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 (4a–q) were designed and synthesized. Biological evaluation indicated that the most active compound 4c produced high levels of NO and inhibited the proliferation of drug-sensitive (HCT-8, IC₅₀ = 0.294 μM) and drug-resistant (HCT-8/5-FU, IC₅₀ = 0.232 μM) colon cancer cells, which were attenuated by an NO scavenger or typical substrate of PepT1. Furthermore, 4c 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, 4c had 4.36–5.53-fold less inhibitory activity against nontumor colon epithelial-like cells (CCD841, IC₅₀ = 1.282 μM) in vitro and inhibited the growth of implanted human drug-resistant colon cancers in mice more potently than CDDO-Me. Together, 4c is a novel trihybrid with potent antitumor activity and may be a promising candidate for the treatment of drug-resistant colon cancer.