title: Antitumor agents 259. Design, syntheses, and structure-activity relationship study of desmosdumotin C analogs.
abstract: Desmosdumotin C (1) and its analogs previously showed potent, selective in vitro anticancer activity. To explore structure-activity relationships of 1 and further increase potency and selectivity, 15 novel analogs (7-15 and 21-26) were synthesized and evaluated for cytotoxity against several human tumor cell lines, as well as inhibition of human endothelial (HUVEC) replication. 4-Bromo-3',3',5'-tripropyl analog 26 showed significant cytotoxity against A549, A431, 1A9, and HCT-8 with ED50 values of 1.0, 1.2, 0.9, and 1.3 mug/mL, respectively. Compound 26 also strongly inhibited the growth of matched tumor cells, KB-VIN and its parent cell KB. Furthermore, analogs 13 and 21 were over 5-fold more potent against KB-VIN than KB. Bromination of ring-B and tripropyl functionalization of ring-A enhanced activity, while alkylation of ring-B promoted KB-VIN/KB selectivity. 2-Furyl analog 16 showed selective activity against HUVEC, suggesting that it may have potential as a new prototype for angiogenesis inhibition.
authors.affiliation: Natural Products Research Laboratories, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nakagawa-Goto
authors.forename: Tzu-Hsuan
authors.initials: TH
authors.lastname: Chen
authors.forename: Chieh-Yu
authors.initials: CY
authors.lastname: Peng
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Bastow
authors.forename: Jiu-Hong
authors.initials: JH
authors.lastname: Wu
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000475:Alkenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D005260:Female; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
chemical_list: D000475:Alkenes; D000970:Antineoplastic Agents; D007659:Ketones; C502470:desmosdumotin C