New Derivatives of N-Hydroxybutanamide: 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 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.