Format

Send to

Choose Destination
J Med Chem. 2013 Jan 24;56(2):483-95. doi: 10.1021/jm3014376. Epub 2013 Jan 4.

Total synthesis and evaluation of vinblastine analogues containing systematic deep-seated modifications in the vindoline subunit ring system: core redesign.

Author information

1
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.

Abstract

The total synthesis of a systematic series of vinblastine analogues that contain deep-seated structural modifications to the core ring system of the lower vindoline subunit is described. Complementary to the vindoline 6,5 DE ring system, compounds with 5,5, 6,6, and the reversed 5,6 membered DE ring systems were prepared. Both the natural cis and unnatural trans 6,6-membered ring systems proved accessible, with the latter representing a surprisingly effective class for analogue design. Following Fe(III)-promoted coupling with catharanthine and in situ oxidation to provide the corresponding vinblastine analogues, their evaluation provided unanticipated insights into how the structure of the vindoline subunit contributes to activity. Two potent analogues (81 and 44) possessing two different unprecedented modifications to the vindoline subunit core architecture were discovered that matched the potency of the comparison natural products and both lack the 6,7-double bond whose removal in vinblastine leads to a 100-fold drop in activity.

PMID:
23252481
PMCID:
PMC3554876
DOI:
10.1021/jm3014376
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for American Chemical Society Icon for PubMed Central
Loading ...
Support Center