Based on the potent anticancer activity of the D-arabino-configured cytosine nucleoside ara-C, novel 2′-substituted-4′- selenoarabinofuranosyl pyrimidines 3a-3u, comprising azido, fluoro, and hydroxyl substituents at C-2′ were designed, synthesized, and evaluated for anticancer activity. The 2′-azido group was stereoselectively introduced by the Mitsunobu reaction using diphenylphosphoryl azide (DPPA), and the 2′-fluoro group was stereoselectively introduced through the double inversions of stereochemistry via the episelenium intermediate, which was formed by the participation of the selenium atom. Among the compounds tested, the 2′-fluoro derivative 3t (X = NH2, Y = H, R = F) was found to be the most potent anticancer agent and showed more potent anticancer activity than the control, ara-C in all tested human cancer cell lines (HCT116, A549, SNU638, T47D, and PC-3) except the leukemia cell lines (K562). The anticancer activity of the 2′-substituted-4′-selenonucleosides is in the following order: 2′-F > 2′-OH > 2′-N3.
- Mitsunobu reaction
- Stereoselective fluorination
- Structure-activity relationship