title: Restoration of Microtubule Interaction and Cytotoxicity in D-seco Taxanes upon Incorporation of 20-Hydroxymethyl-4-allyloxy Groups.
abstract: To probe the exact role of the oxetane D ring in both tubulin binding and cytotoxicity of taxanes, novel D-seco taxanes bearing a C4 ether substituent have been prepared from paclitaxel 1a. Among them, 20-hydroxymethyl-4-allyloxy D-seco taxane 5e is the most active in both tubulin and cytotoxicity assays. It is only slightly less potent than 1a on tubulin polymerization promotion in vitro and the most cytotoxic among all D-seco taxanes known to date. The reason for the loss and restoration of bioactivity for these D-seco taxanes is also discussed with the assistance of NMR and molecular modeling studies. From these results, we draw a conclusion that the intact D ring of taxanes is not strictly necessary for their binding to tubulin and cytotoxic effects.
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College , 2A Nanwei Road, Beijing 100050, China.
authors.forename: Shao-Rong
authors.initials: SR
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College , 2A Nanwei Road, Beijing 100050, China.
authors.forename: Chun-Gang
authors.initials: CG
authors.lastname: Yang
authors.affiliation: Área de Farmacología, Departamento de Ciencias Biomédicas, Universidad de Alcalá, E-28871 Alcalá de Henares, Unidad Asociada al Instituto de Química Médica del CSIC , E-28871 Madrid, Spain.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Sánchez-Murcia
authors.affiliation: Department of Chemistry, Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College , 2A Nanwei Road, Beijing 100050, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Yan
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas , Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Sáez-Calvo
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas , Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: José Fernando
authors.initials: JF
authors.lastname: Díaz
authors.affiliation: Área de Farmacología, Departamento de Ciencias Biomédicas, Universidad de Alcalá, E-28871 Alcalá de Henares, Unidad Asociada al Instituto de Química Médica del CSIC , E-28871 Madrid, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Gago
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College , 2A Nanwei Road, Beijing 100050, China.
authors.forename: Wei-Shuo
authors.initials: WS
authors.lastname: Fang
mesh_terms: D004988:Ethers, Cyclic / Q000737:chemistry; D008870:Microtubules / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D004988:Ethers, Cyclic; C005287:oxetane; D017239:Paclitaxel