A series of marine natural products isolated from the sponge of Verongida have been intensively studied due to the presence of alkaloids with one, or more bromotyrosine residues. Many of these alkaloid metabolites show interesting bioactivity and cytotoxic properties in tumor cell lines. The natural product, 11-Deoxyfistularin-3 is cytotoxic against the estrogen dependant human breast carcinoma cell line MCF-7 (LD50 = 17 mg/L). Since breast cancer is the most common cancer among women, and the second leading cause of cancer death for women, biologically active natural products can serve as a structural template for the construction of more potent synthetic analogues as a non-surgical treatment for breast cancer. One of the interesting structural aspects of this natural product is the presence of two spirocyclic moieties. This research project has three main objectives. The first objective is to develop a synthetic methodology that can be applied toward the asymmetric total synthesis of the biologically active natural product, 11-deoxyfistularin-3. Secondly, we plan to construct synthetic analogues of the natural product to determine if a segment of the natural product can also display biological activity against MCF-7 cells. Our final objective is to determine if any of the MCF-7 active synthetic analogues and the natural product can effectively bind to estrogen receptors. The data generated from these binding assays will lead to theoretical docking studies of the ligand-receptor interactions of the biologically active compound and the estrogen receptor, and the generation of a structure-activity relationship profile of these compounds could potentially lead to synthetic analogues that are more potent than the natural product.

Public Health Relevance

We are investigating a method to make potent compounds to target breast cancer which is the second leading cause of cancer death in women. The compounds that we are targeting are based upon a naturally occurring substance found in the ocean.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Continuance Award (SC3)
Project #
5SC3GM094081-03
Application #
8304237
Study Section
Special Emphasis Panel (ZGM1-MBRS-X (CH))
Program Officer
Krasnewich, Donna M
Project Start
2010-09-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$111,004
Indirect Cost
$36,754
Name
Jackson State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
044507085
City
Jackson
State
MS
Country
United States
Zip Code
39217
Dadiboyena, Sureshbabu; Valente, Edward J; Hamme 2nd, Ashton T (2014) Synthesis and Tautomerism of Spiro-Pyrazolines. Tetrahedron Lett 55:2208-2211
Das, Prasanta; Valente, Edward J; Hamme 2nd, Ashton T (2014) A Model Study toward the Concise Synthesis of Bromotyrosine Derived Spiroisoxazoline Natural Products and Analogous Core Structures. European J Org Chem 2014:2659-2663
Dadiboyena, Sureshbabu; Hamme 2nd, Ashton T (2011) One Pot Spiropyrazoline Synthesis via Intramolecular Cyclization/Methylation. Tetrahedron Lett 52:2536-2539