Hong, JiyongZhao, Yiquan2024-06-062024https://hdl.handle.net/10161/30919<p>Invasive ductal adenocarcinoma of pancreas, commonly known as “pancreatic cancer”, is a highly malignant neoplasm originating in pancreatic tissues, often metastasizing to nearby organs like liver. Most patients only display nontypical symptoms in the early stages and often have metastasis upon diagnosis. Consequently, pancreatic cancer ranks as the seventh leading cause of cancer-related mortality worldwide and the fourth in the United States.Despite surgery being the sole curative option of human pancreatic cancer, clinical care for most patients remains to be systemic chemotherapy. Gemcitabine has served as the standard first-line chemotherapeutic agent for advanced pancreatic cancer for over two decades, but resistance development poses challenges. Moreover, new standard-of-care regimens such as FOLFIRINOX and gemcitabine/nab-paclitaxel offered modest improvements in survival rates and increased toxicities, and future treatments is founded on targeting tumor microenvironment and cancer-specific cell metabolisms. In 2000, Esumi and colleagues proposed the antiausterity strategy to combat cancer cells’ tolerance of nutrient deprivation conditions resulting from the hypovascular nature of the pancreatic tumor. With the screening method established by Esumi, a diverse array of antiausterity agents have since been isolated or synthesized. In 2020, three daucane-type natural products isolated from Ferula hezarlalehzarica demonstrated potent antiausterity activity against PANC-1 pancreatic cancer cells. However, mechanisms of action for these compounds remain incompletely known, and their structure-activity relationships (SAR) and potential for drug discovery are unclear. Therefore, we focuses on the total syntheses of these natural products as well as the design and preparation of analogs to establish SAR. All three target molecules (compounds 1, 2 and 3) are daucane-type sesquiterpenoids featuring a 5,7-fused bicyclic system with trans ring junction and a quaternary carbon center. In our synthesis, we first aimed to stereoselectively install the quaternary center. While attempts of asymmetric conjugate addition with a Cu/NHC-Ag system failed to provide satisfactory enantiomeric excess, the silicon-tethered radical cyclization-trapping strategy achieved installation of the quaternary carbon center. Compound 1 was then successfully prepared after utilizing a ring-closing metathesis to construct the 5,7-fused bicyclic system. Synthesis of compounds 2 and 3 required establishing the allylic alcohol moiety in the 7-membered ring. Unfortunately, our attempted elimination approaches based on the TBS-protected tetraol intermediate, as well as the Bamford-Stevens reaction and the vinyl triflate formation based on the α-hydroxyketone intermediate, did not afford the desired product. Approaches such as epoxide opening, singlet oxygen, and iodocarbonate cyclization based on the jaeschkeanadiol intermediate or derivatives also proved futile. Eventually, we installed the allylic alcohol moiety via a 6-step sequence involving an elimination with a cyclic sulfate leaving group, and we subsequently improved the efficiency of this pathway by utilizing a 2-step Chugaev elimination. Despite that all esterification attempts to prepare compound 2 failed, we were able to synthesize compound 3 by introducing the ester in the early stage. Four analogs have been prepared by modifying key functional groups (e.g. the ester and endocyclic olefin) within the target molecules, and antiausterity activity of these analogs and compounds 1 and 3 are currently being evaluated. The results will help establish SAR and shed light on designing new derivatives that may provide better solutions to treatments of human pancreatic cancer.</p>https://creativecommons.org/licenses/by-nc-nd/4.0/ChemistryDissertation