Design, synthesis, anticancer activity and docking studies of novel 4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives as mTOR inhibitors

Mechanistic/mammalian target of rapamycin: Recent pathological aspects and inhibitors

“…Compound 24 was shown to have an excellent inhibitory activity against mTOR kinase, with 1.71‐fold more activity than the lead compound 24a against kinase in H460 and PC‐3 cell lines. The substitution of the aryl moiety and the hydroxyl group at C4 increased mTOR kinase inhibition and yielded an antitumor activity equal to that of the reference compound 24 .…”

“…Due to the role of the PI3K/AKT/mTOR pathway and its upregulation in hepatocellular carcinoma (HCC), compound 25 (NSC781406; Figure ) was synthesized by Chen et al as a dual PI3K/mTOR inhibitor (IC 50 = 2.0 nM for PI3Kα, 9.4 nM for PI3Kβ, 2.7 nM for PI3Kγ, 14 nM for PI3Kδ, and 5.4 nM for mTOR) with acceptable liver microsome stability ( t 1/2 = 28.96 minutes). Its effect on mTOR and PI3K was evaluated using an NCI‐60 cytotoxicity assay; the mean IC 50 value for compound 25 against the sixty cancer cell lines was 65 nM, and for four cancer cell lines, the IC 50 reached below 10 nM.…”

Recent development of ATP-competitive small molecule phosphatidylinostitol-3-kinase inhibitors as anticancer agents

“…Zhu et al [65] reported the discovery of 7, 8-dihydro-5H-thiopyrano [4, 3-d] pyrimidine derivatives (165-166) as mTOR inhibitors, using scaffold hopping of the lead compound (164, mTOR IC 50 =1.37 µM), a triazinehydrazone derivative. The selected compounds (mTOR IC 50 ~ 0.8-6.93 µM)) showing equal to more potency than the lead were further evaluated for the inhibitory activity against PI3Kα (PI3Kα IC 50 ~ 6.2-24.9 µM).…”

Synthesis of 3-(4-aminophenyl) cyclopropane-1, 1,2,2-tetracarbonitrile

“…Developing an efficiently and safety method to treatment the malignancies has become a hot pot in nowadays. In recent years, many small molecule anticancer drugs had been reported [2][3][4] , such as NVP-BEZ-235, 2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2, 3-dihydro-1H-imidazo [4,5-c] quinolin-1-yl)phenyl) propanenitrile (3), 1-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2, 3-dihydro-1H-imidazo [4,5-c]quinolin-1-yl)phenyl) cyclopropanecarbonitrile(4) [5][6] . 3-(4-aminop henyl) cyclopropane -1, 1, 2, 2 -tetracarbonitrile is the key intermediate and has a wide range of applications in the pharmaceutical and chemical fields.…”