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简化基达托利西布类似物的设计,合成和表型分析

Caroline Marques Xavier Costa^1,2, Cristiane Aparecida-Silva^1,2, Luis Eduardo Reina Gamba^1,2

¹Laboratório 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.

Pharmaceuticals (Basel, Switzerland)

|June 1, 2023

概括

研究人员开发了癌症药物gedatolisib的简化类型. 化合物5f (LASSBio-2252) 通过调节氨酸-3激酶 (PI3K) 途径,对白血病细胞系表现出显著的细胞毒性活性.

科学领域:

药用化学医学化学
药理学药理学是指药理学的学科.
在瘤学瘤学.

背景情况:

向抗瘤治疗提供了新的癌症治疗策略.
酸氨基-3激酶 (PI3K) 是癌症治疗中验证的标.
盖达托利西布是一种已知的PI3K抑制剂,用于癌症治疗.

研究的目的:

设计和合成 gedatolisib. 的简化类似物.
评估这些新型化合物对各种瘤细胞系的细胞毒性活性.
为了确定一种具有潜在癌症治疗功能的改善性质的化合物.

主要方法:

基达托利西布类似物 (5a-f) 的合成.
细胞毒性活性在固体和非粘附性瘤细胞系中的表型评估.
物理化学性质的评估,包括水溶性和分割系数.
使用大鼠肝脏显微体进行代谢稳定性评估.
流细胞计分析以确认PI3K路径调节.

主要成果:

化合物5f (LASSBio-2252) 成为最有前途的模拟物.
5f 具有良好的水溶性 (pH 7.4 的 42.38 μM) 和有利的分割系数 (cLogP = 2.96).
对人类白血病细胞系 (CCRF-CEM,K562,MOLT-4) 观察到显著的细胞毒性活性.
5f表现出良好的代谢稳定性 (t1/2 = 462 分钟) 和低清除率 (Clapp = 0.058 mL/分钟/g).
流细胞计证实,5f调节PI3K通路,类似于gedatolisib.

结论:

成功合成了简化的吉达托利西布类似物.
化合物5f (LASSBio-2252) 是癌症治疗进一步发展的一个有希望的候选物.
5f显示了细胞毒性活性,溶解性,代谢稳定性和PI3K通路抑制的有利概况.

关键词:

一个MTTTT,一个MTTTT.的PI3K抑制剂.癌症癌症癌症癌症癌症流动细胞计量是流动细胞计量的方法.格达托利西布 (Gedatolisib) 是一个

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