Department of Chemistry and Biotechnology, Tallinn University of Technology (TalTech), Akadeemia tee 15, 12618 Tallinn, Estonia.
Biomolecules. 2024 Oct 9;14(10):1269. doi: 10.3390/biom14101269.
Poly(ADP-ribose) polymerases (PARPs) are crucial nuclear proteins that play important roles in various cellular processes, including DNA repair, gene transcription, and cell death. Among the 17 identified PARP family members, PARP1 is the most abundant enzyme, with approximately 1-2 million molecules per cell, acting primarily as a DNA damage sensor. It has become a promising biological target for anticancer drug studies. Enhanced PARP expression is present in several types of tumors, such as melanomas, lung cancers, and breast tumors, correlating with low survival outcomes and resistance to treatment. PARP inhibitors, especially newly developed third-generation inhibitors currently undergoing Phase II clinical trials, have shown efficacy as anticancer agents both as single drugs and as sensitizers for chemo- and radiotherapy. This review explores the properties, characteristics, and challenges of PARP inhibitors, discussing their development from first-generation to third-generation compounds, more sustainable synthesis methods for discovery of new anti-cancer agents, their mechanisms of therapeutic action, and their potential for targeting additional biological targets beyond the catalytic active site of PARP proteins. Perspectives on green chemistry methods in the synthesis of new anticancer agents are also discussed.
聚（ADP-核糖）聚合酶（PARPs）是至关重要的核蛋白，在包括 DNA 修复、基因转录和细胞死亡在内的各种细胞过程中发挥重要作用。在 17 种已鉴定的 PARP 家族成员中，PARP1 是最丰富的酶，每个细胞约有 100 万至 200 万个分子，主要作为 DNA 损伤传感器。它已成为抗癌药物研究中很有前途的生物靶标。在几种类型的肿瘤中，如黑色素瘤、肺癌和乳腺癌中，PARP 表达增强，与低生存率和治疗耐药性相关。PARP 抑制剂，尤其是目前正在进行 II 期临床试验的新开发的第三代抑制剂，作为单一药物和化疗和放疗的增敏剂，已显示出作为抗癌剂的疗效。本综述探讨了 PARP 抑制剂的性质、特征和挑战，讨论了它们从第一代到第三代化合物的发展，以及更可持续的合成方法用于发现新的抗癌剂，它们的治疗作用机制以及它们在 PARP 蛋白的催化活性位点之外针对其他生物靶标的潜力。还讨论了绿色化学方法在新抗癌剂合成中的应用前景。
