The overal objectives of this proposal are to develop new synthetic methods for the synthesis of the neolignan antitumor agent, Megaphone, the antileukemic agent, Sergeolide, and a general class of chiral butyrolactones containing thiophenyl and halogen substituents. This last class of compounds can functions as latent alkylating and acylating agents for cancer chemotherapy. The molecule, Sergeolide, is a representative of a new type of quassinoids, a class of natural products that already has one candidate, Bruceantin, in clinical trials at NCI. Sergeolide contains the new feature of an enol butenolide ring which chemically behaves as a bis-alkylating agent. This proposal will provide direct and efficient methodology to prepare this new functionality in order to probe its effectiveness in the chemotherapy of cancer. All of our simple lactones and many of the synthetic intermediates will be tested for activity at NCI and/or Warner-Lambert Research Laboratories in Ann Arbor.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA022237-09
Application #
3165781
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1978-09-30
Project End
1989-12-31
Budget Start
1988-01-01
Budget End
1988-12-31
Support Year
9
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Arts and Sciences
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Marino, Joseph P; Rubio, Maria B; Cao, Ganfeng et al. (2002) Total synthesis of (+)-aspidospermidine: a new strategy for the enantiospecific synthesis of aspidosperma alkaloids. J Am Chem Soc 124:13398-9
Marino, J P; Anna, L J; Fernandez de la Pradilla, R et al. (2000) Sulfoxide-controlled S(N)2' displacements between cyanocuprates and epoxy vinyl sulfoxides. J Org Chem 65:6462-73