Total synthesis and biological evaluation of tubulysin U, tubulysin V, and their analogues.
A stereoselective total synthesis of the cytotoxic natural products tubulysin U, tubulysin V, and its unnatural epimer epi-tubulysin V, is reported. Simplified analogues containing N,N-dimethyl-D-alanine as a replacement for the N-terminal N-Me-pipecolinic acid residue of the tubulysins are also disclosed. Biological evaluation of these natural products and analogues provided key information with regard to structural and stereochemical requirements for antiproliferative activity and tubulin polymerization inhibition.
Balasubramanian
Ranganathan
R
Department of Medicinal Chemistry, 308 Harvard Street SE, 8-101 Weaver-Densford Hall, University of Minnesota, Minneapolis, Minnesota 55455-0353, USA.
Raghavan
Bhooma
B
Begaye
Adrian
A
Sackett
Dan L
DL
Fecik
Robert A
RA
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010875:Pipecolic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D009842:Oligopeptides; D010875:Pipecolic Acids; C516471:tubulysin U; C516472:tubulysin V