Costa Caroline Marques Xavier, Aparecida-Silva Cristiane, Gamba Luis Eduardo Reina, de Melo Thalita Neves, Barbosa Gisele, Moraes Junior Manoel Oliveira de, de Oliveira Victoria Regina Thomaz, de Amorim Carolinne Souza, Moraes João A, Barreiro Eliezer Jesus, Lima Lídia Moreira
Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio®), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, CCS, Cidade Universitária, Rio de Janeiro 21941-971, RJ, Brazil.
Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, RJ, Brazil.
Pharmaceuticals (Basel). 2023 Jan 30;16(2):209. doi: 10.3390/ph16020209.
Targeted antitumour therapy has revolutionized the treatment of several types of tumours. Among the validated targets, phosphatidylinositol-3 kinase (PI3K) deserves to be highlighted. Several PI3K inhibitors have been developed for the treatment of cancer, including gedatolisib (). This inhibitor was elected as a prototype and molecular modifications were planned to design a new series of simplified gedatolisib analogues (). The analogues were synthesised, and the comparative cytotoxic activity profile was studied in phenotypic models employing solid and nonadherent tumour cell lines. Compound (LASSBio-2252) stood out as the most promising of the series, showing good aqueous solubility (42.38 μM (pH = 7.4); 39.33 μM (pH = 5.8)), good partition coefficient (cLogP = 2.96), cytotoxic activity on human leukemia cell lines (CCRF-CEM, K562 and MOLT-4) and an excellent metabolic stability profile in rat liver microsomes (t = 462 min; Clapp = 0.058 mL/min/g). The ability of to exert its cytotoxic effect through modulation of the PI3K pathway was demonstrated by flow cytometry analysis in a comparative manner to gedatolisib.
靶向抗肿瘤治疗彻底改变了几种肿瘤的治疗方式。在已得到验证的靶点中，磷脂酰肌醇-3激酶（PI3K）值得重点关注。已经开发出几种用于治疗癌症的PI3K抑制剂，包括吉地替尼（）。这种抑制剂被选为原型，并计划进行分子修饰以设计一系列新的简化吉地替尼类似物（）。合成了这些类似物，并在使用实体和非贴壁肿瘤细胞系的表型模型中研究了它们的比较细胞毒性活性谱。化合物（LASSBio-2252）在该系列中表现最为突出，显示出良好的水溶性（42.38 μM（pH = 7.4）；39.33 μM（pH = 5.8））、良好的分配系数（cLogP = 2.96）、对人白血病细胞系（CCRF-CEM、K562和MOLT-4）的细胞毒性活性以及在大鼠肝微粒体中的出色代谢稳定性谱（t = 462分钟；Clapp = 0.058 mL/分钟/克）。通过流式细胞术分析，以与吉地替尼比较的方式证明了其通过调节PI3K途径发挥细胞毒性作用的能力。
