New Derivatives of IN-/IHydroxybutanamide: Preparation, MMP Inhibition, Cytotoxicity, and Antitumor Activity

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 N[sup.1]-hydroxy-N[sup.4]-phenylbut...

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Bibliographic Details
Published in:International journal of molecular sciences 2023-11, Vol.24 (22)
Main Authors: Balakina, Anastasia, Gadomsky, Svyatoslav, Kokovina, Tatyana, Sashenkova, Tatyana, Mishchenko, Denis, Terentiev, Alexei
Format: Article
Language:English
Subjects:
Amino acids
Metalloenzymes
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Summary: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 N[sup.1]-hydroxy-N[sup.4]-phenylbutanediamide showed the inhibition of MMP-2, MMP-9, and MMP-14 with an IC[sub.50] 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 N[sup.1]-hydroxy-N[sup.4]-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 N[sup.1]-hydroxy-N[sup.4]-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.
ISSN:1422-0067
1422-0067
DOI:10.3390/ijms242216360