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

Jin Hee Kim; Jinha Yu; Varughese Alexander; Jung Hee Choi; Jayoung Song; Hyuk Woo Lee; Hea Ok Kim; Jungwon Choi; Sang Kook Lee; Lak Shin Jeong

doi:10.1016/j.ejmech.2014.06.031

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

Jin Hee Kim, Jinha Yu, Varughese Alexander, Jung Hee Choi, Jayoung Song, Hyuk Woo Lee, Hea Ok Kim, Jungwon Choi, Sang Kook Lee, Lak Shin Jeong

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

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.

Original language	English
Pages (from-to)	208-225
Number of pages	18
Journal	European Journal of Medicinal Chemistry
Volume	83
DOIs	https://doi.org/10.1016/j.ejmech.2014.06.031
State	Published - 18 Aug 2014

Bibliographical note

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 ).

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ejmech.2014.06.031

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@article{d5a7e384abdb4d689298a91a2eee21a2,

title = "Structure-activity relationships of 2′-modified-4′- selenoarabinofuranosyl-pyrimidines as anticancer agents",

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",

author = "Kim, {Jin Hee} and Jinha Yu and Varughese Alexander and Choi, {Jung Hee} and Jayoung Song and Lee, {Hyuk Woo} and Kim, {Hea Ok} and Jungwon Choi and Lee, {Sang Kook} and Jeong, {Lak Shin}",

note = "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 ).",

year = "2014",

month = aug,

day = "18",

doi = "10.1016/j.ejmech.2014.06.031",

language = "English",

volume = "83",

pages = "208--225",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

publisher = "Elsevier Masson s.r.l.",

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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

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AN - SCOPUS:84903214329

SN - 0223-5234

VL - 83

SP - 208

EP - 225

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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