title: Total Synthesis and Biological Evaluation of Tubulysin Analogues.
abstract: We report a second-generation synthesis of the exceedingly potent antimitotic agent N14-desacetoxytubulysin H (1) as well as the preparation of nine analogues of this lead structure. Highlights of our synthetic efforts include an efficient late-stage functionalization that allows for the preparation of new side-chain- and backbone-modified analogues. We also discovered C-terminal modifications that preserve the exquisite biological activity of acid 1 and offer the opportunity for effective conjugation to cell type-targeting moieties. All analogues had antiproliferative activities in the high picomolar to low nanomolar range and caused apoptosis and mitotic arrest as measured in a high content nuclear morphology assay. The ten synthetic agents described herein spanned a range of almost 4 orders of magnitude in biological activity and illustrate the continued potential to discover extraordinarily potent antiproliferative compounds based on natural product leads.
authors.affiliation: Department of Chemistry, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.|Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Colombo
authors.affiliation: Department of Chemistry, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Chemistry, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Junyan
authors.initials: J
authors.lastname: Han
authors.forename: Raghavan
authors.initials: R
authors.lastname: Balachandran
authors.forename: Hikmat N
authors.initials: HN
authors.lastname: Daghestani
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Camarco
authors.forename: Andreas
authors.initials: A
authors.lastname: Vogt
authors.forename: Billy W
authors.initials: BW
authors.lastname: Day
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: David
authors.initials: D
authors.lastname: Mendel
authors.affiliation: Department of Chemistry, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D066244:Proton Magnetic Resonance Spectroscopy
chemical_list: C520247:N14-desacetoxytubulysin H; D009842:Oligopeptides