Design, Synthesis, and Cytotoxicity of Novel 3-Arylidenones Derived from Alicyclic Ketones

Document Type

Article

Publication Date

10-2011

Publication Source

Chemical Biology & Drug Design

Volume Number

78

Issue Number

4

First Page

700

Last Page

708

Publisher

Wiley-Blackwell

ISSN

1747-0277

Abstract

Forty-four novel chalcone-inspired analogs having a 3-aryl-2-propenoyl moiety derived from alicyclic ketones were designed, synthesized, and investigated for cytotoxicity against murine B16 and L1210 cancer cell lines. The analogs belong to four structurally divergent series, three of which (series g, h, and i) contain differently substituted cyclopentanone units and the fourth (series j) contains a 3,3-dimethyl-4-piperidinone moiety. Of these, the analogs in series j showed potential cytotoxic activity against murine B16 (melanoma) and L1210 (lymphoma) cells. The most active compounds 5j, 11j, 15j, and 12h produced IC(50) values from 4.4 to 15 mu M against both cell lines. A single-crystal X-ray structure analysis and molecular modeling studies confirmed that these chalcones have an E-geometry about the alkene bond and possess a slightly 'twisted' conformation similar to that of combretastatin A-4. At a concentration of 30 mu M, compounds 5j, 11j, and 15j did not cause microtubule depolymerization in cells, suggesting that they have a different mechanism of action.

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