Synthesis and cytotoxic evaluation of a series of gamma-substituted gamma-aryloxymethyl-alpha-methylene-gamma-butyrolactones against cancer cells.
OBJECTIVE
The main objective of this investigation was to explore the cytotoxic structure-activity relationships of gamma-substituted gamma-aryloxymethyl-alpha-methylene-gamma-butyrolactones against cancer cells.


METHODS
The target compounds were synthesized in two steps commencing with aryl-OH which was treated with a bromomethyl ketone followed by the Reformatsky-type condensation.


RESULTS
Seven types of alpha-methylene-gamma-butyrolactones were evaluated in vitro against 60 human cancer cell lines derived from nine cancer cell types. The average values of log GI50 indicated that for the aryl portion, potencies of these alpha-methylene-gamma-butyrolactones are in a decreasing order of quinolin-2(1H)-one (or 2-hydroxyquinoline, 21, -5.89) > quinoline (19, -5.79) > 2-methylquinoline (20, -5.69) >8-hydroxyquinoline (17,-5.64) > 2-naphthalene (16, -5.59) > benzene (15, -4.90). The same order was obtained for both log TGI and log LC50. However, for the gamma-substituent, the potencies are in a decreasing order of biphenyl (16f-21f) > phenyl and 4-substituted phenyl (16b-e-21b-e) > methyl (16a-21a).


CONCLUSIONS
Unlike cardiovascular activities of alpha-methylene-gamma-butyrolactones in which a gamma-methyl substituent is necessary for vasorelaxing effect while a phenyl or a halogen-substituted phenyl is prefer for the antiplatelet activities, a gamma-biphenyl substituent proved to be the best for their cytotoxicities against various cancer cell lines tested.
Tzeng
C C
CC
School of Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan. tzengch@cc.kmu.edu.tw
Lee
K H
KH
Wang
T C
TC
Han
C H
CH
Chen
Y L
YL
D015107:4-Butyrolactone / Q000138:chemical synthesis* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D004341:Drug Evaluation; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D015107:4-Butyrolactone