Discovery of a Novel [6–6–5–5–6] Pentacyclic Tetrahydrocyclopentaphthalazinone as a Promising PARP Inhibitor Scaffold

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-04-03 DOI:10.1021/acsmedchemlett.4c0060310.1021/acsmedchemlett.4c00603

Yagmur U. Doruk, Morgan E. Diolaiti, Alan Ashworth* and Tanaji T. Talele*,

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Abstract

Inhibitors of poly(ADP-ribose) polymerases (PARPs) have revolutionized the treatment of cancers with DNA repair deficiencies. Here we describe the structure-based discovery and synthesis of 6–6–5–5–6-fused pentacyclic scaffolds 5 and cis-(±)-6 as a novel class of PARP1 inhibitors. Chiral supercritical fluid chromatographic separation of cis-(±)-6 afforded inactive ent-6_P1 and active ent-6_P2. Compound 5 (P-gp ER = 0.9) and ent-6_P2 (P-gp ER = 1.1) demonstrated good Caco-2 permeability and are not actively effluxed by ABC transporters. In vitro analysis in HEK293T cells found that 5, cis-(±)-6, and ent-6_P2 showed near complete inhibition of PARP1 activity at 10 μM. Furthermore, compounds 5, cis-(±)-6, and ent-6_P2 displayed selective cytotoxic activity in BRCA mutant cancer cells but not isogenic BRCA-proficient cells. Taken together, 5 and ent-6_P2 define a novel class of lead PARP inhibitors for further development.

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一种新型[6-6-5 - 6]五环四氢环五酞嗪酮作为PARP抑制剂支架的发现

聚（adp -核糖）聚合酶（PARPs）抑制剂已经彻底改变了DNA修复缺陷癌症的治疗。在这里，我们描述了基于结构的发现和合成6-6-5 - 5 -6融合的五环支架5和顺式-（±）-6作为一类新的PARP1抑制剂。顺式-（±）-6的手性超临界液相色谱分离得到无活性的ent-6_P1和活性的ent-6_P2。化合物5 （P-gp ER = 0.9）和nt- 6_p2 （P-gp ER = 1.1）表现出良好的Caco-2渗透性，不受ABC转运蛋白的积极外排。在HEK293T细胞中的体外分析发现，5、顺式-（±）-6和ent-6_P2在10 μM下几乎完全抑制PARP1的活性。此外，化合物5、顺式-（±）-6和t- 6_p2在BRCA突变的癌细胞中表现出选择性的细胞毒活性，而在BRCA精通的细胞中则没有。综上所述，5和ent-6_P2确定了一类新的PARP先导抑制剂，有待进一步开发。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.