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<p>Previously, we proposed a pharmacophoric model of inhibitors of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9). The new inhibitor of MMP-2 and MMP-9 1-{4-[(2,4-dichlorobenzoyl)amino]phenyl}sulfonyl-(2<i>S</i>,4<i>R</i>)-4-hydroxypyrrolidine-2-carboxylic acid (working code GGM-27) was designed and synthesized based on this model and a molecular docking method. <i>In vitro</i> experiments using the fluorogenic substrate Mca-Lys-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH<sub>2</sub> and recombinant human MMP-2 and MMP-9 showed the inhibitory activity of GGM-27 towards MMP-2 (Ki 9.4 × 10<sup>–5</sup> M) and MMP-9 (Ki 9.0 × 10<sup>–4</sup> M). A study of the Ca755 breast adenocarcinoma model in female C57Bl/6 mice showed the antitumor activity of the compound GGM-27 at doses of 1 and 10 mg/kg with 14-d intraperitoneal administration. Tumor growth inhibition (TGI) values under the influence of GGM-27 at doses of 1 and 10 mg/kg were 76 and 71%, respectively, on the 15<sup>th</sup> day of tumor development; 63 and 62%, on the 21<sup>st</sup> day. The increases in the average lifespan of mice after using the compound at the same doses were 45 and 47%. Thus, the phenylsulfonyl-L-hydroxyproline derivative GGM-27, which has the properties of an inhibitor of MMP-2 and MMP-9, was found to have antitumor activity in the Ca755 breast adenocarcinoma model.</p>

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Synthesis of the New Matrix Metalloproteinase Type-2 and Type-9 Inhibitor 1-{4-[(2,4-Dichlorobenzoyl)-Amino]Phenyl}Sulfonyl-(2S,4R)-4-Hydroxypyrrolidine-2-Carboxylic Acid and its Anticancer Activity in a Breast Adenocarcinoma Experimental Model

  • 期刊论文

  • 发表日期：

    2025年5月1日

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  • O. S. Grigorkevich,
  • L. P. Kovalenko,
  • R. V. Zhurikov,
  • A. S. Pantileev,
  • O. Yu. Kravtsova,
  • A. G. Rebeko,
  • G. V. Mokrov,
  • L. G. Kolik,
  • T. A. Gudasheva,
  • A. D. Durnev,
  • V. L. Dorofeev

摘要

Previously, we proposed a pharmacophoric model of inhibitors of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9). The new inhibitor of MMP-2 and MMP-9 1-{4-[(2,4-dichlorobenzoyl)amino]phenyl}sulfonyl-(2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (working code GGM-27) was designed and synthesized based on this model and a molecular docking method. In vitro experiments using the fluorogenic substrate Mca-Lys-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 and recombinant human MMP-2 and MMP-9 showed the inhibitory activity of GGM-27 towards MMP-2 (Ki 9.4 × 10–5 M) and MMP-9 (Ki 9.0 × 10–4 M). A study of the Ca755 breast adenocarcinoma model in female C57Bl/6 mice showed the antitumor activity of the compound GGM-27 at doses of 1 and 10 mg/kg with 14-d intraperitoneal administration. Tumor growth inhibition (TGI) values under the influence of GGM-27 at doses of 1 and 10 mg/kg were 76 and 71%, respectively, on the 15th day of tumor development; 63 and 62%, on the 21st day. The increases in the average lifespan of mice after using the compound at the same doses were 45 and 47%. Thus, the phenylsulfonyl-L-hydroxyproline derivative GGM-27, which has the properties of an inhibitor of MMP-2 and MMP-9, was found to have antitumor activity in the Ca755 breast adenocarcinoma model.