title: Antitumor agents. 280. Multidrug resistance-selective desmosdumotin B analogues.
abstract: 6,6,8-Triethyldesmosdumotin B (2) was discovered as a MDR-selective flavonoid with significant in vitro anticancer activity against a multidrug resistant (MDR) cell line (KB-VIN) but without activity against the parent cells (KB). Additional 2 analogues were synthesized and evaluated to determine the effect of B-ring modifications on MDR-selectivity. Analogues with a B-ring Me (3) or Et (4) group had substantially increased MDR selectivity. Three new disubstituted analogues, 35, 37, and 49, also had high collateral sensitivity (CS) indices of 273, 250, and 100, respectively. Furthermore, 2-4 also displayed MDR selectivity in an MDR hepatoma-cell system. While 2-4 showed either no or very weak inhibition of cellular P-glycoprotein (P-gp) activity, they either activated or inhibited the actions of the first generation P-gp inhibitors verapamil or cyclosporin, respectively.
authors.affiliation: Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. goto@email.unc.edu
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nakagawa-Goto
authors.forename: Po-Cheng
authors.initials: PC
authors.lastname: Chang
authors.forename: Chin-Yu
authors.initials: CY
authors.lastname: Lai
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Hung
authors.forename: Tzu-Hsuan
authors.initials: TH
authors.lastname: Chen
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Wu
authors.forename: Hao
authors.initials: H
authors.lastname: Zhu
authors.forename: Alexander
authors.initials: A
authors.lastname: Sedykh
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Bastow
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D047309:Flavones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D013329:Structure-Activity Relationship
chemical_list: C552711:6,6,8-triethyldesmosdumotin B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D047309:Flavones