Synthesis of N-aryl-2,6-diphenyl-2H-pyrazolo[4,3-c]pyridin-7-amines and their photodynamic properties in the human skin melanoma cell line G361

• Published in: Bioorganic chemistry 2022-02, Vol.119, p.105570-105570, Article 105570
• Main Authors: Razmienė, Beatričė, Vojáčková, Veronika, Řezníčková, Eva, Malina, Lukáš, Dambrauskienė, Vaida, Kubala, Martin, Bajgar, Robert, Kolářová, Hana, Žukauskaitė, Asta, Arbačiauskienė, Eglė, Šačkus, Algirdas, Kryštof, Vladimír
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Buchwald–Hartwig amination; Cell Proliferation - drug effects; Cell Survival - drug effects; Cytotoxicity; DNA damage; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Light; Melanoma - drug therapy; Melanoma - metabolism; Melanoma - pathology; Molecular Structure; Photochemotherapy; Photodynamic effect; Photosensitizing Agents - chemical synthesis; Photosensitizing Agents - chemistry; Photosensitizing Agents - pharmacology; Pyrazole; Reactive oxygen species; Skin Neoplasms - drug therapy; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Structure-Activity Relationship; Tumor Cells, Cultured
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105570

[Display omitted] •Synthesis of N-aryl-2,6-diphenyl-2H-pyrazolo[4,3-c]pyridin-7-amines.•Photodynamic effect and no dark toxicity in melanoma G361 cells.•Cell death through production of ROS and DNA damage. A small series of N-aryl-2,6-diphenyl-2H-pyrazolo[4,3-c]pyridin-7-amines was synthesized from easily accessible 1-phenyl-1H-pyrazol-3-ol via 7-iodo-2,6-diphenyl-2H-pyrazolo[4,3-c]pyridine and 7-iodo-4-methyl-2,6-diphenyl-2H-pyrazolo[4,3-c]pyridine intermediates and their subsequent use in palladium catalyzed Buchwald-Hartwig cross-coupling reaction with various anilines. Majority of the compounds were not significantly cytotoxic to melanoma G361 cells in the dark up to 10 µM concentration, but their activity could be increased by irradiation with visible blue light (414 nm). The most active compound 10 possessed EC50 values of 3.5, 1.6 and 0.9 µM in cells irradiated with 1, 5 and 10 J/cm2, respectively. The treatment caused generation of reactive oxygen species in cells and extensive DNA damage, documented by the comet assay and by detection of phosphorylated histone H2A.X, followed by apoptotic cell death. Our results suggest that N-aryl-2,6-diphenyl-2H-pyrazolo[4,3-c]pyridin-7-amines could serve as a potential source of photosensitizing compounds with anticancer activities.