Synthesis, cytotoxicity and antioxidant activity of new conjugates of N-acetyl-d-glucosamine with α-aminophosphonates

• Published in: Carbohydrate research Vol. 541; p. 109146
• Main Authors: Khabibulina, Leysan R., Garifullin, Bulat F., Aznagulov, Ravil F., Andreeva, Olga V., Strobykina, Irina Yu, Belenok, Mayya G., Voloshina, Alexandra D., Abramova, Dinara F., Vyshtakalyuk, Alexandra B., Lyubina, Anna P., Amerhanova, Syumbelya K., Sharipova, Radmila R., Kataev, Vladimir E.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01-07-2024
• Subjects: 1,2,3-Triazole; Acetylglucosamine - chemistry; Acetylglucosamine - pharmacology; Anticancer activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antioxidant activity; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Click-chemistry; D-glucosamine; Drug Screening Assays, Antitumor; Glucoconjugates; Glucosylaminophosphonates; Humans; Molecular Docking Simulation; Molecular Structure; Organophosphonates - chemical synthesis; Organophosphonates - chemistry; Organophosphonates - pharmacology; Structure-Activity Relationship; The kabachnik-fields reaction; The pudovik reaction; α-Aminophosphonate; The pudovik reaction; α-Aminophosphonate; Glucoconjugates; Antioxidant activity; Anticancer activity; D-glucosamine; The kabachnik-fields reaction; 1,2,3-Triazole; Glucosylaminophosphonates; Click-chemistry
• ISSN: 0008-6215; 1873-426X
• DOI: 10.1016/j.carres.2024.109146

A series of the first conjugates of N-acetyl-d-glucosamine with α-aminophosphonates was synthesized using the Kabachnik-Fields reaction, the Pudovik reaction, a copper(I)-catalyzed azide-alkyne cycloaddition reaction (CuAAC) and evaluated for the in vitro cytotoxicity against human cancer cell lines M − HeLa, HuTu-80, A549, PANC-1, MCF-7, T98G and normal lung fibroblast cells WI-38. The tested conjugates, with exception of compound 21b, considered as a lead compound, were either inactive against the used cancer cells or showed moderate cytotoxicity in the range of IC50 values 33−80 μM. The lead compound 21b, being non cytotoxic against normal human cells WI-38 (IC50 = 90 μM), demonstrated good activity (IC50 = 17 μM) against breast adenocarcinoma cells (MCF-7) which to be 1.5 times higher than the activity of the used reference anticancer drug tamoxifen (IC50 = 25.0 μM). A flexible receptor molecular docking simulation showed that the cytotoxicity of the synthesized conjugates of N-acetyl-d-glucosamine with α-aminophosphonates against breast adenocarcinoma MCF-7 cell line is due to their ability to inhibit EGFR kinase domain. In addition, it was found that conjugates 22a and 22b demonstrated antioxidant activity that was not typical for α-aminophosphonates.
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•A series of N-acetyl-glucosamine conjugates with α-aminophosphonates was synthesized.•The lead conjugate 21b demonstrated good activity against cancer cells MCF-7.•The activity of 21b against MCF-7 is due of its binding with the EGFR kinase domain.•Unusual for α-aminophosphonates antioxidant activity was discovered.