Design, Synthesis, and in vitro Biological Evaluation of 3,5‐Dimethylisoxazole Derivatives as BRD4 Inhibitors,ChemMedChem

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Design, Synthesis, and in vitro Biological Evaluation of 3,5‐Dimethylisoxazole Derivatives as BRD4 Inhibitors
ChemMedChem ( IF 3.6 ) Pub Date : 2018-05-29 , DOI: 10.1002/cmdc.201800074
Xiangyang Li ₁ , Jian Zhang ₂ , Leilei Zhao ₂ , Yifei Yang ₁ , Huibin Zhang ₂ , Jinpei Zhou ₁

Affiliation

BRD4 has been identified as a potential target for blocking proliferation in a variety of cancer cell lines. In this study, 3,5‐dimethylisoxazole derivatives were designed and synthesized with excellent stability in liver microsomes as potent BRD4 inhibitors, and were evaluated for their BRD4 inhibitory activities in vitro. Gratifyingly, compound 11 h [3‐((1‐(2,4‐difluorophenyl)‐1H‐1,2,3‐triazol‐4‐yl)methyl)‐6‐(3,5‐dimethylisoxazol‐4‐yl)‐4‐phenyl‐3,4‐dihydroquinazolin‐2(1H)‐one] exhibited robust potency for BRD4(1) and BRD4(2) inhibition with IC₅₀ values of 27.0 and 180 nm, respectively. Docking studies were performed to illustrate the strategy of modification and analyze the conformation in detail. Furthermore, compound 11 h was found to potently inhibit cell proliferation in the BRD4‐sensitive cell lines HL‐60 and MV4‐11, with IC₅₀ values of 0.120 and 0.09 μm, respectively. Compound 11 h was further demonstrated to downregulate c‐Myc levels in HL‐60 cells. In summary, these results suggest that compound 11 h is most likely a potential BRD4 inhibitor and is a lead compound for further investigations.

中文翻译：

3,5-二甲基异恶唑衍生物作为BRD4抑制剂的设计，合成和体外生物学评估

BRD4已被确定为阻断多种癌细胞系增殖的潜在靶标。在这项研究中，设计并合成了3,5-二甲基异恶唑衍生物作为有效的BRD4抑制剂，在肝微粒体中具有出色的稳定性，并对其在体外的BRD4抑制活性进行了评估。令人欣慰的是，化合物11 h [3-（（（1-（2,4-二氟苯基）-1 H -1,2,3-三唑-4-基）甲基）-6-（3,5-二甲基异恶唑-4-基）-4-苯基-3,4-二氢喹唑啉-2（1 H）-一]对BRD4（1）和BRD4（2）的抑制作用强，IC ₅₀值为27.0和180 n m，分别。进行了对接研究以说明修饰策略并详细分析构象。此外，化合物11 H被发现有效地抑制细胞增殖在BRD4-敏感的细胞系HL-60和MV4-11，与IC ₅₀的0.120和0.09μ值米分别。化合物11 h进一步证明可下调HL-60细胞中的c-Myc水平。总之，这些结果表明化合物11 h最有可能是潜在的BRD4抑制剂，并且是进一步研究的先导化合物。

更新日期：2018-05-29

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