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.

Automated summary

In this study, new derivatives containing dithiocarbamate were designed and synthesized to investigate their inhibitory activities on PI3K. Compound 13 showed strong efficacy in inhibiting PI3K and two tumor cell lines, and induced tumor regression in a mouse model.