Synthesis of Hydroxycinnamate Derivatives and Characterization of Bioactivity as Radical Scavengers and α-Glucosidase Inhibitors

Author

Cate Simmermaker, University of the PacificFollow

Date of Award

2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Andreas Franz

First Committee Member

Liang Xue

Second Committee Member

Jerry W. Tsai

Third Committee Member

Skylar Carlson

Fourth Committee Member

Caroline Chu

Abstract

Hydroxycinnamic acids (HCAs), a class of polyphenols commonly found in regularly consumed fruits and vegetables, have been investigated for efficacy as radical scavengers and glycosidase inhibitors. These compounds could mitigate the negative health effects of free radicals in oxidative stress diseases including neurodegeneration, cancer and diabetes. The HCAs investigated were caffeic acid (1), p-coumaric acid (2), ferulic acid (3), and sinapic acid (4). The compounds were derivatized with synthetically prepared amino acid esters through a four-step synthesis including protective acetylation, chlorination of the carboxylic acid, amidation, and subsequent deprotection of all applied protecting groups. The inclusion of diverse derivative groups allowed for the investigation of structure activity relationships through radical scavenging and enzyme inhibition assays. An assay with 2,2-diphenyl-1-picrylhydrazyl (DPPH) revealed the effect of the phenolic structure and capacity of the most active portion of the compound, but also the nature of the reaction through constant tracking, as opposed to only final capacity. Stabilization of the HCA’s radical structure by aromatic substituents was found to be most important. However, structural modification of HCAs with various amino acids affected the initial rate of reaction based on the carbon chain length between the amide and amino acid carboxylic acid and the number of carboxylic acids present on the amino acid residue. Following previous investigations of α-amylase inhibition by similar compounds, our study showed a ranked inhibition ability of 2≈1>3>4. The derivatized HCAs created for this study have been analyzed for protein-ligand interaction via the molecular docking program AutoDock Vina, Saturation-Transfer Difference (STD)-NMR, intrinsic fluorescence quenching and a robust starch-iodine microwell plate inhibition assay. Additional characterization of the protein-ligand interaction points to π-π stacking as the major contributor, similar to previously tested polyphenols, and a mechanism different from positive control inhibitors.

Pages

200

Recommended Citation

Simmermaker, Cate. (2024). Synthesis of Hydroxycinnamate Derivatives and Characterization of Bioactivity as Radical Scavengers and α-Glucosidase Inhibitors. University of the Pacific, Dissertation. https://scholarlycommons.pacific.edu/uop_etds/4259