Araújo Flávio Henrique Souza de, Figueiredo Débora Rojas de, Auharek Sarah Alves, Pesarini João Renato, Meza Alisson, Gomes Roberto da Silva, Monreal Antônio Carlos Duenhas, Antoniolli-Silva Andréia Conceição Milan Brochado, Lima Dênis Pires de, Kassuya Candida Aparecida Leite, Beatriz Adilson, Oliveira Rodrigo Juliano
Centro de Estudos em Célula Tronco, Terapia Celular e Genética Toxicológica, Hospital Universitário "Maria Aparecida Pedrossian", Empresa Brasileira de Serviços Hospitalares, Campo Grande, MS, Brazil.
Programa de Mestrado em Farmácia, Centro de Ciências Biológicas e da Saúde, Universidade Federal de Mato Grosso do Sul, Campo Grande, MS, Brazil.
Genet Mol Biol. 2017;40(3):665-675. doi: 10.1590/1678-4685-GMB-2016-0316.
Chemotherapy is one of the major approaches for the treatment of cancer. Therefore, the development of new chemotherapy drugs is an important aspect of medicinal chemistry. Chemotherapeutic agents include isocoumarins, which are privileged structures with potential antitumoral activity. Herein, a new 3-substituted isocoumarin was synthesized from 2-iodo-3,5-dimethoxy-benzoic acid and oct-1-yne in a cross-coupling Sonogashira reaction followed by a copper iodide-catalyzed intramolecular cyclization as key step using MeOH/Et3N as the solvent system. The present study also evaluated the leukometry, phagocytic activity, genotoxic potential and cell death induction of three different doses (5 mg/kg, 10 mg/kg and 20 mg/kg) of this newly synthesized isocoumarin, alone and in combination with the commercial chemotherapeutic agents cyclophosphamide (100 mg/kg) and cisplatin (6 mg/kg) in male Swiss mice. The results suggest that the isocoumarin has genotoxicity and causes cell death. Noteworthy, this new compound can increase splenic phagocytosis and lymphocyte frequency, which are related to immunomodulatory activity. When combined with either cyclophosphamide or cisplatin, chemopreventive activity led to a reduction in the effects of both chemotherapeutic drugs. Thus, the new isocoumarin is not a candidate for chemotherapeutic adjuvant in treatments using cyclophosphamide or cisplatin. Nevertheless, the compound itself is an important prototype for the development of new antitumor drugs.
化疗是癌症治疗的主要方法之一。因此，开发新型化疗药物是药物化学的一个重要方面。化疗药物包括异香豆素，它们是具有潜在抗肿瘤活性的优势结构。在此，以2-碘-3,5-二甲氧基苯甲酸和1-辛炔为原料，通过交叉偶联Sonogashira反应，然后以甲醇/三乙胺为溶剂体系，以碘化铜催化的分子内环化反应为关键步骤，合成了一种新型3-取代异香豆素。本研究还评估了单独使用以及与商业化疗药物环磷酰胺（100 mg/kg）和顺铂（6 mg/kg）联合使用时，三种不同剂量（5 mg/kg、10 mg/kg和20 mg/kg）的这种新合成异香豆素对雄性瑞士小鼠的白细胞计数、吞噬活性、遗传毒性潜力和细胞死亡诱导作用。结果表明，该异香豆素具有遗传毒性并能导致细胞死亡。值得注意的是，这种新化合物可以增加脾脏吞噬作用和淋巴细胞频率，这与免疫调节活性有关。当与环磷酰胺或顺铂联合使用时，化学预防活性导致两种化疗药物的效果降低。因此，这种新异香豆素不是环磷酰胺或顺铂治疗中化疗辅助剂的候选药物。然而，该化合物本身是开发新型抗肿瘤药物的重要原型。
