Ramos-Inza Sandra, Aliaga Cesar, Encío Ignacio, Raza Asif, Sharma Arun K, Aydillo Carlos, Martínez-Sáez Nuria, Sanmartín Carmen, Plano Daniel
Department of Pharmaceutical Technology and Chemistry, University of Navarra, Irunlarrea 1, 31008 Pamplona, Spain.
Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain.
Antioxidants (Basel). 2023 Aug 24;12(9):1666. doi: 10.3390/antiox12091666.
The introduction of selenium (Se) into organic scaffolds has been demonstrated to be a promising framework in the field of medicinal chemistry. A novel design of nonsteroidal anti-inflammatory drug (NSAID) derivatives based on a bioisosteric replacement via the incorporation of Se as diacyl diselenide is reported. The antioxidant activity was assessed using the DPPH radical scavenging assay. The new Se-NSAID derivatives bearing this unique combination showed antioxidant activity in a time- and dose-dependent manner, and also displayed different antiproliferative profiles in a panel of eight cancer cell lines as determined by the MTT assay. Ibuprofen derivative was not only the most antioxidant agent, but also selectively induced toxicity in all the cancer cell lines tested (IC < 10 µM) while sparing nonmalignant cells, and induced apoptosis partially without enhancing the caspase 3/7 activity. Furthermore, NSAID derivative significantly suppressed tumor growth in a subcutaneous colon cancer xenograft mouse model (10 mg/kg, TGI = 72%, and T/C = 38%) without exhibiting any apparent toxicity. To our knowledge, this work constitutes the first report on in vitro and in vivo anticancer activity of an unprecedented Se-NSAID hybrid derivative and its rational use for developing precursors for bioisosteric selenocompounds with appealing therapeutic applications.
将硒（Se）引入有机支架已被证明是药物化学领域一个有前景的框架。本文报道了一种基于生物电子等排体替换的新型非甾体抗炎药（NSAID）衍生物设计，通过引入二酰基二硒化物形式的硒来实现。使用DPPH自由基清除试验评估抗氧化活性。带有这种独特组合的新型硒 - NSAID衍生物表现出时间和剂量依赖性的抗氧化活性，并且通过MTT试验测定，在一组八种癌细胞系中也显示出不同的抗增殖谱。布洛芬衍生物不仅是最强的抗氧化剂，而且在所有测试的癌细胞系中均选择性地诱导毒性（IC < 10 µM），同时对非恶性细胞无影响，并且部分诱导细胞凋亡而不增强caspase 3/7活性。此外，NSAID衍生物在皮下结肠癌异种移植小鼠模型中显著抑制肿瘤生长（10 mg/kg，TGI = 72%，T/C = 38%），且未表现出任何明显毒性。据我们所知这项工作首次报道了一种前所未有的硒 - NSAID杂化衍生物的体外和体内抗癌活性及其合理用于开发具有吸引人治疗应用的生物电子等排体硒化合物前体。
