title: Discovery of potent cytotoxic ortho-aryl chalcones as new scaffold targeting tubulin and mitosis with affinity-based fluorescence.
abstract: A series of new ortho-aryl chalcones have been designed and synthesized. Many of these compounds were found to exhibit significant antiproliferation activity toward a panel of cancer cell lines. Selected compounds show potent cytotoxicity against several drug resistant cell lines including paclitaxel (Taxol) resistant human ovarian carcinoma cells, vincristine resistant human ileocecum carcinoma cells, and doxorubicin resistant human breast carcinoma cells. Further investigation revealed that active analogues could inhibit the microtubule polymerization by binding to colchicine site and thus induce multipolar mitosis, G2/M phase arrest, and apoptosis of cancer cells. Furthermore, affinity-based fluorescence enhancement was observed during the binding of active compounds with tubulin, which greatly facilitated the determination of tubulin binding site of the compounds. Finally, selected compound 26 was found to exhibit obvious in vivo antitumor activity in A549 tumor xenografts model. Our systematic studies implied a new scaffold targeting tubulin and mitosis for novel antitumor drug discovery.
authors: School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou 510006, China.
authors: Cuige
authors: C
authors: Zhu
authors: Yinglin
authors: Y
authors: Zuo
authors: Ruimin
authors: R
authors: Wang
authors: Baoxia
authors: B
authors: Liang
authors: Xin
authors: X
authors: Yue
authors: Gesi
authors: G
authors: Wen
authors: Nana
authors: N
authors: Shang
authors: Lei
authors: L
authors: Huang
authors: Yu
authors: Y
authors: Chen
authors: Jun
authors: J
authors: Du
authors: Xianzhang
authors: X
authors: Bu
mesh_terms: D000814:Aniline Compounds; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D047188:Chalcones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003078:Colchicine / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005453:Fluorescence; D059565:G2 Phase Cell Cycle Checkpoints; D064593:Heterografts; D006801:Humans; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects / Q000648:ultrastructure; D008938:Mitosis / Q000187:drug effects*; D009368:Neoplasm Transplantation; D058105:Polymerization; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C000607804:3-(4-(dimethylamino)phenyl)-1-(4'-fluoro(1,1'-biphenyl)-2-yl)prop-2-en-1-one; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D047188:Chalcones; D014404:Tubulin; D050257:Tubulin Modulators; D003078:Colchicine