Synthesis of CDDO–Amino Acid–Nitric Oxide Donor Trihybrids as Potential Antitumor Agents against Both Drug-Sensitive and Drug-Resistant Colon Cancer

Seventeen CDDO–amino acid–NO donor trihybrids (<b>4a</b>–<b>q</b>) were designed and synthesized. Biological evaluation indicated that the most active compound <b>4c</b> produced high levels of NO and inhibited the proliferation of drug-sensitive (HCT-8, IC<sub>50</sub> = 0.294 μM) and drug-resistant (HCT-8/5-FU, IC<sub>50</sub> = 0.232 μM) colon cancer cells, which were attenuated by an NO scavenger or typical substrate of PepT1. Furthermore, <b>4c</b> triggered HCT-8 and HCT-8/5-FU cell apoptosis more strongly than CDDO-Me, inhibited the HIF-1α, Stat3, AKT, and ERK signaling, and induced the nitration of P-gp, MRP1, and BCRP proteins in HCT-8/5-FU cells. Finally, <b>4c</b> had 4.36–5.53-fold less inhibitory activity against nontumor colon epithelial-like cells (CCD841, IC<sub>50</sub> = 1.282 μM) in vitro and inhibited the growth of implanted human drug-resistant colon cancers in mice more potently than CDDO-Me. Together, <b>4c</b> is a novel trihybrid with potent antitumor activity and may be a promising candidate for the treatment of drug-resistant colon cancer.