One of the most promising totally synthetic approaches to steroids is via biomimetic polyene cyclization methodology. The major aim of this proposal is to expand the present state of the art of this methodology so that it may be employed to synthesize certain medicinally (see below) useful compounds, making them more readily accessible than by presently available methods. High priority projects include plans for developing new concepts for the rational design of: (a) improved cyclization initiator functions that can be fine-tuned with respect to their electrophilicity and (b) improved cyclization terminator functions that effect highly regio- and diastereoselective ring closure to give products with functionality that can be readily manipulated for the production of useful structures, e.g., the corticoid side-chain. Another top priority project is to test a new concept of tandem cyclization as follows. A (tandem) function is positioned part way along the polyene chain of the substrate so that when the cyclization process reaches this point, the auxiliary function is converted into a resonance-stabilized cation of a known type that should be effective for initiating further cyclization. Thus a tetracyclization is envisaged as being achieved by two sequential high yield bicyclization processes. All of the aforementioned methodology studies will be addressed within the context of realizing asymmetric cyclizations and synthesizing products of known or potential medicinal value. Immediate targets are, e.g., mineralotropic and anti-inflammatory corticoids (for treatment of various diseases, e.g., arthritis), 19-norsteroidal compounds (for oral contraception), vitamin D3 metabolites and analogs (for control of disorders involving calcium metabolism, e.g., osteodystophy), and bile acids such as chenodesoxycholic acid (for dissolution of gallstones). Ancillary studies involve the development of enzyme models as well as template systems that may assist biomimetic polyene cyclizations. It is proposed also to exploit any especially promising novel behavior encountered in the aforementioned studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK003787-28
Application #
3224416
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1975-06-01
Project End
1990-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
28
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
Schools of Arts and Sciences
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Taton, M; Benveniste, P; Rahier, A et al. (1992) Inhibition of 2,3-oxidosqualene cyclases. Biochemistry 31:7892-8