Synthesis of CDDO–Amino Acid–Nitric Oxide Donor Trihybrids as Potential Antitumor Agents against Both Drug-Sensitive and Drug-Resistant Colon Cancer
Citations Over TimeTop 10% of 2015 papers
Abstract
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.
Related Papers
- → A novel fluorescent probe for the detection of nitric oxide in vitro and in vivo(2008)70 cited
- Nitric oxide :principles and actions(1996)
- → Fluorofuroxans: Synthesis and Application as Photoinduced Nitric Oxide Donors(2016)19 cited
- → Multifunctional role of nitric oxide in inflammation(1994)108 cited
- → Selective Fluorescent Activation for Bioimaging the Expression of Nitric Oxide in Cellular and In Vivo Systems(2010)1 cited