A series of eudesmanolide sesquiterpenoid structures incorporating the α-methylene-g-lactone moiety or its amino conjugates was synthesised from α-santonin and screened against lymphoblastic leukemia, promyelocytic leukemia and colorectal cancer cell lines. The α-methylene group or the amino conjugate and at least one of the double bonds of the dienone of the santonin parent are prerequisites for activity. Most of the amino adducts showed activity equal to or poorer than the parent α-methylene-g-lactones against the colorectal cancer cell line, but several examples exhibited improved or similar activity against the promyelocytic leukemia cell line with improved toxicity profiles against non-cancerous, rapidly dividing cells (as measured by activity against WI38 fibroblasts). Enhanced activity was observed against the lymphoblastic leukaemia cell line with improved toxicity profiles (WI38 fibroblasts) when compared to the parent α-methylene-g -lactone. The 2-fluorobenzyl adduct (8p), with IC50 = 7.4μM, 5.6μM and 56μM against promyelocytic, lymphoblastic leukaemia and WI38 fibroblasts respectively, showed both improved potency and leukemia selectivity compared with the α-methylene-g-lactone parent (7). Analogues with small aliphatic amino substitution such as dimethylamino (8a) showed selectivity towards promyelocytic leukemia over all other cell lines examined and useful toxicity profiles [IC50 (HL60) = 6.3μM, IC50 (WI38) = 66μM].
|Number of pages||16|
|Journal||Journal of Chemical and Pharmaceutical Research|
|Publication status||Published - 2015|
Westhuyzen, C. V. D., Rousseau, L. L., Hoppe, H., Kolesnikova, N., & Parkinson, C. (2015). Synthesis of novel substituted a-methylamino derivatives of a-santonin as potential anticancer agents-Part 1: Eudesmanolide derivatives. Journal of Chemical and Pharmaceutical Research, 7(5), 855-870.