| Pancreatic cancer is one of the deadliest cancers in the United States, with a five year survival rate of <4%. Pancreatic cancer is resistant to most therapies including chemotherapy, radiation, and combination therapy. This refractory nature of pancreatic cancer clearly demonstrates the need for novel drug discovery research specifically targeting pancreatic carcinoma. The NF-κB pathway plays a critical role in many types of cancer and is constitutively active in most human pancreatic cancer cell lines and tissues, but not in non-carcinoma cells. Inhibition of constitutive NF-κB activity not only inhibits tumorigenesis and metastasis, but also sensitizes pancreatic cancer cell lines to chemotherapy induced apoptosis. Therefore, developing novel NF-κB inhibitors may provide effective clinical options for this deadly disease.;Macrocyclic diarylether heptanoids (MDEHs) are natural product derived small molecules found in stem barks traditionally used in Eastern folk medicine. This class of compounds exhibits inhibitory activity against the NF-κB pathway. The total synthesis of Engelhardione, Platycarynol, and Galeon MDEH natural products and their analogs was accomplished using a Grubbs catalyzed cross-metathesis/Ullmann cyclization strategy. Screening of a small MDEH library led to the identification of compound 9b as a low μM NF-κB transcription activation inhibitor. Further evaluation of 9b revealed its ability to sensitize pancreatic cancer cell lines to gemcitabine mediated growth inhibition and apoptosis.;The quinoxaline pharmacophore is characterized as privileged due to the frequency with which it is found in molecules with varying bioactivities. In the quest to identify novel small molecule NF-κB inhibitors, an in-house library of quinoxaline containing compounds was screened using a κB-luciferase reporter assay. This led to the identification of compound 13-197 as a low μM inhibitor of NF-κB transcription activation. Investigation into a possible mechanism of action for this inhibitory activity of 13-197 revealed this compound’s ability to inhibit TNF-α induced p65 nuclear translocation and phosphorylation of newly synthesized IκBα, but not existing IκBα. Further studies demonstrated that 13-197 inhibited pancreatic cancer cell growth in the low μM range and induced apoptosis in a caspase-dependent manner.;The pharmacophores evaluated here represent potential leads for the development of novel pancreatic cancer chemotherapeutics. |
