No abstract

Recent studies have shown that phosphoinositide 3kinase (PI3K) plays a vital role in cell division, and it has become a therapeutic target for many cancers. In this paper, some new 1,3,5triazine or pyrimidine skeleton derivatives containing dithiocarbamate were designed and synthesized based on the reasonable drug design strategy from the previously effective compound 2- -474), in order to get effective selective PI3Kα inhibitors that have not been reported in the literature. In addition, the inhibitory activities of these compounds on PI3Kα and two tumor cell lines in vitro (HCT-116, U87-MG) were evaluated. The representative compound 13 showed a half-maximal inhibitory concentration (IC 50 ) value of 1.2 nM for PI3Kα and an exciting kinase selectivity. Compound 13 displayed strong efficacy in HCT-116 and U87-MG cell lines with IC 50 values of 0.83 and 1.25 μM, respectively. In addition, compound 13 induced obvious tumor regression in the U87-MG cell line xenografts mouse model, with no obvious signs of toxicity after intraperitoneal injection at a dose of 40 mg/kg. Compound 13 can be an effective selective inhibitor of PI3Kα, and it provides patients with an opportunity to avoid the side effects related to the wider inhibition of the class I PI3K family.

This paper reports the efficient synthesis of substituted (Z)-N-allyl sulfonamides via a palladium-catalyzed threecomponent tandem reaction of N-buta-2,3-dienyl sulfonamides with iodides and sulfonyl hydrazide or sulfinic acid sodium salt as nucleophiles. Pd(PPh 3 ) 4 (2.5 mol %), K 2 CO 3 , and THF were used as the optimal catalyst, base, and solvent, respectively. The substituted (Z)-N-allyl sulfonamides were obtained in a 30−83% overall yield. Mechanistic investigations revealed that the formation of the single (Z)-isomer was controlled by the formation of a six-membered palladacycle intermediate.