NEW 1,3-DIHIDROXYACRIDONE DERIVATES: SYNTHESIS AND EVALUATION AS AKT INHIBITORS OF SIGNALING PATHWAY IN SKELETAL MUSCLE CELLS

GONZALEZ AGUSTINA; IRAZOQUI, A. PAULA; MENÉNDEZ, CINTIA A.; STEINGRUBER SEBASTIÁN; APPIGNANESI GUSTAVO; BUITRAGO C; GERBINO, DARÍO C.

Congreso; Reunion conjunta SAIC, SAI & FAIC, SAFIS 2022; 2022

PI3K/Akt signaling pathway is crucial in cell growth, survival, and differentiation, and is also involved in tumorigenesis. This route constitutes an alternative and attractive therapeutic target for the development of new antitumor agents. An interesting strategy applied to the discovery of new drugs consists of the use of so-called "privileged structures" such as acridones (dibenzo-4-pyridones) and their congeners, which represent a biocompatible system against different biological targets. Based on the acridone scaffold, four new prototypes (named 3a-3d) were efficiently synthesized following simple operating procedures and subsequently biologically tested in skeletal muscle (C2C12) and rhabdomyosarcoma (RD) cells. Our results showed no significant change in the number of viable cell (staining with Trypan blue and counted in a Neubauer chamber) when they were treated with the compounds (1 µM) for 24 or 48 hours. Western blot assays revealed that acridone derivatives 3a-3d (0.5 µM) effectively inhibited Akt activation in C2C12 at 24 h, whereas only 3a and 3b compounds at 1 µM were efficient in inhibiting Akt. RD cells showed a different response pattern. These cells treated with 3a (0.5 µM), 3b (0.5 µM) or 3d (0.5 or 1 µM) for 24 h showed significant inhibition of Akt. Furthermore, 3a-3d (1 µM) were highly successful inhibiting Akt phosphorylation at 48 h of treatment. Biological studies revealed that 3b compound could be considered the most promising prototype for the development of new antitumor agents, as it even has a higher inhibitory effect than LY294002, the well-known commercial Akt inhibitor.