Synthesis, antiproliferative, and vasorelaxing evaluations of coumarin alpha-methylene-gamma-butyrolactones.
Certain coumarin alpha-methylene-gamma-butyrolactones were synthesized and evaluated for antiproliferative and vasorelaxing activities. These compounds were synthesized via alkylation of hydroxycoumarins 2a-f followed by oxidation and the Reformatsky-type condensation. The results of this study are as follows (1) for the vasorelaxing activity, coumarin-7-yl alpha-methylene-gamma-butyrolactone 6d, with an IC50 value of 9.4 microM against pig coronary arterial contraction induced by KCl, is a more active vasorelaxant than its coumarin-4-yl counterpart 6a and its gamma-methyl congener 1. A methyl group substituted at C-4 of the coumarin-7-yl moiety reduced the vasorelaxing effect (6d vs 6e) while the 3,4,8-trimethyl derivative 6f was inactive. (2) For the antiproliferative activity, coumarin-4-yl alpha-methylene-gamma-butyrolactone 6a, which exhibited the most potent antiproliferative activity on the growth of MCF7, NCI-H460, and SF-268 with IC50 values of 6.97, 14.68, and 8.36 microM, respectively, is more cytotoxic than its coumarin-7-yl counterpart 6d and the 6,7-dimethyl derivative 6b. For the coumarin-7-yl derivatives, 6d is more active than its gamma-methyl congener 1, indicating that substitution at the gamma-position decreased cytotoxicity.
Faculty of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan. yeloch@kmu.edu.tw
Yeh-Long
YL
Chen
Chih-Ming
CM
Lu
Shoiw-Ju
SJ
Lee
Daih-Huang
DH
Kuo
I-Li
IL
Chen
Tai-Chi
TC
Wang
Cherng-Chyi
CC
Tzeng
D015107:4-Butyrolactone / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*
D015107:4-Butyrolactone