Synthesis and biological evaluation of oridonin derivatives as antiproliferative agents against colorectal cancer
TL;DR
Mechanistic studies and structure–activity relationship analysis identify compound 11b as a valuable scaffold for further development of novel anticancer agents targeting CRC, and reduce intracellular ROS levels and attenuated mTOR signaling.
Abstract
In this study, a series of oridonin (ORI 1) derivatives were synthesized, and their antiproliferative activities were evaluated against colorectal cancer (CRC) cell lines. Structure–activity relationship (SAR) analysis revealed that aromatic and heteroaromatic substitutions significantly enhanced the antiproliferative potency compared to the parent compound. Among the synthesized derivatives, difuroate enmein-type compound 11b emerged as the most interesting candidate (IC50 = 0.49 μM), displaying a favorable balance between anticancer activity and cytotoxicity toward normal colon cells. Mechanistic studies revealed that compound 11b significantly inhibited the proliferation of SW620 cells, increased the doubling time, and induced S and G2/M cell cycle arrest. In addition, treatment with this compound reduced intracellular ROS levels, decreased the expression of CDK1 and CDK6, and attenuated mTOR signaling. Collectively, these findings identify compound 11b as a valuable scaffold for further development of novel anticancer agents targeting CRC.