Synthesis of novel dual target inhibitors of PARP and HSP90 and their antitumor activities
Synthesis of novel dual target inhibitors of PARP and HSP90 and their antitumor activities
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PARP和HSP90新型双靶点抑制剂的合成及其抗肿瘤活性。
DOI：
10.1016/j.bmc.2020.115434
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发表时间：
2020-05-01
影响因子：
3.5
通讯作者：
Wu, Lixian
中科院分区：
文献类型：
--
作者：
Lin, Shanshan;Zhang, LingYu;Wu, Lixian
多聚腺苷二磷酸核糖聚合酶（Poly（ADP-ribose）polymerase，PARP）抑制剂在临床应用中取得了巨大成功，尤其是在延长顺铂敏感性卵巢癌患者的生存期方面。然而，仍然有许多患者对PARP抑制剂没有反应。迫切需要具有更高活性的新型PARP抑制剂。本文报道了一系列由PARP-1抑制剂Olaparib（奥拉）和HSP 90抑制剂C 0817（一种姜黄素衍生物）通过分子杂交合成的化合物。所有合成的化合物进行了评估，其抗增殖活性在体外，和一些进一步评估其抑制活性的PARP酶和HSP 90的亲和力。结果表明，化合物4能与HSP 90结合并引起静态猝灭，表明化合物4能与HSP 90结合，并能降低下游分子乳腺癌1（BRAC-1）。结论：PARP和HSP 90双靶点抑制剂具有较强的选择性细胞毒作用。
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.