title: Enhanced microtubule binding and tubulin assembly properties of conformationally constrained paclitaxel derivatives.
abstract: Microtubule binding and tubulin assembly promotion by a series of conformationally restricted paclitaxel (PTX) derivatives was investigated. In these derivatives, the C-4 acetate of the taxane is tethered to the C-3' phenyl at ortho and meta positions with different length linkers. The apparent affinity of these derivatives for GMPCPP-stabilized microtubules was assessed by a competition assay, and their influence on microtubule polymerization was evaluated by measuring the critical concentration of GDP-tubulin in the presence of the respective molecule. In general, taxane derivatives with higher apparent affinity for microtubules induced tubulin assembly more efficiently. Among the derivatives, molecules with the shortest tether display the strongest affinity for microtubules. These derivatives exhibited enhanced microtubule stabilization properties and efficiently induced GDP-tubulin assembly into microtubules at low temperature of 12 degrees C and in the absence of Mg2+ ions in 0.1 M PIPES. Based on molecular dynamics simulations, we propose that the enhanced ability to assemble microtubules by these taxane derivatives is linked to their ability to effectively shape the conformation of the M-loop of tubulin for cross-protofilament interaction.
authors: Department of Chemistry, Binghamton University, State University of New York, Binghamton, New York 13902, USA.
authors: Natasha
authors: N
authors: Shanker
authors: David G I
authors: DG
authors: Kingston
authors: Thota
authors: T
authors: Ganesh
authors: Chao
authors: C
authors: Yang
authors: Ana A
authors: AA
authors: Alcaraz
authors: Matthew T
authors: MT
authors: Geballe
authors: Abhijit
authors: A
authors: Banerjee
authors: Dennis
authors: D
authors: McGee
authors: James P
authors: JP
authors: Snyder
authors: Susan
authors: S
authors: Bane
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain; D002417:Cattle; D007700:Kinetics; D008870:Microtubules / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014404:Tubulin; D017239:Paclitaxel