Design, synthesis and anticancer activity of fluorocyclopentenyl-purines and – pyrimidines.

Based on the potent anticancer activity of 6′-fluorocyclopentenyl-cytosine 2b in phase IIa clinical trials for the treatment of gemcitabine-resistant pancreatic cancer, we carried out a systematic structure-activity relationship study of 6′-fluorocyclopentenyl-pyrimidines 3a - i and -purines 3j - o to discover novel anticancer agents. We also synthesized the phosphoramidate prodrug 3p of adenine derivative 1b to determine if the anticancer activity depended on the inhibition of DNA and/or RNA polymerase in cancer cells and/or on the inhibition of S -adenosylhomocysteine (SAH) hydrolase. All of the synthesized pyrimidine nucleosides exhibited much less potent anticancer activity in vitro than the cytosine derivative 2b , acting as RNA and/or DNA polymerase inhibitor, indicating that they could not be efficiently converted to their triphosphates for anticancer activity. Among all the synthesized purine nucleosides, adenine derivative 1b and N 6 -methyladenine derivative 3k showed potent anticancer activity, showing equipotent inhibitory activity as the positive control, neplanocin A ( 1a ) or Ara-C. However, the phosphoramidate prodrug 3p showed less anticancer activity than 1b , indicating that it did not act as a RNA and/or DNA polymerase inhibitor like 2b . This result also demonstrates that the anticancer activity of 1b largely depends on the inhibition of histone methyltransferase, resulting from strong inhibition of SAH hydrolase. The deamination of the N 6 -amino group, the addition of the bulky alkyl group at the N 6 -amino group, or the introduction of the amino group at the C2 position almost abolished the anticancer activity. [ABSTRACT FROM AUTHOR]