| Summary: | 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 (<b>4</b>). This inhibitor was elected as a prototype and molecular modifications were planned to design a new series of simplified gedatolisib analogues (<b>5a-f</b>). The analogues were synthesised, and the comparative cytotoxic activity profile was studied in phenotypic models employing solid and nonadherent tumour cell lines. Compound <b>5f</b> (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<sub>1/2</sub> = 462 min; Clapp = 0.058 mL/min/g). The ability of <b>5f</b> to exert its cytotoxic effect through modulation of the PI3K pathway was demonstrated by flow cytometry analysis in a comparative manner to gedatolisib.
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