Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues.

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.

• Authors: Caroline Marques Xavier Costa, Cristiane Aparecida-Silva, Luis Eduardo Reina Gamba, Thalita Neves de Melo, Gisele Barbosa, Manoel Oliveira de Moraes Junior, Victoria Regina Thomaz de Oliveira, Carolinne Souza de Amorim, João A Moraes, Eliezer Jesus Barreiro, Lídia Moreira Lima
• Journal: Pharmaceuticals (Basel, Switzerland) (Pharmaceuticals (Basel)) Vol. 16 Issue 2 (Jan 30 2023) ISSN: 1424-8247 [Print] Switzerland
• PMID: 37259357 (Publication Type: Journal Article)