Dissertation - Open Access
Doctor of Philosophy (PhD)
Chemistry and Biochemistry
Fathi T. Halaweish
Pancreatic cancer is currently the fourth most deadly type of cancer globally. It is expected to become the second by 2030, due to its poor prognosis and its resistance to the current standard treatment, Gemcitabine. Moreover, the survival rate after treatment is low compared to other cancer types, which suggests an urgent need for new potent and safe treatment agents. Recently, the triterpenoid, cucurbitacin, has shown promising antiproliferative activity against human pancreatic cancer cells in a dose- and timedependent manner, and decreased pancreatic tumor size in combination with gemcitabine in vivo. However, the use of cucurbitacin in clinical studies has been hindered by its low yield from natural sources and challenging total chemical synthesis. In order to overcome this obstacle, we have developed molecular-modeling based strategy that resulted in the installation of cucurbitacin pharmacophores onto an estrone scaffold to generate novel hybrid analogs that showed a promising antiproliferative activity. In-silico drug design results showed that modification of these compounds at C11 possessing high binding affinity towards more than one of pancreatic molecular targets such as EGFR, and Erk, kinase domains. Based on that total of 25 novel analogs have been synthesized by adopting multiple step organic synthesis. The ant proliferation activities of the novel analogs were biologically investigated against PANC-I, AsPC-I, and BXPC-3 pancreatic cell lines in 2D and 3D models using MTT and CellTiter assays, respectively. Five analogs showed potent IC50 values compared to gemcitabine and cucurbitacin B, and were further studied for cell cycle inhibition, EGFR signaling and caspase 3/7 activity in 2D models. Additional studies showed these analogs arrested the cell cycle in the G1 phase, inhibited activation of EGFR and the downstream MAP kinase Erk. The present study shows, for the first time, that C11 modified cucurbitacin-estrone hybrid analogs possess more antiproliferative activities than the standard chemotherapy regimen against pancreatic cancer cell lines and provide potential drug candidates for preclinical application.
Number of Pages
South Dakota State University
In Copyright - Educational Use Permitted
Alseud, Khaled, "Design, Synthesis and Biological Screening of Novel Cucs-inspired Estrone Analogs towards Treatment of Pancreatic Adenocarcinoma" (2019). Electronic Theses and Dissertations. 3380.
Available for download on Saturday, July 25, 2020