期刊
BIOCHIMIE
卷 92, 期 9, 页码 1164-1172出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biochi.2010.04.022
关键词
beta-Amino alcohol; Src kinase; Cancer; Cell proliferation; Epoxide
资金
- National Medicinal Plant Board, New Delhi
- American Cancer Society [RSG-07-290-01-CDD]
- University of Delhi, Department of Biotechnology
- University Grant Commision (New Delhi, India)
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [748555] Funding Source: National Science Foundation
A series of 3-(N-alkyl-N-phenylamino)propan-2-ol derivatives were synthesized from epichlorohydrine in a multi-step strategy and were evaluated as Src kinase inhibitors. First, epoxy ring opening of epichlorohydrine was carried out in the presence of N-alkylanilines to yield 3-(N-alkyl-N-phenylamino)-1-chloro-propan-2-ol derivatives using Ca(OTf)(2) as catalyst based on our previous studies [1]. Second, ring closure was performed under basic conditions to afford N-epoxymethyl N-alkylaniline derivatives. Finally, the epoxide ring opening with four different secondary amines and three nucleobases afforded the final products, i.e., a series of beta-amino alcohols. All compounds were screened for their inhibitory activity against Src kinase and anticancer activity on human breast carcinoma cells, BT-20 cell line. Among all compounds, 3-N-methyl-N-phenylamino-1-(pyrrolidin-1-yl)propan-2-ol (13b) exhibited the highest inhibitory potency (IC50 = 66.1 mu M) against Src kinase. Structure-activity relationship studies suggested that the incorporation of bulky groups at position I and N-substitution with groups larger than methyl moiety, reduced the inhibitory potency of the compound significantly. Compounds 3-(N-ethyl-N-phenylamino-)-1-(4-methylpiperazin-1-yl)propan-2-ol (14c) and 3-(N-ethyl-N-phenylamino)-1-(thymine-1-yl)propan-2-ol (17) were found to inhibit the growth of breast carcinoma cells by approximately 45-49% at concentration of 50 mu M. (C) 2010 Elsevier Masson SAS. All rights reserved.
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