Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry RAS, 142432 Chernogolovka, Russia.
Faculty of Fundamental Physical-Chemical Engineering of M.V. Lomonosov MSU, Leninskie Gory, 119991 Moscow, Russia.
Int J Mol Sci. 2023 Nov 15;24(22):16360. doi: 10.3390/ijms242216360.
Using a novel method of -substituted succinimide ring opening, new -hydroxybutanamide derivatives were synthesized. These compounds were evaluated for their ability to inhibit matrix metalloproteinases (MMPs) and their cytotoxicity. The iodoaniline derivative of -hydroxy--phenylbutanediamide showed the inhibition of MMP-2, MMP-9, and MMP-14 with an IC 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 -hydroxy--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 -hydroxy--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.
采用新型的 -取代琥珀酰亚胺环开环方法，合成了新的 -羟基丁酰胺衍生物。评估了这些化合物抑制基质金属蛋白酶（MMPs）的能力及其细胞毒性。 -羟基--苯基丁二酰胺的碘苯胺衍生物对 MMP-2、MMP-9 和 MMP-14 的抑制作用的 IC 为 1-1.5 μM。所有化合物对宫颈癌 HeLa 和 HepG2 细胞系表现出低毒性。碘苯胺衍生物对神经胶质瘤细胞系 A-172 和 U-251 MG 也有轻微毒性。非癌细胞系 FetMSC 和 Vero 对所有化合物的敏感性最低。体内研究表明， -羟基--苯基丁二酰胺的碘苯胺衍生物具有低急性毒性。在 B16 黑色素瘤小鼠模型中，该化合物表现出抗肿瘤和抗转移作用，肿瘤生长抑制率为 61.5%，转移抑制率为 88.6%。我们的研究结果表明， -羟基--苯基丁二酰胺的碘苯胺衍生物具有作为新型 MMP 抑制剂的潜在先导结构。我们的新合成方法可以成为具有潜在抗肿瘤作用的金属蛋白酶抑制剂的经济有效的合成方法。
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