This proposal will detail studies directed towards the total synthesis of (+)- and (-)-Spiroxins A-E, new members of the bisnaphthospiroketal class of natural products. Spiroxin A has been shown to possess very promising biological activity, exhibiting antitumor activity in nude mice against ovarian carcinoma (59 percent inhibition after 21 days) at 1mg/kg dosing and cytotoxicity with a mean IC50 value of 0.09 mg/mL against a panel of 25 diverse cell lines. The mechanism of this activity is not known, nor are the biological activities of spiroxins B-E. The spiroxins are therefore very attractive targets for synthesis and analog preparation. Furthermore, the absolute stereochemistry of these natural products is not known, nor are the relative stereochemistries of Spiroxins D and E. The syntheses proposed herein would therefore also serve to provide critical stereochemical information by accessing the unnatural enantiomers and diastereomers which may themselves possess important biological activity. The proposed synthetic route is convergent, incorporates new methodology for the asymmetric preparation of naphthoquinols, and expands the utility of existing biaryl ether-forming methodologies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32CA093134-01
Application #
6404822
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Lohrey, Nancy
Project Start
2001-09-17
Project End
Budget Start
2001-09-17
Budget End
2002-09-16
Support Year
1
Fiscal Year
2001
Total Cost
$33,260
Indirect Cost
Name
Harvard University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
071723621
City
Cambridge
State
MA
Country
United States
Zip Code
02138