quercetin and Colorectal-Neoplasms

Topics: Antineoplastic Agents; Cell Line; Cell Proliferation; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Quinoxalines; Structure-Activity Relationship

In the course of our ongoing efforts to develop novel quercetin conjugates with enhanced stability profiles, we introduced an isopropyloxycarbonylmethoxy (POC) group to 7-OH and/or 3-OH of quercetin and prepared three novel quercetin conjugates. The quercetin-POC conjugates were stable up to 96 h in PBS but slowly hydrolyzed with half-lives of 1-54 h in cell-free culture medium, which is reminiscent of the stability profiles of the previously reported quercetin-POM (pivaloxymethyl) conjugates. However, the quercetin-POC conjugates were more susceptible to passive transport, intracellular hydrolysis, and metabolism in breast cancer (MCF-7) cell line compared with their POM congeners to result in low concentration of quercetin in this cell line and thereby low antiproliferative effect. In contrast, upon incubation with colorectal carcinoma HCT116 cells, the quercetin-POC conjugates were shown to undergo slow hydrolysis and metabolism to maintain concentrations of the active quercetin species high enough to exert enhanced cytotoxicity. Taken together, the quercetin-POC conjugates synthesized in this study exhibited cell type-specific stability as well as bioactivity profiles, which warrants further investigation into the underlying mechanisms and therapeutic potential.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Drug Stability; Female; Humans; Hydrolysis; Quercetin; Solubility