Department of Industrial Chemistry, Alagappa University, Karaikudi 630006, India.
Department of Biotechnology, School of Chemical & Biotechnology, SASTRA Deemed University, Thanjavur 613401, India.
Bioorg Chem. 2019 Mar;84:493-504. doi: 10.1016/j.bioorg.2018.12.014. Epub 2018 Dec 12.
Human kinesin Eg5 is a potential inhibiting site for cancer chemotherapy. Blocking metaphase by binding foreign inhibitors with Eg5 eventually leads to apoptotic cell death. Here, we report the pyrazolopyrimidine derivates as potent inhibitors of Eg5 that prevents mitotic kinesin progression. IC values were evaluated against the motor domain of Eg5 using steady-state ATPase assay. To better understanding, we have performed molecular docking simulation. It reveals that the interactions of the proposed inhibitors with both the allosteric sites (helices α2, α3 and loopL5, and helices α4 & α6). Out of fifteen pyrazolopyrimidine derivates, three compounds (12, 25, and 27) have shown significant inhibition of Eg5. The synthesized compounds (12, 25, and 27) were tested for their in-vitro anticancer activity against cervical cancer cell line (HeLa).
人驱动蛋白 Eg5 是癌症化疗的潜在抑制位点。通过将外来抑制剂与 Eg5 结合来阻断中期，最终导致细胞凋亡。在这里，我们报告了吡唑并嘧啶衍生物作为 Eg5 的有效抑制剂，可阻止有丝分裂驱动蛋白的进展。使用稳态 ATP 酶测定法评估 IC 值以评估对 Eg5 的运动结构域的抑制作用。为了更好地理解，我们进行了分子对接模拟。结果表明，所提出的抑制剂与别构位点（α2、α3 和 L5 环以及α4 和α6 螺旋）之间的相互作用。在十五个吡唑并嘧啶衍生物中，有三个化合物（12、25 和 27）对 Eg5 表现出显著的抑制作用。合成的化合物（12、25 和 27）已针对宫颈癌细胞系（HeLa）进行了体外抗癌活性测试。
