设计、合成和评价基于酞嗪酮硫代乙内酰脲的衍生物作为有效的 PARP-1 抑制剂。
Design, synthesis and evaluation of phthalazinone thiohydantoin-based derivative as potent PARP-1 inhibitors.
机构信息
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
出版信息
Bioorg Chem. 2019 Oct;91:103181. doi: 10.1016/j.bioorg.2019.103181. Epub 2019 Aug 3.
Two new series of compounds were designed and synthesized as potent PARP-1 inhibitors. These compounds were evaluated for PARP-1 enzyme and cellular inhibitory activities. All efforts lead to the identification of 9k (named as LG-12) with efficient potency both for PARP-1 and BRCA1 deficient MDA-MB-436 cells. Additionally, the novel PARP-1 inhibitor LG-12 is an efficient chemosensitizer, which could potentiate the anti-cancer effect of TMZ. Our data presented herein provide a comprehensive preclinical in vitro evaluation of the potential therapeutic efficacy and potency of chemotherapeutic agent-PARP-1 inhibitor combinations for LG-12. The combined results indicated that LG-12 could be a promising candidate for further study.
设计并合成了两个新系列的化合物作为有效的 PARP-1 抑制剂。评估了这些化合物对 PARP-1 酶和细胞抑制活性的抑制作用。所有的努力都导致了 9k（命名为 LG-12）的鉴定，它对 PARP-1 和 BRCA1 缺陷的 MDA-MB-436 细胞都具有高效的效力。此外，新型 PARP-1 抑制剂 LG-12 是一种有效的化疗增敏剂，可增强 TMZ 的抗癌作用。本文提供了对 LG-12 的潜在治疗功效和效力的全面的体外临床前评估。联合结果表明，LG-12 可能是进一步研究的有前途的候选物。
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