Synthesis of 15-methylene-eburnamonine from (+)-vincamine, evaluation of anticancer activity, and investigation of mechanism of action by quantitative NMR.
The biological role of installing a critical exocyclic enone into the structure of the alkaloid, (-)-eburnamonine, and characterization of the new chemical reactivity by quantitative NMR without using deuterated solvents are described. This selective modification to a natural product imparts potent anticancer activity as well as bestows chemical reactivity toward nucleophilic thiols, which was measured by quantitative NMR. The synthetic strategy provides an overall conversion of 40%. In the key synthetic step, a modified Peterson olefination was accomplished through the facile release of trifluoroacetate to create the requisite enone in the presence of substantial steric hindrance.
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, United States.
James R
JR
Woods
Mark V
MV
Riofski
Mary M
MM
Zheng
Melissa A
MA
O'Banion
Huaping
H
Mo
Julia
J
Kirshner
David A
DA
Colby
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D014748:Vinca Alkaloids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014749:Vincamine / Q000737:chemistry*
D000970:Antineoplastic Agents; D014748:Vinca Alkaloids; D014749:Vincamine; C016422:eburnamonine
Alkaloid; Anticancer agent; Covalent; Mechanism of action; NMR