Design, synthesis and anti-tumor evaluation of 1,2,4-triazol-3-one derivatives and pyridazinone derivatives as novel CXCR2 antagonists

• Published in: European journal of medicinal chemistry Vol. 226; p. 113812
• Main Authors: Zhang, Xun, Luo, Jingyi, Li, Qinyuan, Xin, Qilei, Ye, Lizhen, Zhu, Qingyun, Shi, Zhichao, Zhan, Feng, Chu, Bizhu, Liu, Zijian, Jiang, Yuyang
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.12.2021; Elsevier
• Subjects: 1,2,4-Triazol-3-one; Antagonists; Anti-tumor; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemistry, Medicinal; CXCR2; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Life Sciences & Biomedicine; Molecular Structure; Pharmacology & Pharmacy; Pyridazines - chemical synthesis; Pyridazines - chemistry; Pyridazines - pharmacology; Pyridazinone; Receptors, Interleukin-8B - antagonists & inhibitors; Receptors, Interleukin-8B - metabolism; Science & Technology; Structure-Activity Relationship; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; Triple-negative breast cancer; Antagonists; Pyridazinone; Anti-tumor; 1,2,4-Triazol-3-one; CXCR2; Triple-negative breast cancer; MOIETY; ANGIOGENESIS; CANCER; DISCOVERY; POTENT; GROWTH; CHEMOKINE RECEPTORS; INHIBITOR; 4-PHENOXYQUINOLINE DERIVATIVES; TUMOR MICROENVIRONMENT
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113812

Chemokine receptor 2 (CXCR2) is the receptor of glutamic acid–leucine–arginine sequence-contained chemokines CXCs (ELR+ CXCs). In recent years, CXCR2-target treatment strategy has come a long way in cancer therapy. CXCR2 antagonists could block CXCLs/CXCR2 axis, and are widely used in regulating immune cell migration, tumor metastasis, apoptosis and angiogenesis. Herein, two series of new CXCR2 small-molecule inhibitors, including 1,2,4-triazol-3-one derivatives 1–11 and pyridazinone derivatives 12–22 were designed and synthesized based on the proof-to-concept. The pyridazinone derivative 18 exhibited good CXCR2 antagonistic activity (69.4 ± 10.5 %Inh at 10 μM) and demonstrated its significant anticancer metastasis activity in MDA-MB-231 cells and remarkable anti-angiogenesis activity in HUVECs. Furthermore, noteworthy was that 18 exhibited an obvious synergistic effect with Sorafenib in anti-proliferation assay in MDA-MB-231 cells. Moreover, 18 showed a distinct reduction of the phosphorylation levels of both PI3K and AKT proteins in MDA-MB-231 cells, and also affected the expression levels of other PI3K/AKT signaling pathway-associated proteins. The molecular docking studies of 18 with CXCR2 also verified the rationality of our design strategy. All of these results revealed pyridazinone derivative 18 as a promising CXCR2 antagonist for future cancer therapy. [Display omitted] •Novel CXCR2 antagonists 1,2,4-triazol-3-one and pyridazinone derivatives were developed.•18 reduced the phosphorylation levels of both PI3K and AKT proteins in MDA-MB-231 cells.•18 showed significant anticancer metastasis activity in MDA-MB-231 cells.•18 showed remarkable anti-angiogenesis activity in HUVEC cells.•18 caused a comforting synergistic effect with Sorafenib and enhanced the efficiency of Sorafenib in MDA-MB-231 cells.