title: Synthesis and structure-activity relationships of taxuyunnanine C derivatives as multidrug resistance modulator in MDR cancer cells.
abstract: A series of new generation taxoids bearing a bulky group on different positions such as C-2, C-5, C-7, C-9, C-10 or C-14 were obtained by chemical modifications and biotransformation of taxuyunnanine C (1) and its analogs, 4, 5, and 10. Compounds 3, 5, 6, 8, and 9a showed significant activity toward calcein accumulation in MDR 2780AD cells. The most effective compound 9a with a cinnamoyloxy group at C-14 and a hydroxyl group at C-10 was actually efficient for the cellular accumulation of the anticancer agent, vincristine, in MDR 2780AD cells. The enhancing effects of 6 and 9a for taxol, adriamycin, and vincristine were at the same levels as those of verapamil toward MDR 2780AD cells. Thus, compounds 6 and 9a can modulate the multidrug resistance of cancer cells. The cytotoxicity (IC(50)) of the compounds was examined against human normal cell line, WI-38, and cancer model cell lines, VA-13 and HepG2. Since compounds 6 and 8 had no cytotoxicity, they were expected to be lead compounds of MDR cancer reversal agents. On the contrary, compounds 3, 5, and 9a showed cell growth inhibitory activity toward VA-13 and/or HepG2 as well as accumulation activity of calcein and/or vincristine in MDR 2780AD and they were expected to be lead compounds of new-type anticancer agents.
authors.affiliation: Graduate School of Science and Technology, Niigata University, Ikarashi, 2-8050, Niigata 950-2181, Japan. toshiaki-hasegawa@mgc.co.jp <toshiaki-hasegawa@mgc.co.jp>
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hasegawa
authors.forename: Jiao
authors.initials: J
authors.lastname: Bai
authors.forename: Jungui
authors.initials: J
authors.lastname: Dai
authors.forename: Liming
authors.initials: L
authors.lastname: Bai
authors.forename: Junichi
authors.initials: J
authors.lastname: Sakai
authors.forename: Shigenori
authors.initials: S
authors.lastname: Nishizawa
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Bai
authors.forename: Midori
authors.initials: M
authors.lastname: Kikuchi
authors.forename: Mariko
authors.initials: M
authors.lastname: Abe
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tomida
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsuruo
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Hirose
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Ando
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001681:Biological Assay; D002460:Cell Line; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005452:Fluoresceins / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D013329:Structure-Activity Relationship; D043823:Taxoids / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D005452:Fluoresceins; D043823:Taxoids; C494600:taxuyunnanine C; C007740:fluorexon