Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues
Caroline Marques Xavier Costa, Cristiane Aparecida-Silva, Luis Eduardo Reina Gamba, Thalita Neves de Melo, Gisele Barbosa, Manoel Oliveira de Moraes, Victoria Regina T. de Oliveira, Carolinne Souza Amorim, João Alfredo Moraes, Eliezer J. Barreiro, Lı́dia Moreira Lima
Abstract
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 (4). This inhibitor was elected as a prototype and molecular modifications were planned to design a new series of simplified gedatolisib analogues (5a-f). The analogues were synthesised, and the comparative cytotoxic activity profile was studied in phenotypic models employing solid and nonadherent tumour cell lines. Compound 5f (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 (t1/2 = 462 min; Clapp = 0.058 mL/min/g). The ability of 5f to exert its cytotoxic effect through modulation of the PI3K pathway was demonstrated by flow cytometry analysis in a comparative manner to gedatolisib.