Discovery of 5-Cyano-6-phenylpyrimidin Derivatives Containing an Acylurea Moiety as Orally Bioavailable Reversal Agents against P-Glycoprotein-Mediated Mutidrug Resistance

作者：Wang, Bo; Ma, Li-Ying; Wang, Jing-Quan; Lei, Zi Ning; Gupta, Pranav; Zhao, Yuan-Di; Li, Zhong-Hua; Liu, Ying; Zhang, Xin-Hui; Li, Ya-Nan; Zhao, Bing^*; Chen, Zhe-Sheng^*; Liu, Hong-Min^*

来源：Journal of Medicinal Chemistry, 2018, 61(14): 5988-6001.

DOI：10.1021/acs.jmedchem.8b00335

• OVERCOMING MULTIDRUG-RESISTANCE
• POTENTIAL ANTICANCER AGENTS
• CANCER DRUG-RESISTANCE
• 1,2,3-TRIAZOLE-PYRIMIDINE HYBRIDS
• TRANSPORTER INHIBITORS
• GP INHIBITORS
• TRIAZOLE CORE
• DESIGN
• BINDING
• ABCB1

P-glycoprotein (ABCB1)-mediated multidrug resistance (MDR) has become a major obstacle in successful cancer chemotherapy, which attracted much effort to develop clinically useful compounds to reverse MDR. Here, we designed and synthesized a novel series of derivatives with a 5-cyano-6-phenylpyrimidine scaffold and evaluated their potential reversal activities against MDR. Among these compounds, 55, containing an acylurea appendage, showed the most potent activity in reversing paclitaxel resistance in SW620/AD300 cells. Further studies demonstrated 55 could increase accumulation of PTX, interrupt ABCBl-mediated Rhl23 accumulation and efflux, stimulate ABCB1 ATPase activity, and especially have no effect on CYP3A4 activity, which avoid drug interaction caused toxicity. More importantly, 55 significantly enhanced the efficacy of PTX against the SW620/AD300 cell xenograft without obvious side effects for orally intake. Given all that, the pyrimidme-acylurea based ABCB1 inhibitor may be a promising lead in developing new efficacious ABCBl-dependent MDR modulator.

• 出版日期2018-7-26
• 单位郑州大学