Qin Hongyu, Zhang Jian, Zhao Yilu, Zhang Lihui, Feng Jinhong, Zhang Lei
Department of Medicinal Chemistry, School of Pharmacy, Weifang Medical University, Weifang, Shandong, China.
School of Stomatology, Weifang Medical University, Weifang, Shandong, China.
Front Pharmacol. 2023 Jan 9;13:1054616. doi: 10.3389/fphar.2022.1054616. eCollection 2022.
Development of Poly (ADP-ribose) polymerase (PARP) inhibitors has been extensively studied in cancer treatment. Olaparib, the first approved PARP inhibitor, showed potency in the inhibition of both BRCA (breast cancer associated)-mutated and BRCA-unmutated cancers. Aiming to the discovery of olaparib analogs for the treatment of cancer, structural modifications were performed based on the scaffold of olaparib. In the first series, reduction of carbonyl group to CH led to decrease of PARP1 inhibitory activity. Preserving the original carbonyl group, molecules with potent PARP1 inhibitory activities were derived by introduction of hydrazide and aromatic nitrogen mustard groups. The synthesized compounds were evaluated in the in the PARP1 enzyme inhibitory screening, cancer cell based antiproliferative assay, cell cycle arrest and apoptosis studies. It is remarkable that, molecule with chlorambucil substitution, exhibited potent PARP1 inhibitory activity and a broad-spectrum of anticancer potency in the antiproliferative assay. Compared with olaparib and chlorambucil, molecule also showed significant potency in inhibition of a variety of BRCA-unmutated cell lines. Further analysis revealed the effects of in induction of G2/M phase cell cycle arrest and promotion of apoptosis. Collectively, the olaparib-chlorambucil hybrid molecule could be utilized as a lead compound for further drug design.
聚（ADP - 核糖）聚合酶（PARP）抑制剂在癌症治疗方面已得到广泛研究。奥拉帕尼是首个获批的PARP抑制剂，对BRCA（乳腺癌相关）突变和非BRCA突变的癌症均显示出抑制效力。为了发现用于癌症治疗的奥拉帕尼类似物，基于奥拉帕尼的骨架进行了结构修饰。在第一个系列中，羰基还原为CH导致PARP1抑制活性降低。保留原始羰基，通过引入酰肼和芳香氮芥基团得到了具有强效PARP1抑制活性的分子。对合成的化合物进行了PARP1酶抑制筛选、基于癌细胞的抗增殖测定、细胞周期阻滞和凋亡研究。值得注意的是，具有苯丁酸氮芥取代的分子在抗增殖测定中表现出强效的PARP1抑制活性和广谱抗癌效力。与奥拉帕尼和苯丁酸氮芥相比，该分子对多种非BRCA突变细胞系也显示出显著的抑制效力。进一步分析揭示了其诱导G2/M期细胞周期阻滞和促进凋亡的作用。总体而言，奥拉帕尼 - 苯丁酸氮芥杂合分子可作为进一步药物设计的先导化合物。
