Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
Eur J Med Chem. 2013;70:1-9. doi: 10.1016/j.ejmech.2013.09.040. Epub 2013 Oct 2.
In this research work we report the synthesis of a new series of triazene prodrugs designed for Melanocyte-Directed Enzyme Prodrug Therapy (MDEPT). These compounds are derived from the N-acyltyrosine amino acid - a good enzyme substrate for the tyrosinase enzyme, which is significantly overexpressed in melanoma cells. We analysed their chemical stability and plasma enzymatic hydrolysis, and we also evaluated the release of the antitumoral drug in the presence of the tyrosinase. Subsequently, we performed the evaluation of the prodrug cytotoxicity in melanoma cell lines with different levels of tyrosinase activity. Prodrug 5c showed the highest cytotoxicity against melanoma cell lines, and this effect correlated well with the tyrosinase activity suggesting that prodrug cytotoxicity is tyrosinase-dependent.
在这项研究工作中，我们报告了一系列新的三氮烯前药的合成，这些前药旨在用于黑色素细胞定向酶前药疗法（MDEPT）。这些化合物是从 N-酰基酪氨酸氨基酸衍生而来的，它是酪氨酸酶的一种很好的酶底物，酪氨酸酶在黑色素瘤细胞中显著过表达。我们分析了它们的化学稳定性和血浆酶水解，并评估了在酪氨酸酶存在下抗肿瘤药物的释放。随后，我们在具有不同酪氨酸酶活性的黑色素瘤细胞系中评估了前药的细胞毒性。前药 5c 对黑色素瘤细胞系表现出最高的细胞毒性，这一效果与酪氨酸酶活性密切相关，表明前药的细胞毒性依赖于酪氨酸酶。
