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Geiparvarin Analogues: Synthesis and Anticancer Evaluation of α ‐Methylidene‐ γ ‐butyrolactone‐Bearing Coumarins
Author(s) -
Chen YehLong,
Wang TaiChi,
Tzeng CherngChyi,
Chang NeinChen
Publication year - 1999
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/(sici)1522-2675(19990210)82:2<191::aid-hlca191>3.0.co;2-p
Subject(s) - chemistry , substituent , moiety , stereochemistry , coumarin , furan , potency , derivative (finance) , in vitro , biochemistry , organic chemistry , economics , financial economics
To determine some of the structural features of geiparvarin that account for its cytostatic activity in vitro , certain geiparvarin analogues modified in the furan‐3(2 H )‐one moiety and the alkenyloxy substituent were synthesized and tested against the growth of 60 human cancer cell lines derived from nine cancer‐cell types. These compounds demonstrated a strong growth‐inhibitory activity against leukemia cell lines but were relatively inactive against non‐small‐cell lung cancers and CNS cancers. Comparison of the mean log GI 50 values of γ ‐[( E )‐1‐methylprop‐1‐enyl]‐ α ‐methylidene‐ γ ‐butyrolactones 7 – 9 revealed that 7‐[( E )‐3‐(2,3,4,5‐tetrahydro‐4‐methylidene‐5‐oxofuran‐2‐yl)but‐2‐enyloxy]‐2 H ‐ 1‐benzopyran‐2‐one ( 8 ; −5.47) was more active than its 6‐substituted counterpart 7 (−5.21) and its 3‐chloro‐4‐methyl derivative 9 (−5.31) and had a potency similar to that of geiparvarin (log GI 50 =−5.41). These results indicated that the furan‐3(2 H )‐one moiety of geiparvarin could be replaced by an α ‐methylidene‐ γ ‐butyrolactone unit without losing the anticancer potency, and that the best substitution site at the coumarin moiety was C(7). The alkenyloxy substituent of 8 was also replaced by a methoxy substituent. Among these α ‐methylidene‐ γ ‐butyrolactones, 7‐[(2,3,4,5‐tetrahydro‐4‐methylidene‐5‐oxo‐2‐phenylfuran‐2‐yl)methoxy]‐2 H ‐1‐benzopyran‐2‐one ( 11 ) was the most potent with a mean log GI 50 value of −5.83 and a range value of 132 (10 2.12 ).