title: A remarkable series of vinblastine analogues displaying enhanced activity and an unprecedented tubulin binding steric tolerance: C20' urea derivatives.
abstract: A systematic series of previously inaccessible key C20' urea and thiourea derivatives of vinblastine were prepared from 20'-aminovinblastine that was made accessible through a unique Fe(III)/NaBH(4)-mediated alkene functionalization reaction of anhydrovinblastine. Their examination defined key structural features of the urea-based analogues that contribute to their properties and provided derivatives that match or exceed the potency of vinblastine by as much as 10-fold in cell-based functional assays, which is directly related to their relative tubulin binding affinity. In contrast to expectations based on apparent steric constraints of the tubulin binding site surrounding the vinblastine C20' center depicted in an X-ray cocrystal structure, remarkably large C20' urea derivatives are accommodated.
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Erick K
authors.initials: EK
authors.lastname: Leggans
authors.forename: Katharine K
authors.initials: KK
authors.lastname: Duncan
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Barker
authors.forename: Kristin D
authors.initials: KD
authors.lastname: Schleicher
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D007942:Leukemia, Experimental / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D014404:Tubulin / Q000378:metabolism*; D014508:Urea / Q000737:chemistry*; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014404:Tubulin; D014747:Vinblastine; D014508:Urea