基于三唑并喹喔啉的 DNA 插入剂-拓扑异构酶 II 抑制剂：设计、合成、对接、ADMET 和抗增殖评估。

Triazoloquinoxalines-based DNA intercalators-Topo II inhibitors: design, synthesis, docking, ADMET and anti-proliferative evaluations.

机构信息

Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.

Pharmaceutical Chemistry Department, College of Pharmacy, The Islamic University, Najaf, Iraq.

出版信息

J Enzyme Inhib Med Chem. 2022 Dec;37(1):1556-1567. doi: 10.1080/14756366.2022.2080205.

Sixteen [1, 2, 4]triazolo[4,3-a]quinoxalines as DNA intercalators-Topo II inhibitors have been prepared and their anticancer actions evaluated towards three cancer cell lines. The new compounds affected on high percentage of MCF-7. Derivatives , and exhibited the highest anticancer activities. Their activities were higher than that of doxorubicin. Molecular docking studies showed that the HBA present in the chromophore, the substituted distal phenyl moiety and the extended linkers enable our derivatives to act as DNA binders. Also, the pyrazoline moiety formed six H-bonds and improved affinities with DNA active site. Finally, , and exhibited the highest DNA affinities and act as traditional intercalators of DNA. The most active derivatives , and were subjected to evaluate their Topo II inhibition and DNA binding actions. Derivative exhibited the highest binding affinity. It intercalates DNA at IC = 29.06 µM. Moreover, compound potently intercalates DNA at an IC value of 31.24 µM. Finally, compound demonstrated the most potent Topo II inhibitor at a value of 0.890 µM. Compound exhibited an equipotent IC value (0.940 µM) to that of doxorubicin. Furthermore, derivatives and displayed a high ADMET profile.

十六个[1, 2, 4]三唑并[4,3-a]喹喔啉作为 DNA 嵌入剂拓扑异构酶 II 抑制剂已被制备，并对三种癌细胞系进行了抗癌作用评估。新化合物对 MCF-7 的影响很大。衍生物和表现出最高的抗癌活性。它们的活性高于阿霉素。分子对接研究表明，发色团中存在的 HBA、取代的远端苯基部分和扩展的连接子使我们的衍生物能够作为 DNA 结合剂发挥作用。此外，吡唑啉部分形成了六个氢键，提高了与 DNA 活性位点的亲和力。最后，和表现出最高的 DNA 亲和力，并作为 DNA 的传统嵌入剂。最活跃的衍生物、和被用来评估它们的拓扑异构酶 II 抑制和 DNA 结合作用。衍生物表现出最高的结合亲和力。它在 IC = 29.06 µM 时嵌入 DNA。此外，化合物在 IC 值为 31.24 µM 时有效地嵌入 DNA。最后，化合物作为拓扑异构酶 II 抑制剂，其值为 0.890 µM。化合物的 IC 值与阿霉素相当（0.940 µM）。此外，衍生物和表现出良好的 ADMET 特性。