Stem Cells, Vol 12, 7-12, Copyright © 1994 by AlphaMed Press
The design and synthesis of a new anticancer drug based on a natural product lead compound: from neplanocin A to cyclopentenyl cytosine (CPE- C)
JS Driscoll and VE Marquez
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
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.
