Ketoprofen and Loxoprofen Platinum(IV) Complexes Displaying Antimetastatic Activities by Inducing DNA Damage, Inflammation Suppression, and Enhanced Immune Response,Journal of Medicinal Chemistry

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Ketoprofen and Loxoprofen Platinum(IV) Complexes Displaying Antimetastatic Activities by Inducing DNA Damage, Inflammation Suppression, and Enhanced Immune Response
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-12-01 , DOI: 10.1021/acs.jmedchem.1c01236
Zuojie Li ₁ , Qingpeng Wang _{1,

2} , Linming Li ₁ , Yan Chen ₁ , Jichun Cui ₃ , Min Liu ₁ , Ning Zhang ₁ , Zhifang Liu ₁ , Jun Han _{1,

2} , Zhengping Wang _{1,

2}

Affiliation

Metastasis is a major contributor of death in cancer patients, and there is an urgent need for effective treatments of metastatic malignancies. Herein, ketoprofen (KP) and loxoprofen (LP) platinum(IV) complexes with antiproliferative and antimetastatic properties were designed and prepared by integrating chemotherapy and immunotherapy targeting cyclooxygenase-2 (COX-2), matrix metalloproteinase-9 (MMP-9), and programmed death ligand 1 (PD-L1), besides DNA. A mono-KP platinum(IV) complex with a cisplatin core is screened out as a candidate possessing potent anti-proliferative and anti-metastasis activities both in vitro and in vivo. It induces serious DNA damage and further leads to high expression of γ-H2AX and p53. Moreover, it promotes apoptosis of tumor cells through mitochondrial apoptotic pathway Bcl-2/Bax/caspase3. Then, COX-2, MMP-9, NLRP3, and caspase1 as pivotal enzymes igniting inflammation and metastasis are obviously inhibited. Notably, it significantly improves immune response through restraining the expression of PD-L1 to increase CD3⁺ and CD8⁺ T infiltrating cells in tumor tissues.

中文翻译：

酮洛芬和洛索洛芬铂 (IV) 复合物通过诱导 DNA 损伤、抑制炎症和增强免疫反应而显示出抗转移活性

转移是癌症患者死亡的主要原因，迫切需要有效治疗转移性恶性肿瘤。在此，通过整合靶向环氧合酶2（COX-2）、基质金属蛋白酶9（MMP-9）的化学疗法和免疫疗法，设计制备了具有抗增殖和抗转移特性的酮洛芬（KP）和洛索洛芬（LP）铂（IV）复合物，除 DNA 外，还有程序性死亡配体 1 (PD-L1)。筛选出具有顺铂核心的单 KP 铂 (IV) 配合物作为在体外和体内均具有有效抗增殖和抗转移活性的候选物。它诱导严重的 DNA 损伤并进一步导致 γ-H2AX 和 p53 的高表达。此外，它通过线粒体凋亡途径 Bcl-2/Bax/caspase3 促进肿瘤细胞的凋亡。然后，COX-2、MMP-9、NLRP3、和caspase1作为引发炎症和转移的关键酶受到明显抑制。值得注意的是，它通过抑制 PD-L1 的表达以增加 CD3 来显着改善免疫反应⁺和 CD8 ⁺ T 在肿瘤组织中浸润细胞。

更新日期：2021-12-23

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