Expedient synthesis of N-methyl tubulysin analogues with high cytotoxicity.
An optimized and highly efficient synthesis of potent, bioactive N-methyl tubulysin analogues 2 and 4 has been achieved with > 40% overall yields. This synthesis represents a significant improvement over previously reported syntheses of these and related tubulysin analogues. The stereoselective synthesis of the unnatural amino acid tubuvaline is accomplished using tert-butanesulfinamide chemistry. N-Alkylation to form N-methyl tubuvaline is performed without protection of the tubuvaline alcohol by implementing a unique N-methylation strategy via formation and reduction of a 1,3-tetrahydrooxazine heterocycle. Acylation of the hindered N-methyl tubuvaline amine utilizes a novel sequence of O-acylation followed by an O- to N-acyl transfer to form the hindered amide bond between N-methyl tubuvaline and isoleucine. This high-yielding synthesis should enable the production of large quantities of material for biological studies.
Patterson
Andrew W
AW
Department of Chemistry, University of California, Berkeley, CA 94720, USA.
Peltier
Hillary M
HM
Ellman
Jonathan A
JA
D004354:Drug Screening Assays, Antitumor; D009682:Magnetic Resonance Spectroscopy; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D016339:Spectrometry, Mass, Fast Atom Bombardment
D009842:Oligopeptides