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- Title
New Derivatives of N- Hydroxybutanamide: Preparation, MMP Inhibition, Cytotoxicity, and Antitumor Activity.
- Authors
Balakina, Anastasia; Gadomsky, Svyatoslav; Kokovina, Tatyana; Sashenkova, Tatyana; Mishchenko, Denis; Terentiev, Alexei
- Abstract
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.
- Subjects
CYTOTOXINS; ANTINEOPLASTIC agents; MATRIX metalloproteinases; SUCCINIMIDES; METALLOENZYMES
- Publication
International Journal of Molecular Sciences, 2023, Vol 24, Issue 22, p16360
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms242216360