title: Antitumor agents 292. Design, synthesis and pharmacological study of S- and O-substituted 7-mercapto- or hydroxy-coumarins and chromones as potent cytotoxic agents.
abstract: Thirty-five S- and O-substituted 7-mercaptocoumarin (9-23) and 7-hydroxy- or 7-mercapto-chromone (24-43) analogs were designed, synthesized and evaluated in vitro against four human tumor cell lines [KB (nasopharyngeal), KB-vin (vincristine-resistant subline), A549 (lung) and DU145 (prostate)] with paclitaxel as the positive control. Many of the synthesized compounds exhibited potent cytotoxic activity. Among them, compounds 10 and 18 showed broad spectrum activity with GI(50) values ranging from 0.92 to 2.11 μM and 2.06-14.07 μM, respectively. However, 33, a 3-brominated compound, displayed significant and selective inhibition against MDR KB-vin with a GI(50) of 5.84 μM. Regardless of the size of the 7-alkoxy group, 2-α-bromoethyl-8-bromomethyl compounds (40-43) exhibited increased cytotoxicity compared with 2-ethyl-8-bromomethyl compounds (36-39). Moreover, in a preliminary pharmacological study, 10 not only remarkably increased cellular apoptosis in a concentration-dependent manner, but also clearly induced A549 cell cycle arrest at the G2/M phase. Thus, these coumarin derivatives merit investigation as novel potential antitumor agents with further structural modification to produce an optimal lead compound and elucidate the detailed pharmacological mechanism(s).
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Hong-Rui
authors.initials: HR
authors.lastname: Liu
authors.forename: Hong-Shan
authors.initials: HS
authors.lastname: Liu
authors.forename: Ming
authors.initials: M
authors.lastname: Cheng
authors.forename: Peng
authors.initials: P
authors.lastname: Xia
authors.forename: Keduo
authors.initials: K
authors.lastname: Qian
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Wu
authors.forename: Chin-Yu
authors.initials: CY
authors.lastname: Lai
authors.forename: Yi
authors.initials: Y
authors.lastname: Xia
authors.forename: Zheng-Yu
authors.initials: ZY
authors.lastname: Yang
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002867:Chromones / Q000737:chemistry* / Q000494:pharmacology*; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology*; D003603:Cytotoxins / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; D003374:Coumarins; D003603:Cytotoxins