Wong Way W, O'Brien-Gortner Sophia F, Anderson Robert F, Wilson William R, Hay Michael P, Dickson Benjamin D
Auckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland Private Bag 92019 Auckland 1010 New Zealand
Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland Symonds St Auckland 1010 New Zealand.
RSC Med Chem. 2023 Jun 8;14(7):1309-1330. doi: 10.1039/d3md00117b. eCollection 2023 Jul 20.
Poly(ADP-ribose)polymerase inhibitors (PARPi) are used for treatment of tumours with a defect in homologous recombination (HR) repair. Combination with radio- or chemotherapy could broaden their applicability but a major hurdle is enhancement of normal tissue toxicity. Development of hypoxia-activated prodrugs (HAPs) of PARPi has potential to restrict PARP inhibition to tumours thereby avoiding off-target toxicity. We have designed and synthesised phenolic derivatives of olaparib (termed phenolaparibs) and corresponding ether-linked HAPs. Phenolaparib cytotoxicity in HR-proficient and deficient cell lines was consistent with inhibition of PARP-1. Prodrugs were deactivated relative to phenolaparibs in biochemical PARP-1 inhibition assays, and cell culture. Prodrug 7 was selectively converted to phenolaparib 4 under hypoxia and demonstrated hypoxia-selective cytotoxicity, including chemosensitisation of HR-proficient cells in combination with temozolomide. This work demonstrates the feasibility of a HAP approach to PARPi for use in combination therapies.
聚（ADP-核糖）聚合酶抑制剂（PARPi）用于治疗同源重组（HR）修复存在缺陷的肿瘤。与放疗或化疗联合使用可扩大其应用范围，但一个主要障碍是会增强正常组织毒性。开发PARPi的缺氧激活前药（HAPs）有可能将PARP抑制作用局限于肿瘤，从而避免脱靶毒性。我们设计并合成了奥拉帕利的酚类衍生物（称为酚奥拉帕利）以及相应的醚键连接的HAPs。酚奥拉帕利在HR功能正常和缺陷的细胞系中的细胞毒性与对PARP-1的抑制作用一致。在生化PARP-1抑制试验和细胞培养中，前药相对于酚奥拉帕利失活。前药7在缺氧条件下被选择性地转化为酚奥拉帕利4，并表现出缺氧选择性细胞毒性，包括与替莫唑胺联合使用时对HR功能正常的细胞具有化学增敏作用。这项工作证明了HAP方法用于PARPi联合治疗的可行性。
