Chemistry Masters Candidate Thesis Defense Presentation
Patricia Tumfuo, Candidate
Dr. Wei Shi & Dr. Robert Sammelson (Advisors)
"Exploration Towards the Synthesis of a-Cyanocinnamate Modified Open-Ring Analogs of Ipomoeassin F"
Friday, June 5th, 10am
Foundational Science Building - FB-253
Abstract: Through the implementation of medicinal chemistry studies, ipomoeassin F (Ipom-F), a fraction of the ipomoeassin series obtained from the leaves of Ipomeoea squamosa (morning glory) is found to possess most potent cytotoxicity when tested against different cell lines compared to the other fractions. Removal of the entire cinnamate moiety of Ipom-F caused over 1000-fold reduction in biological activity. Removal or reducing the double bond in the cinnamate moiety decreased the biological activity by over 150 times. The significance of the a,ß-unsaturated system led to our group introducing a cyano group to the a position. We hypothesize that enhancing the partial positive charge on the ß carbon of the a-cyanocinnamate analogues would strengthen their binding affinity to the target protein Sec61a.
Although Ipom-F is a macrocyclic natural product, the medicinal chemistry study proposed here will focus on new ring-opened analogues of Ipom-F containing different a-cyanocinnamic acids. Based on our previous structure-activity relationship (SAR) studies, it was found that the ring-opened scaffolds, with more convenient syntheses, demonstrated biological activities comparable to Ipom-F.
In addition to the medicinal chemistry studies, we are facing two challenges in the chemical synthesis:(1) difficulty in forming the ester when an electron withdrawing group is present on the benzene ring; (2) removal of the TBS (tert-butyldimethylsilyl) protecting group using tert-butylammonium fluoride (TBAF) cleaves the cinnamate portion of the product when an electron donating group is present on the benzene ring; This thesis research is focusing on exploration of the first challenge.