Poly(ADP-ribose) polymerases-1 (PARP-1) are involved in DNA repair damage and so PARP-1 inhibitors have been used as potentiators in combination with DNA damaging cytotoxic agents to compromise the cancer cell DNA repair mechanism, resulting in genomic dysfunction and cell death. In this study, we report the synthesis of a novel series of pyrano[2,3-d]pyrimidine-2,4-dione analogues as potential inhibitors against PARP-1. All the newly synthesized compounds were evaluated for their inhibitory activity towards PARP-1 and examined for their anti-proliferative activity against MCF-7 and HCT116 human cancer cell lines. The synthesized compounds showed promising activity where compounds S2 and S7 emerged as the most potent PARP-1 inhibitors with an IC₅₀ value of 4.06 ± 0.18 and 3.61 ± 0.15 nM, respectively compared to that of Olaparib 5.77 nM and high cytotoxicity against MCF-7 with IC₅₀ 2.65 ± 0.05 and 1.28 ± 1.12 μM, respectively (Staurosporine 7.258 μM). Compound S8 remarkably showed the highest cell growth inhibition against MCF-7 and HCT116 with an IC₅₀ value of 0.66 ± 0.05 and 2.76 ± 0.06 μM, respectively. Furthermore, molecular docking of the compounds into the PARP-1 active site was performed to explore the probable binding mode. Finally, most of the synthesized compounds were predicted to have good pharmacokinetics properties in a theoretical kinetic study.

中文翻译：

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吡喃并[2,3-d]嘧啶-2,4-二酮衍生物作为新型PARP-1抑制剂的发现：设计、合成和抗肿瘤活性

聚（ADP-核糖）聚合酶 1（PARP-1）参与 DNA 修复损伤，因此 PARP-1 抑制剂已被用作增强剂与 DNA 损伤细胞毒剂结合使用，以破坏癌细胞 DNA 修复机制，导致基因组功能障碍和细胞死亡。在这项研究中，我们报告了一系列新型 pyrano[2,3 - d ]pyrimidine-2,4-dione 类似物的合成，作为 PARP-1 的潜在抑制剂。评估了所有新合成的化合物对 PARP-1 的抑制活性，并检查了它们对 MCF-7 和 HCT116 人类癌细胞系的抗增殖活性。合成的化合物显示出有希望的活性，其中化合物S2和S7成为最有效的 PARP-1 抑制剂，具有 IC₅₀值分别为 4.06 ± 0.18 和 3.61 ± 0.15 nM，与 Olaparib 的 5.77 nM 和对 MCF-7 的高细胞毒性相比，IC ₅₀分别为 2.65 ± 0.05 和 1.28 ± 1.12 μM (Staurosporine 7.258 μM)。化合物S8对 MCF-7 和 HCT116 显示出最高的细胞生长抑制作用，IC ₅₀值分别为 0.66 ± 0.05 和 2.76 ± 0.06 μM。此外，将化合物分子对接到 PARP-1 活性位点以探索可能的结合模式。最后，在理论动力学研究中预测大多数合成的化合物具有良好的药代动力学特性。