Syntheses of 5a'-homo-vinblastine and congeners designed to establish structural determinants for isolation of atropisomers.
The syntheses of 5a'-homo-vinblastine (3a) and its C-20' methyl congener 62a were achieved. In contrast to vinblastine, these compounds did not allow isolation of atropisomers because of their lower conformational inversion barrier. However, annelation of a six-membered ring to the conformationally mobile D'-piperidine ring provided an isolated atropisomer 81a, which could be converted to its lower energy conformation 65a on heating. The 5a'-homo-vinblastine congeners 3a, 62a, and 65a showed vinblastine-like inhibition of tubulin polymerization and cytotoxicity to L1210 leukemia cells, albeit at lower potency for the latter activity, than that found with the corresponding compounds in the vinblastine series.
Kuehne
M E
ME
Department of Chemistry, University of Vermont, Burlington, 05405, USA. mkuehne@zoo.uvm.edu
Cowen
S D
SD
Xu
F
F
Borman
L S
LS
D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004852:Epoxy Compounds / Q000138:chemical synthesis / Q000737:chemistry; D008968:Molecular Conformation; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C434287:5a'-homo-vinblastine; D000972:Antineoplastic Agents, Phytogenic; D004852:Epoxy Compounds; C009667:vindoline; D014747:Vinblastine