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 cytotoxi against the estrogen dependant human breast carcinoma cell line MCF-7 (LD50 = 17 mg/L). The World Health Organization (WHO) recently predicted that death caused by cancer is expected to increase to 13.1 million by 2030. Among all other deadly cancers, invasive breast cancer is the most recurrently diagnosed malignant tumor among women (31% in the US and 27% in Europe) and the second leading cause of cancer related death subsequent to lung cancer. Women have a 32% lifetime risk of developing breast cancer and 15% risk of breast cancer causing death in the US. We plan to address the challenge of improving the aforementioned statistics through developing derivatives of the natural product, 11-deoxyfustularin-3, that will have sub-micromolar activity against MCF-7 breast cancer. 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 the construction of synthetic analogues that possess sub-micromolar activity against breast cancer cells.
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.
|Das, Prasanta; Hamme 2nd, Ashton T (2017) Zinc Mediated Direct Transformation of Propargyl N-hydroxylamines to ?,?-Unsaturated Ketones and Mechanistic Insight. Tetrahedron Lett 58:1086-1089|
|Ezzat, Abdelrahman E M; El-Begermy, Marwa M; Mahmoud, Ahmed M A et al. (2015) COMPARISON OF NATURAL AND SYNTHETIC MATERIALS TO IMPROVE HEARING AFTER OBLITERATION OF THE MASTOID CAVITY. J Hear Sci 4:OA36-41|
|Das, Prasanta; Omollo, Ann O; Sitole, Lungile J et al. (2015) Synthesis and Investigation of Novel Spiro-isoxazolines as Anti-Cancer Agents. Tetrahedron Lett 56:1794-1797|
|Ezzat, Abdelrahman E M; Eid, Mustafa I (2014) Evaluation of using Bioglass(®) in obliteration of mastoid cavity. Curr Sci Int 3:87-94|
|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; Valente, Edward J; Hamme 2nd, Ashton T (2014) Synthesis and Tautomerism of Spiro-Pyrazolines. Tetrahedron Lett 55:2208-2211|
|Dadiboyena, Sureshbabu; Hamme 2nd, Ashton T (2013) Environmentally Benign Lewis Acid Promoted [2+3]-Dipolar Cycloaddition Reactions of Nitrile Imines with Alkenes in Water. European J Org Chem 2013:7567-7574|
|Dadiboyena, Sureshbabu; Hamme 2nd, Ashton T (2011) One Pot Spiropyrazoline Synthesis via Intramolecular Cyclization/Methylation. Tetrahedron Lett 52:2536-2539|