2. Academic Validation
  3. Structure-activity relationships of 2'-modified-4'-selenoarabinofuranosyl-pyrimidines as anticancer agents

Structure-activity relationships of 2'-modified-4'-selenoarabinofuranosyl-pyrimidines as anticancer agents

  • Eur J Med Chem. 2014 Aug 18:83:208-25. doi: 10.1016/j.ejmech.2014.06.031.
Jin-Hee Kim 1,  Jinha Yu 1,  Varughese Alexander 1,  Jung Hee Choi 1,  Jayoung Song 2,  Hyuk Woo Lee 1,  Hea Ok Kim 1,  Jungwon Choi 3,  Sang Kook Lee 2,  Lak Shin Jeong 4
Affiliations

Affiliations

  • 1 College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea.
  • 2 College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
  • 3 Department of Chemistry, The University of Suwon, Kyunggi-do 445-743, Republic of Korea.
  • 4 College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea; College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: lakjeong@snu.ac.kr.
PMID: 24956556 DOI: 10.1016/j.ejmech.2014.06.031
Abstract

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.

Keywords

4′-Selenonucleosides; Antimetabolite; Mitsunobu reaction; Stereoselective fluorination; Structure–activity relationship.

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