Synthesis and structure-activity studies of schweinfurthin B analogs: Evidence for the importance of a D-ring hydrogen bond donor in expression of differential cytotoxicity.
The synthesis and biological evaluation of several enantioenriched schweinfurthin B analogs were undertaken to develop structure-activity relationships and guide design of probes for their putative molecular target. The desired stilbenes contain a common left-half hexahydroxanthene ring system and an aromatic right-half with varied substituents. The synthesis involves penultimate Horner-Wadsworth-Emmons coupling of one of several right-half phosphonates with the aldehyde comprising the left-half of 3-deoxyschweinfurthin B. Preparation of the requisite phosphonates, and the respective stilbenes, as well as the cytotoxicity profiles of these new compounds in the National Cancer Institute's 60 cell-line anticancer screen is described. Several of these analogs displayed cytotoxicity patterns well-correlated with the natural product and differences in activity of approximately 10(3) across the various cell lines. Together, these assay results indicate the importance of at least one free phenol group on the aromatic D-ring of this system for differential cytotoxicity.
Neighbors
Jeffrey D
JD
Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA.
Salnikova
Maya S
MS
Beutler
John A
JA
Wiemer
David F
DF
D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006860:Hydrogen Bonding; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D013267:Stilbenes; C117233:schweinfurthin B