New Derivatives of N-Hydroxybutanamide: Preparation, MMP Inhibition, Cytotoxicity, and Antitumor Activity

International Journal of Molecular Sciences. 2023. Vol. 24. No. 22. Article 16360.

Балакина А. А., Гадомский С. Я., Коковина Т. С., Сашенкова Т. Е., Мищенко Д. В., Terentiev A.

Using a novel method of N-substituted succinimide ring opening, new N-hydroxybutanamide derivatives were synthesized. These compounds were evaluated for their ability to inhibit matrix metalloproteinases (MMPs) and their cytotoxicity. The iodoaniline derivative of N1-hydroxy-N4-phenylbutanediamide showed the inhibition of MMP-2, MMP-9, and MMP-14 with an IC50 of 1–1.5 µM. All the compounds exhibited low toxicity towards carcinoma cell lines HeLa and HepG2. The iodoaniline derivative was also slightly toxic to glioma cell lines A-172 and U-251 MG. Non-cancerous FetMSC and Vero cells were found to be the least sensitive to all the compounds. In vivo studies demonstrated that the iodoaniline derivative of N1-hydroxy-N4-phenylbutanediamide had low acute toxicity. In a mouse model of B16 melanoma, this compound showed both antitumor and antimetastatic effects, with a 61.5% inhibition of tumor growth and an 88.6% inhibition of metastasis. Our findings suggest that the iodoaniline derivative of N1-hydroxy-N4-phenylbutanediamide has potential as a lead structure for the development of new MMP inhibitors. Our new synthetic approach can be a cost-effective method for the synthesis of inhibitors of metalloenzymes with promising antitumor potential.

Keywords: цитотоксичность, Antitumor activity, matrix metalloproteinases, cytotoxicity, hydroxamic acids, imide ring opening, гидроксамовые кислоты, раскрытие имидного цикла, N-hydroxybutanamides, acute toxicity, antimetastatic activity, N-гидроксибутанамиды, матриксные металлопротеиназы, острая токсичность, противоопухолевая активность, антиметастатическая активность