TY - JOUR
T1 - Structure-activity relationships of 2′-modified-4′- selenoarabinofuranosyl-pyrimidines as anticancer agents
AU - Kim, Jin Hee
AU - Yu, Jinha
AU - Alexander, Varughese
AU - Choi, Jung Hee
AU - Song, Jayoung
AU - Lee, Hyuk Woo
AU - Kim, Hea Ok
AU - Choi, Jungwon
AU - Lee, Sang Kook
AU - Jeong, Lak Shin
N1 - Funding Information:
This work was supported by the grants from Mid-career Research Program ( 2010-0026203 ) through the National Research Foundation, Korea and Seoul R&BD Program ( ST100039 ).
PY - 2014/8/18
Y1 - 2014/8/18
N2 - 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.
AB - 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.
KW - 4′-Selenonucleosides
KW - Antimetabolite
KW - Mitsunobu reaction
KW - Stereoselective fluorination
KW - Structure-activity relationship
UR - http://www.scopus.com/inward/record.url?scp=84903214329&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2014.06.031
DO - 10.1016/j.ejmech.2014.06.031
M3 - Article
C2 - 24956556
AN - SCOPUS:84903214329
VL - 83
SP - 208
EP - 225
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -
