Synthesis and biological evaluation of novel carnosic acid derivatives with anticancer activity

Abstract

Novel derivatives of carnosic acid 1 with ester or carbamate groups at C-20 and derivatives with these functional groups combined with benzylic modifications (C-7) were synthesized and evaluated in a colorectal cancer cell line (HCT116). Compound 8, which featured a butyl ester at C-20 and a carbonyl group at C-7, and compound 17, which featured a 2-methylpropyl carbamate at C-20, achieved the best results in HCT116 cells. Compounds 8 and 17 also demonstrated better ability to inhibit the growth of other cancer cell lines than CA 1. In general, the best results were achieved with compound 17, which exhibited higher potency against SW480 cells (IC₅₀ = 6.3 μM). This compound also showed selectivity for cancer cells compared to normal cells. Compound 17 was subjected to additional studies to elucidate the mechanism responsible for its antiproliferative activity in SW480 cells. At 24 h, compound 17 arrested the cell cycle at the G0/G1 phase by decreasing the CDK4/CDK6 levels. It also reduced ROS levels by increasing the expression of SOD2/MnSOD. However, at 48 h, compound 17 induced cell cycle arrest in the S phase and increased ROS levels. At 72 h, compound 17 elevated the ROS levels without inducing cell cycle arrest. Additionally, molecular docking studies showed that compound 17 establishes several interactions with the amino acids of the CDK6 active site. In conclusion, compound 17 is a promising candidate for the development of novel anticancer drugs.