Design, synthesis and bioevaluation of novel substituted triazines as potential dual PI3K/mTOR inhibitors.

摘要: Abstract A series of novel substituted triazines bearing a benzimidazole scaffold were designed and synthesized based on the structures known anti-cancer agents, namely gedatolisib alpelisib. All target compounds screened for inhibitory activity against PI3Kα mTOR kinases. Notably, most analogs exhibited IC50 in nanomolar range. Investigation isozyme selectivity indicated that remarkable PI3Kδ, especially compound 19f showed an value 2.3 nM PI3Kδ moderate δ-isozyme over other class I PI3K isoforms (with values 14.6, 34.0, 849.0 15.4 nM PI3Kα, β, γ mTOR, respectively). An in vitro MTT assay was conducted to assess antiproliferative cytotoxic effects prepared analogs. It revealed displayed significant activities HCT116 human colon cancer cell line. Compound 19i 4.7-fold higher potency than positive control (0.3 vs. 1.4 μM, values). Phosphoblot studies demonstrated 19c could significantly suppress PI3K/Akt/mTOR signaling pathway at 10 μM. Moreover, 19b, better stability artificial gastric fluids gedatolisib, while not very stable rat liver microsomes, may occur phase metabolic transformations.