School of Medicine and Pharmacy, Ocean University of China, Qingdao 266071, Shandong, China.
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, Shandong, China.
Bioorg Med Chem. 2022 Sep 1;69:116892. doi: 10.1016/j.bmc.2022.116892. Epub 2022 Jun 20.
Poly(ADP-ribose) polymerase-1 (PARP1) is an enzyme that catalyzes the polymerization of ADP-ribose units to target proteins, and it is a potential target for anti-cancer drug discovery, especially for BRAC1/2 mutated tumors. In this study, a series of 2-aminoimidazole Lissodendrins B derivatives were designed, synthesized, and evaluated as PARP1 inhibitors. We found that compound D is better due to its PARP enzyme inhibitory activity and in vitro anti-cancer activity compared with other tested compounds. It could inhibit PARP1 enzymatic activity (IC = 17.46 µM) in the non-cell system and BRCA1-deficient HCC1937 and MDA-MB-436 cells growth (IC = 17.81 and 12.63 µM, respectively). Further study demonstrated that compound D inhibits tumor growth through multiple mechanisms, such as reduction of PARylation, accumulation of cellular DNA double-strand breaks, induction of G2/M cell cycle arrest, and subsequent apoptosis of BRCA1-deficient cells. Besides, the molecular docking study also confirmed that compound D could effectively occupy the active pocket of PARP1. Our findings provide a new skeleton structure for PARP1 inhibitor, and the results suggested that the compound D may serve as a potential lead compound to develop novel PARP1 inhibitors for cancer therapy.
聚（ADP-核糖）聚合酶 1（PARP1）是一种能够催化 ADP-核糖单位聚合到靶蛋白上的酶，它是抗癌药物发现的潜在靶点，特别是针对 BRAC1/2 突变的肿瘤。在这项研究中，设计、合成并评估了一系列 2-氨基咪唑 Lissodendrins B 衍生物作为 PARP1 抑制剂。我们发现化合物 D 由于其对 PARP 酶的抑制活性和体外抗癌活性优于其他测试化合物。它可以抑制非细胞系统中的 PARP1 酶活性（IC = 17.46 µM）以及 BRCA1 缺陷型 HCC1937 和 MDA-MB-436 细胞的生长（IC = 17.81 和 12.63 µM，分别）。进一步的研究表明，化合物 D 通过多种机制抑制肿瘤生长，例如减少 PAR 化、积累细胞 DNA 双链断裂、诱导 G2/M 细胞周期停滞以及随后的 BRCA1 缺陷细胞凋亡。此外，分子对接研究也证实了化合物 D 可以有效地占据 PARP1 的活性口袋。我们的研究结果为 PARP1 抑制剂提供了新的骨架结构，并表明化合物 D 可能作为一种潜在的先导化合物，用于开发新型的 PARP1 抑制剂用于癌症治疗。
