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

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Discovery of 5-Cyano-6-phenylpyrimidin Derivatives Containing an Acylurea Moiety as Orally Bioavailable Reversal Agents against P-Glycoprotein-Mediated Mutidrug Resistance
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-07-05 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00335
Bo Wang ₁ , Li-Ying Ma ₁ , Jing-Quan Wang ₂ , Zi-Ning Lei ₂ , Pranav Gupta ₂ , Yuan-Di Zhao ₁ , Zhong-Hua Li ₁ , Ying Liu ₁ , Xin-Hui Zhang ₁ , Ya-Nan Li ₁ , Bing Zhao ₁ , Zhe-Sheng Chen ₂ , Hong-Min Liu ₁

Affiliation

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 ABCB1-mediated Rh123 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 pyrimidine-acylurea based ABCB1 inhibitor may be a promising lead in developing new efficacious ABCB1-dependent MDR modulator.

中文翻译：

含酰基脲部分的5-氰基-6-苯基嘧啶衍生物的发现，作为口服生物可利用的逆转剂，抵抗P-糖蛋白介导的多药耐药性

P-糖蛋白（ABCB1）介导的多药耐药性（MDR）已成为成功进行癌症化学疗法的主要障碍，这吸引了巨大的努力来开发可逆转MDR的临床有用化合物。在这里，我们设计和合成了一系列具有5-氰基-6-苯基嘧啶骨架的新型衍生物，并评估了其对MDR的潜在逆转活性。在这些化合物中，含有酰基脲附件的55种化合物在SW620 / AD300细胞中逆转紫杉醇耐药性方面表现出最有效的活性。进一步的研究表明55可以增加PTX的积累，中断ABCB1介导的Rh123积累和流出，刺激ABCB1 ATPase活性，特别是对CYP3A4活性无影响，避免了药物相互作用引起的毒性反应。更重要的是，55显着增强了PTX对抗SW620 / AD300细胞异种移植的功效，而口服摄入没有明显的副作用。考虑到所有这些，基于嘧啶-酰基脲的ABCB1抑制剂可能是开发新的有效ABCB1依赖性MDR调节剂的有前途的线索。

更新日期：2018-07-05

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