Total synthesis and biological evaluation of (-)apicularen A and analogues thereof.
Apicularen A (1) and related benzolactone acylenamines belong to a growing class of novel natural products possessing highly cytotoxic properties. The challenging structure of 1 includes a 10-membered macrolactone ring, a tetrahydropyran system, an o,m-substituted phenol and a doubly unsaturated acyl group attached on the side chain enamine functionality. The total synthesis of apicularen A described herein involves a strategy equivalent to its proposed biosynthesis and entails a reiterative two-step procedure featuring allylation and ozonolytic cleavage to grow the molecule's chain by one acetate unit at a time. The developed synthetic technology was applied to the construction of a series of apicularen A analogues whose biological evaluation established a set of structure-activity relationships in this new area of potential importance in cancer chemotherapy.
Nicolaou
K C
KC
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. kcn@scripps.edu
Kim
David W
DW
Baati
Rachid
R
O'Brate
Aurora
A
Giannakakou
Paraskevi
P
D000588:Amines / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001555:Benzene Derivatives / Q000737:chemistry / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007783:Lactones / Q000737:chemistry; D018942:Macrolides / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D010051:Ovarian Neoplasms / Q000188:drug therapy; D010636:Phenols / Q000737:chemistry; D011714:Pyrans / Q000737:chemistry; D013329:Structure-Activity Relationship
D000588:Amines; D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007783:Lactones; D018942:Macrolides; D010636:Phenols; D011714:Pyrans; C117813:apicularen A