Targeting oncogenic K-Ras and monoamine oxidase B utilizing chalcones bearing the 3,4,5-trimethoxyphenyl motif

Targeting oncogenic K-Ras and monoamine oxidase B utilizing chalcones bearing the 3,4,5-trimethoxyphenyl motif

Bibliographic Details
Main Author: Fourman, Cody
Language:English
Published: Wright State University / OhioLINK 2020
Subjects:
Chemistry
Medicine
chalcones
oncogenic K-Ras
MAO-B
trimethoxy
anti-cancer
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=wright1596823680746445
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-wright15968236807464452021-08-03T07:16:12Z Targeting oncogenic K-Ras and monoamine oxidase B utilizing chalcones bearing the 3,4,5-trimethoxyphenyl motif Fourman, Cody Chemistry Medicine chalcones oncogenic K-Ras MAO-B trimethoxy anti-cancer 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. 2020-08-11 English text Wright State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=wright1596823680746445 http://rave.ohiolink.edu/etdc/view?acc_num=wright1596823680746445 unrestricted This thesis or dissertation is protected by copyright: some rights reserved. It is licensed for use under a Creative Commons license. Specific terms and permissions are available from this document's record in the OhioLINK ETD Center.
collection NDLTD
language English
sources NDLTD
topic Chemistry
Medicine
chalcones
oncogenic K-Ras
MAO-B
trimethoxy
anti-cancer
spellingShingle Chemistry
Medicine
chalcones
oncogenic K-Ras
MAO-B
trimethoxy
anti-cancer
Fourman, Cody
Targeting oncogenic K-Ras and monoamine oxidase B utilizing chalcones bearing the 3,4,5-trimethoxyphenyl motif
author Fourman, Cody
author_facet Fourman, Cody
author_sort Fourman, Cody
title Targeting oncogenic K-Ras and monoamine oxidase B utilizing chalcones bearing the 3,4,5-trimethoxyphenyl motif
title_short Targeting oncogenic K-Ras and monoamine oxidase B utilizing chalcones bearing the 3,4,5-trimethoxyphenyl motif
title_full Targeting oncogenic K-Ras and monoamine oxidase B utilizing chalcones bearing the 3,4,5-trimethoxyphenyl motif
title_fullStr Targeting oncogenic K-Ras and monoamine oxidase B utilizing chalcones bearing the 3,4,5-trimethoxyphenyl motif
title_full_unstemmed Targeting oncogenic K-Ras and monoamine oxidase B utilizing chalcones bearing the 3,4,5-trimethoxyphenyl motif
title_sort targeting oncogenic k-ras and monoamine oxidase b utilizing chalcones bearing the 3,4,5-trimethoxyphenyl motif
publisher Wright State University / OhioLINK
publishDate 2020
url http://rave.ohiolink.edu/etdc/view?acc_num=wright1596823680746445
work_keys_str_mv AT fourmancody targetingoncogenickrasandmonoamineoxidasebutilizingchalconesbearingthe345trimethoxyphenylmotif
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