Design and Synthesis of 1,3,5-Triazines or Pyrimidines Containing Dithiocarbamate Moiety as PI3K & alpha; Selective Inhibitors

Recent studies have shown that phosphoinositide 3-kinase(PI3K)plays a vital role in cell division, and it has become a therapeutictarget for many cancers. In this paper, some new 1,3,5-triazine orpyrimidine skeleton derivatives containing dithiocarbamate were designedand synthesized based on the reasonable drug design strategy fromthe previously effective compound 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK-474), in order to geteffective selective PI3K & alpha; inhibitors that have not been reportedin the literature. In addition, the inhibitory activities of thesecompounds on PI3K & alpha; and two tumor cell lines in vitro (HCT-116, U87-MG) were evaluated. The representative compound 13 showed a half-maximal inhibitory concentration (IC50) value of 1.2 nM for PI3K & alpha; and an exciting kinaseselectivity. Compound 13 displayed strong efficacy inHCT-116 and U87-MG cell lines with IC50 values of 0.83 and 1.25 & mu;M, respectively. In addition, compound 13 induced obvious tumor regression in the U87-MG cell line xenograftsmouse model, with no obvious signs of toxicity after intraperitonealinjection at a dose of 40 mg/kg. Compound 13 can be aneffective selective inhibitor of PI3K & alpha;, and it provides patientswith an opportunity to avoid the side effects related to the widerinhibition of the class I PI3K family.