Daniel M. Ketcha, Ph.D. (Advisor); Eric Fossum, Ph.D. (Committee Member); Kuppuswamy Arumugam, Ph.D. (Committee Member); Kwang-jin Cho, Ph.D. (Committee Member)
Master of Science (MS)
Oncogenic K-Ras is a driver protein found in specific cancers and was once thought to be “undruggable.” However, recent advances have suggested that mislocalizing K-Ras from the plasma membrane could be a viable strategy to target these cancers. The objective of this project was to identify a lead compound and determine a structure-activity relationship from chalcones bearing the 3,4,5-trimethoxy motif towards oncogenic K-Ras and MAO-B. This was accomplished by keeping the trimethoxy group consistent on one ring while varying the electron-donating or -withdrawing groups on the opposite ring. Previous work showed chalcones of this specific archetype exhibiting indiscriminate MAO inhibition, which justified testing trimethoxy chalcones for MAO-B inhibition as well. Structures were identified via 1H and 13C NMR and melting point comparison (where appropriate), and trends observed were based on activity and the type of functional group present in concert with the trimethoxy pharmacophore. It was determined that the lead compound 41 showed the highest K-Ras mislocalization and inhibited cell growth of pancreatic and lung cancers selectively bearing oncogenic K-Ras. Despite difluoro chalcones 50 and 56 showing prominent activity, it was realized that trimethoxy chalcones possessed more consistent activity when paired with electron-donating groups. While the trimethoxy group showed poor MAO-B inhibition overall, promising activity was observed with the 2,6-difluoro motif, and a follow-up analysis confirms that fluorinated functional groups play a massive role in MAO-B inhibition. In summation, the 3,4,5-trimethoxy pharmacophore shows potential as an effective archetype for oncogenic K-Ras but not MAO-B, and difluoro substitution patterns warrant further exploration for both targets.
Year Degree Awarded
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