DESIGN, SYNTHESIS AND EVALUATION OF ACYL DERIVATIVES OF HYDROXYLATED EUDESMANOLIDES AS ANTI-COLORECTAL CANCER AGENTS

Abstract

Colorectal cancer (CRC) is the third most common cancer worldwide. Due to side effects of current cancer therapies, the development of therapeutic colorectal cancer agents with safer and more effective are urgently required. Acyls of hydroxylated eudesmanolides, RNS (2) and STM (3) were reported to possess diverse bioactivities, especially anti-cancer activity. This study aimed to synthesize acyl derivatives, RNS (2) and STM (3) and to evaluate their cytotoxicity against human colorectal HCT-116 cancer cells. The hydroxylated eudesmanolide, a Δ^3,4 double bond containing STM (3), showed slightly more potent than RNS (2), a Δ^4,15 double bond derivative, with IC₅₀ values 15.41 and 18.17 µM, respectively. Among acyl derivatives, compound 3d showed the most potent activity against HCT-116 cells with IC₅₀ value of 13.51 µM, as well as slightly stronger than parent compound. Additionally, the results obtained beneficial SAR information for further study. Benzoyl derivatives, 2d and 3d, displayed stronger cytotoxicity than cinnamoyl derivative series (a-c), indicating the C2 extension between benzene ring and carbonyl moiety caused the decrease in activity. It was also seen that the existence of p-nitro group on benzene ring and the double bond hydrogenation of cinnamoyl moiety decreased activity compared to original cinnamoyl derivatives (2a and 3a)