Universidade Federal de Viçosa, Departamento de Bioquímica e Biologia Molecular, Viçosa, MG, Brazil.
Universidade Federal de Viçosa, Departamento de Química, Viçosa, MG, Brazil.
Eur J Med Chem. 2017 Jul 7;134:97-109. doi: 10.1016/j.ejmech.2017.03.078. Epub 2017 Mar 31.
The serine/arginine-rich protein kinases (SRPKs) have frequently been found with altered activity in a number of cancers, suggesting they could serve as potential therapeutic targets in oncology. Here we describe the synthesis of a series of twenty-two trifluoromethyl arylamides based on the known SRPKs inhibitor N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) and the evaluation of their antileukemia effects. Some derivatives presented superior cytotoxic effects against myeloid and lymphoid leukemia cell lines compared to SRPIN340. In particular, compounds 24, 30, and 36 presented IC values ranging between 6.0 and 35.7 μM. In addition, these three compounds were able to trigger apoptosis and autophagy, and to exhibit synergistic effects with the chemotherapeutic agent vincristine. Furthermore, compound 30 was more efficient than SRPIN340 in impairing the intracellular phosphorylation status of SR proteins as well as the expression of MAP2K1, MAP2K2, VEGF, and RON oncogenic isoforms. Therefore, novel compounds with increased intracellular effects against SRPK activity were obtained, contributing to medicinal chemistry efforts towards the development of new anticancer agents.
丝氨酸/精氨酸丰富蛋白激酶（SRPKs）在多种癌症中常被发现活性改变，表明它们可能成为肿瘤学中潜在的治疗靶点。在这里，我们描述了基于已知的 SRPKs 抑制剂 N-(2-(哌啶-1-基)-5-(三氟甲基)苯基)异烟酸酰胺（SRPIN340）合成的一系列二十二个三氟甲基芳酰胺，并评估了它们的抗白血病作用。与 SRPIN340 相比，一些衍生物对髓系和淋巴白血病细胞系表现出更好的细胞毒性作用。特别是化合物 24、30 和 36 的 IC 值范围在 6.0 和 35.7 μM 之间。此外，这三种化合物能够触发细胞凋亡和自噬，并与化疗药物长春新碱表现出协同作用。此外，化合物 30 在损害 SR 蛋白的细胞内磷酸化状态以及 MAP2K1、MAP2K2、VEGF 和 RON 致癌异构体的表达方面比 SRPIN340 更有效。因此，获得了对 SRPK 活性具有增强细胞内作用的新型化合物，为开发新的抗癌药物的药物化学努力做出了贡献。
