Design, Synthesis, and Biological Evaluation of Novel Urea-Containing Carnosic Acid Derivatives with Anticancer Activity

A series of novel carnosic acid <b>1</b> derivatives incorporating urea moieties at the C-20 position was synthesized and evaluated for their antiproliferative activity against the HCT116 colorectal cancer cell line. Most derivatives demonstrated enhanced antiproliferative activity compared to that of carnosic acid <b>1</b>. The most promising derivatives were tested in other colorectal cancer cell lines (SW480, SW620, and Caco-2), melanoma (A375), and pancreatic cancer (MiaPaca-2). Derivative <b>14</b> consistently demonstrated the highest activity across all tested cancer cell lines, showing selectivity for cancer cells over normal cells. Further investigation of the mechanism of action in SW480 cells revealed that compound <b>14</b> induced cell cycle arrest at the G0/G1 phase by downregulating CDK4 and CDK6. Molecular docking studies revealed that compound <b>14</b> established several interactions with key residues in the active site of CDK6. Additionally, compound <b>14</b> also reduced ROS production. In summary, our results strongly indicate that compound <b>14</b> has potential as a lead compound in the development of innovative anticancer drugs.