PARP-1/PI3K双靶点抑制剂的设计、合成与生物活性
Design, synthesis and biological evaluation of PARP-1/PI3K dual-target inhibitors
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摘要: 磷脂酰肌醇3-激酶（phosphatidylinositol-3-kinase, PI3K）抑制剂可以增加肿瘤细胞对聚腺苷酸二磷酸核糖聚合酶-1（poly ADP-ribose polymerase-1, PARP-1）抑制剂的敏感性，因此，同时抑制PARP-1和PI3K活性有望克服PARP-1抑制剂的耐药性。本课题组前期获得了两个对PARP-1和PI3K均具有优良抑制活性的化合物XW-1和WZ-1，但是由于水溶性差限制其进一步研究。本研究以XW-1和WZ-1为先导化合物，通过连接脲基团引入成盐位点以提高化合物的水溶性，设计合成了11个目标化合物。所有目标化合物的结构经1H NMR、13C NMR和HRMS确认。测定了化合物对PARP-1和PI3K的酶抑制活性，结果显示，大部分化合物对PARP-1和PI3K的抑制活性均较好。在此基础上，采用MTT法测定了化合物8b、8e和8f对MDA-MB-231、MDA-MB-468、HCC1937、HCT116以及对奥拉帕尼耐药的HCT116R等5种肿瘤细胞的增殖抑制活性，并进行了构效关系讨论。结果显示，3个化合物都具有优异的抗肿瘤细胞增殖活性。其中，化合物8f对5种肿瘤细胞的抗增殖活性都显著强于阳性药奥拉帕尼，并与BKM120相当。选择化合物8b和8f制成相应的盐酸盐，并测定其水溶性，结果显示两个化合物的水溶性都得到了显著性提升。本研究为进一步研发成药性好且抑制活性强的PARP-1/PI3K双靶点抑制剂提供了实验依据。Abstract: Phosphatidylinositol-3-kinase (PI3K) inhibitors can increase the sensitivity of tumor cells to Poly ADP-ribose polymerase-1 (PARP-1) inhibitors. Therefore, the simultaneous inhibition of the PARP-1 and PI3K activities are expected to overcome the drug resistance of PARP-1 inhibitors.In our previous work, two compounds XW-1 and WZ-1 with excellent activities against PARP-1 and PI3K were obtained with the limitation to further study due to their poor water solubility.Therefore, XW-1 and WZ-1 were chosen as lead compounds to optimize their solubility by introducing a salt-forming site via a urea group, and 11 novel compounds were designed and synthesized. The structure of all target compounds was confirmed by 1H NMR, 13C NMR, and HRMS.The enzyme activities of the compounds against PARP-1 and PI3K were measured, and the results showed that most of the compounds demonstrated good inhibitory activities against PARP-1 and PI3K.Based on the above result, the inhibitory activities of compounds 8b, 8e, and 8f against MDA-MB-231, MDA-MB-468, HCC1937, HCT116, and olaparib-resistant HCT116R were determined by MTT, respectively.Additionally, the structure-activity relationship was discussed. The results showed that these compounds displayed excellent antiproliferation activity.Among them, compound 8f demonstrated antiproliferation remarkably against all five tumor cells, which was more potent than that of olaparib, and was comparable to that of BKM120.Furthermore, the solubility of hydrochloride salts of compound 8b and 8f was significantly improved compared to the lead compounds.The results of this study will provide a theoretical basis for the further development of PARP-1 and PI3K dual-target inhibitors with good pharmaceutical properties and strong inhibitory activities.
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Keywords:
- PARP-1 inhibitor /
- PI3K inhibitor /
- dual-target /
- antitumor /
- pharmaceutical optimization
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