title: Design, synthesis, and cytotoxicity of novel 3-arylidenones derived from alicyclic ketones.
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 μm 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 μm, compounds 5j, 11j, and 15j did not cause microtubule depolymerization in cells, suggesting that they have a different mechanism of action.
authors.affiliation: Division of Natural and Applied Sciences and Department of Chemistry, Hope College, Holland, MI 49423, USA.
authors.forename: Vijay
authors.initials: V
authors.lastname: Satam
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Bandi
authors.forename: Ajaya K
authors.initials: AK
authors.lastname: Behera
authors.forename: Bijay K
authors.initials: BK
authors.lastname: Mishra
authors.forename: Samuel
authors.initials: S
authors.lastname: Tzou
authors.forename: Olivia
authors.initials: O
authors.lastname: Brockway
authors.forename: Balaji
authors.initials: B
authors.lastname: Babu
authors.forename: Matthias
authors.initials: M
authors.lastname: Zeller
authors.forename: Cara
authors.initials: C
authors.lastname: Westbrook
authors.forename: Susan L
authors.initials: SL
authors.lastname: Mooberry
authors.forename: Moses
authors.initials: M
authors.lastname: Lee
authors.forename: Hari
authors.initials: H
authors.lastname: Pati
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001632:Bibenzyls / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D007659:Ketones / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001632:Bibenzyls; D047188:Chalcones; D007659:Ketones; D013267:Stilbenes; D050257:Tubulin Modulators; C040105:combretastatin; C058728:fosbretabulin