytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques
D000998:Antiviral Agents; D003562:Cytidine; C045911:cyclopentenyl cytosine; C031096:neplanocin A; D000241:Adenosine