Synthesis of asiatic acid derivatives and their cytotoxic activity

Abstract

Twenty-eight compounds, including 24 new (4–22, 25–26, and 28–30) and four known (2, 23, 24, and 27) have been synthesized starting from asiatic acid (1), which was isolated from Centella asiatica. The preparation procedure included the acetylation, hydrolyzation on the 2-, 3-, 23-, and the side chain hydroxyl, amino groups, as well as the amidation of the 28-carboxylic group. All the synthesized derivatives were structurally confirmed by 1H, 13C NMR, and MS spectra. Besides, they were evaluated for their cytotoxicity against three cancer cell lines: KB (human carcinoma in the mouth), HepG2 (human hepatocellular carcinoma), and SK-LU-1 (human lung carcinoma). Eleven of the tested compounds, including nine newly synthesized and two known ones showed very strong activity against three tested cell lines with the IC50 values ranging from 0.67 to 37.39 µM. Three compounds showed good activity against KB and HepG2 cell lines with the IC50 values ranging from 1.95 to 32.12 µM. The activity against the KB and HepG2 cell lines was in general higher than that against the SK-LU-1 cell line. The acetylation of the hydroxyl groups in the A-ring and the OH or NH groups in the amide side chains strongly enhanced the activity of the compounds. In addition, five potent compounds (9, 12, and 15–17) were also evaluated for apoptosis-inducing activities. The ratio of apoptosis and necrotic cells increased when lung cancer cells were treated with these compounds. On the other hand, compound 9 increased caspase 3 activities (P < 0.05). Thus, these compounds induced lung cancer cell death by apoptosis and necrosis.