Department of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China; Institute of Materia Medica, Fujian Medical University (FMU), Fuzhou, PR China; Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University (FMU), Fuzhou, PR China.
Department of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China; Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University (FMU), Fuzhou, PR China; Department of Public Technology Service Center, Fujian Medical University (FMU), Fuzhou, PR China.
Bioorg Med Chem. 2020 May 1;28(9):115434. doi: 10.1016/j.bmc.2020.115434. Epub 2020 Mar 13.
Poly (ADP-ribose) polymerase (PARP) inhibitors have achieved great success in clinical application, especially for the prolonged survival of cisplatin-sensitive ovarian cancer patients. However, there are still many patients who do not respond to PARP inhibitors. Novel PARP inhibitors with higher activity are urgently needed. Herein we report a series of compounds by molecular hybridization PARP-1 inhibitor Olaparib (Ola) with HSP90 inhibitor C0817 (one curcumin derivative). All synthesized compounds were evaluated for their antiproliferative activity in vitro, and some were further assessed for their inhibitory activities of the PARP enzyme and HSP90 affinity. Our results indicated that compound 4 could bind to HSP90 and cause static quenching, indicating that compound 4 was able to bind to HSP90, moreover, downstream molecular breast cancer 1 (BRAC-1) was reduced. In conclusion, dual target inhibitors of PARP and HSP90 exhibited stronger selective cytotoxicities against cancer.
聚（ADP-核糖）聚合酶（PARP）抑制剂在临床应用中取得了巨大成功，尤其是延长了顺铂敏感型卵巢癌患者的生存时间。然而，仍有许多患者对 PARP 抑制剂没有反应。因此，迫切需要具有更高活性的新型 PARP 抑制剂。在此，我们通过分子杂交将 PARP-1 抑制剂奥拉帕尼（Ola）与 HSP90 抑制剂 C0817（一种姜黄素衍生物）进行组合，报道了一系列化合物。所有合成的化合物均在体外进行了抗增殖活性评估，部分化合物进一步评估了其对 PARP 酶和 HSP90 亲和力的抑制活性。结果表明，化合物 4 能够与 HSP90 结合并导致静态猝灭，表明化合物 4 能够与 HSP90 结合，此外，下游乳腺癌 1 型分子（BRAC-1）减少。总之，PARP 和 HSP90 的双重靶标抑制剂对癌症表现出更强的选择性细胞毒性。
