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

被引：71

作者：

Ai, Yong ^{[1
,2
]}

Kang, Fenghua ^{[1
,2
]}

Huang, Zhangjian ^{[1
,2
]}

Xue, Xiaowen ^{[1
]}

Lai, Yisheng ^{[1
,2
]}

Peng, Sixun ^{[1
,2
]}

Tian, Jide ^{[3
]}

Zhang, Yihua ^{[1
,2
]}

机构：

[1] China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Jiangsu, Peoples R China

[2] China Pharmaceut Univ, Jiangsu Key Lab Drug Discovery Metab Dis, Nanjing 210009, Jiangsu, Peoples R China

[3] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 05期

基金：

中国国家自然科学基金;

关键词：

MULTIDRUG-RESISTANCE; LUNG-CANCER; PEPTIDE TRANSPORTERS; OLEANOLIC ACID; OLIGOPEPTIDE TRANSPORTER; P-GLYCOPROTEIN; ESTER PRODRUGS; CELL-LINE; IN-VIVO; APOPTOSIS;

D O I：

10.1021/jm5019302

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

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 mu M) and drug-resistant (HCT-8/5-FU, IC50 = 0.232 mu M) 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-1a, 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 mu M) 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.

引用

页码：2452 / 2464

页数：13

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