title: Structure-activity relationships of some taxoids as multidrug resistance modulator.
abstract: 1,7-Deoxy-4-deacetylbaccatin III (12) and its five analogues 6-9, 13, and their oxetane ring opened derivatives 14, 16, and 17, which were synthesized from taxinine, showed significant activity as MDR reversal agent by the assay of the calcein accumulation toward MDR human ovarian cancer 2780AD cells. The most effective compound 12 in this assay is actually efficient for the recovery of cytotoxic activity of paclitaxel (taxol), adriamycin (ADM), and vincristine (VCR) toward MDR 2780AD cells at the same level toward parental 2780 cells. This activity of 12 is very interesting because baccatin III (4) has no such MDR reversal activity but has cytotoxic activity. The essential functional groups inducing such a difference in biological activity between 4 and 12 are 4alpha-acetoxyl for 4 and 4alpha-hydroxyl for 12. In seven compounds possessing MDR reversal activity, compound 12 is the most desirable compound for anti-MDR cancer reversal agent, because it has the highest accumulation ability of anticancer agent in MDR cancer cells and weak cytotoxic activity. Compounds 8 and 13 showed significant cytotoxic activity toward HepG2 and VA-13, respectively, as well as MDR reversal activity. They are expected to become lead compounds for new types of anticancer agent or anti-MDR cancer agent.
authors.affiliation: Graduate School of Science and Technology, Niigata University, Ikarashi, 2-8050, Niigata 950-2181, Japan. toshiaki-hasegawa@mgc.co.jp
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hasegawa
authors.forename: Jao
authors.initials: J
authors.lastname: Bai
authors.forename: Shujun
authors.initials: S
authors.lastname: Zhang
authors.forename: Jinlan
authors.initials: J
authors.lastname: Wang
authors.forename: Junichi
authors.initials: J
authors.lastname: Matsubara
authors.forename: Junichi
authors.initials: J
authors.lastname: Kawakami
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: Junichi
authors.initials: J
authors.lastname: Sakai
authors.forename: Midori
authors.initials: M
authors.lastname: Kikuchi
authors.forename: Mariko
authors.initials: M
authors.lastname: Abe
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Ando
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D013329:Structure-Activity Relationship; D043823:Taxoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020946:Taxus / Q000737:chemistry
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D005452:Fluoresceins; D043823:Taxoids; C073950:baccatin III; C007740:fluorexon