title: Synthesis of CDDO-amino acid-nitric oxide donor trihybrids as potential antitumor agents against both drug-sensitive and drug-resistant colon cancer.
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.
authors: State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, PR China.
authors: Yong
authors: Y
authors: Ai
authors: Fenghua
authors: F
authors: Kang
authors: Zhangjian
authors: Z
authors: Huang
authors: Xiaowen
authors: X
authors: Xue
authors: Yisheng
authors: Y
authors: Lai
authors: Sixun
authors: S
authors: Peng
authors: Jide
authors: J
authors: Tian
authors: Yihua
authors: Y
authors: Zhang
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D020030:Nitric Oxide Donors / Q000737:chemistry*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D000596:Amino Acids; D000970:Antineoplastic Agents; D020030:Nitric Oxide Donors; D009828:Oleanolic Acid