The synthesis of antitumor gilvocarcin antibiotics (la-h) is based on a novel strategy (Scheme 1, P. 18) in which a C-1 lithiated glycal is added to a quinone acetal (e.g. 6+7 -> 8). The concurrent aromatization of the adduct and antiMarkovnikov hydration of the glycal double bond is then accomplished with diborane; this reaction, developed during the course of work on this project affords a C-aryl glycoside (e.g. adduct 8 will be converted to 9). Appropriately substituted C-aryl glycosides 10 will be converted to chromium carbenes which will be added to the acetylene 11 (R=CH=CH2) (readily available by a five-step procedure) to afford the V series of gilvocarcins (la-c, and e).The M series of gilvocarcins can be prepared by parallel scheme. In addition to the model gilvocarcin 43 (from D-glucose) and the natural products la-e, the disaccharide analog 65 will be prepared. Ravidomycin (la, authentic natural product ) and synthetic gilvocarcins will be subjected to DNA binding studies in an effort to clarify the mechanism of action of the gilvocarcin series.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA050720-02
Application #
3195373
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1990-12-15
Project End
1993-11-30
Budget Start
1991-12-01
Budget End
1992-11-30
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Brown University
Department
Type
Schools of Arts and Sciences
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912