Discovery, optimization, and cellular activities of 2-(aroylamino)cinnamamide derivatives against colon cancer

Abstract

Curcumin and trans-cinnamaldehyde are acrolein-based Michael acceptor compounds that are commonly found in domestic condiments, and known to cause cancer cell death via redox mechanisms. Based on the structural features of these compounds we designed and synthesized several 2-cinnamamido-N-substituted-cinnamamide (bis-cinnamamide) compounds. One of the derivatives, (Z)-2-[(E)-cinnamamido]-3-phenyl-N-propylacrylamide (1512) showed a moderate antiproliferative potency (HT116 cell line inhibition of 32.0 {micro}M {+/-} 2.6) with proven cellular activities leading to apoptosis. Importantly, 1512 exhibited good selectivity toxicity on cancer cells over noncancerous cells (IC50 of C-166 cell lines >100 {micro}M), and low cancer cell resistance at 100 {micro}M dose (growth rate 10.1{+/-}1.1%). We subsequently carried out structure activity relationship studies with 1512. Derivatives with electron rich moiety at the aryl ring of the 2-aminocinnamaide moiety exhibited strong antiproliferative action while electron withdrawing groups caused loss of activity. Our most promising compound, 4112 [(Z)-3-(1H-indol-3-yl)-N-propyl-2-[(E)-3-(thien-2-yl)propenamido)propenamide] killed cancer cells at IC50 = 0.89 {+/-} 0.04 {micro}M (Caco-2), 2.85 {+/-} 1.5 (HCT-116) and 1.65 {+/-} 0.07 (HT-29), while exhibiting much weaker potency on C-166 and BHK normal cell lines (IC50 = 71 {+/-} 5.12 and 77.6 {+/-} 6.2 {micro}M, respectively). Cellular studies towards identifying the compounds mechanism of cytotoxic activities revealed that apoptotic induction occurs in part due to oxidative stress. Importantly, the compounds showed inhibition of cancer stem cells that are critical for maintaining the potential for self-renewal and stemness. The results presented here show discovery of Michael addition compounds that potently kill cancer cells by a defined mechanism, with minimal effect on normal noncancerous cell.