Document Type

Thesis - Open Access

Award Date


Degree Name

Doctor of Philosophy (PhD)

Department / School

Chemistry and Biochemistry

First Advisor

Fathi Halaweish


Drug Design, Drug Resistance, Epidermal Growth Factor Receptor, Pancreatic Ductal Adenocarcinoma, Triazole


Cancer is a malicious disease with low survivability rates primarily due to lack of reliable treatment options. Treatments are often non-specific for patients, and cancer resistance to treatment is becoming more prevalent as fast as new therapies are created. Previous studies in our laboratory have focused on the Epidermal Growth Factor Receptor (EGFR) and its downstream kinase family members as a key target for cancer. This cascade controls cell proliferation, anti-apoptotic effects, cell regulation, and other survival factors. Additionally, ABC transporters, responsible for efflux of chemotherapeutic material from cells, are key targets to combat drug resistance. We first evaluated a set of previously synthesized triazole-estradiol analogs using ovarian (A2780) and colorectal (HT-29) cancer cell lines. Colorectal cancer is the second deadliest cancer and is often difficult to treat. Current chemotherapies limit survivability rates to on average an extension of only 6-8 months. Ovarian cancer is the deadliest reproductive cancer and is known as a silent killer due to its difficulty in detection and ability to resist drug action. We found that lead analog Fz25 shows low micromolar cytotoxicity in both lines (15.29 ± 2.19 μM and 15.98 ± 0.39 μM respectively). Inhibition studies in both cell lines show inhibition against various proteins in the EGFR pathway, namely EGFR (23%), STAT3 (65%), ERK (27%), and mTOR (26%). Fz25 was also studied against ABC Transporters and was found to inhibit P-glycoprotein up to 50% as the known inhibitor and Breast Cancer Resistance Protein better than the known inhibitor, suggesting it plays a role in combating drug resistance. Additional studies were performed to monitor the binding effects of Fz25 using molecular dynamic simulations and molecular docking and were found to compliment biological findings. In a second study, we wanted to focus on design of a new analog for treating pancreatic cancer. Pancreatic cancer, typically in the form of pancreatic ductal adenocarcinoma (PDAC), has a low 5-year survivability rate of only 5%, and a new treatment option is needed. Previous studies in our lab prompted the creation of twelve novel heterocyclic estrone analogs that were synthesized and evaluated on two pancreatic cancer cell lines AsPC-1 and Panc-1. Lead analog TR26 had an IC50 of 10.16 ± 0.83 μM in Panc-1 as compared to Gemcitabine standard with an IC50 above 50 micromolar. TR26 was also shown to arrest cells in the G0/G1 phase of the cell cycle by 12%. Additionally, TR26 was able to inhibit ERK by 25% at twice its IC50 value, and molecular dynamic studies performed suggested that key hydroxyl residues in its structure are important for binding. These heterocyclic analogs were studied further by members in our group and were found to be cytotoxic to non-small cell lung cancer cells (down to 15.7μM) as well as triple negative breast cancer cells (down to 3.18 μM). They were also additionally able to restore sensitivity of vincristine, an anticancer drug, to a resistant cell line. Finally, molecular dynamic simulations were performed to validate biological data; this showed TR26 binding to ERK complemented our findings with its 80% inhibition in-vitro. These heterocyclic estrone analogs proved moderately effective against pancreatic cancer analogs in-vitro, and modification with C-11 oxygenation increases their effectiveness in another study from our laboratory. Using Bioisosterism we theorize that the installation of a nitrogenous group at this carbon will increase their effectiveness due to their increased hydrogen bonding capabilities and similar atomic properties. Molecular modeling was performed with 650+ analogs created and docked within various EGFR pathway proteins; in specific those of the ERK/MAPK pathway and STAT3 pathway. Various C-11 amine analogs showed promising binding activities in-silico as opposed to known pancreatic cancer standard Gemcitabine, as well as to previously synthesized analogs tested against pancreatic cancer (2-5 fold better). This prompted their synthetic creation. Optimization of the C-11 ketone intermediate was first performed to limit the use of harsh chemicals which cause lower yields, such as hydroboration agents, as well as those that produce multiple by-products. Many iterations were then performed to obtain the C- 11 amine from the C-11 ketone, and eventually it was obtained through installation of a benzylamine intermediate followed by hydrogenation. We ultimately propose a full-scale synthesis for C-11 amino analogs with heterocyclic side chains as new lead analogs to eventually be tested in pancreatic cancer.

Library of Congress Subject Headings

Drugs -- Design.
Drug resistance in cancer cells.
Antineoplastic agents.

Number of Pages



South Dakota State University



Rights Statement

In Copyright