6,7-Dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives as selective inhibitors of PI3Kα

Yin, Yong; Zhang, Yanqing; Jin, Biao; Sha, Shao; Wu, Xun; Sangani, Chetan B.; Wang, She-Feng; Qiao, Fang; Lu, Ai‐Min; Lv, Peng‐Cheng; Zhu, Hai‐Liang

doi:10.1016/j.bmc.2015.01.052

Cited by 30 publications

(18 citation statements)

References 23 publications

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“…The most well‐known examples of 1,4‐oxazepines include half and fully saturated (i.e., dihydro, tetrahydro and perhydro), benzo‐, dibenzo‐, and pyrido‐fused, and/or oxo derivatives. 1,4‐Oxazepine derivatives have been reported to display a wide range of biological properties, including analgesic, antiallergic, antibacterial, anticonvulsant, antidepressant,, antihistaminic,, antiinflammatory, antipsychotic, anxiolytic, antiulcer, and antitumor, activities. They have also been often used as histamine H 4 receptor (H 4 R) agonist, progesterone receptor agonists, calcium antagonist, PGE 2 antagonist, non‐nucleoside inhibitor of HIV‐1 reverse transcriptase, and PI3Ka selective inhibitor .…”

Section: Introductionmentioning

confidence: 99%

“…1,4‐Oxazepine derivatives have been reported to display a wide range of biological properties, including analgesic, antiallergic, antibacterial, anticonvulsant, antidepressant,, antihistaminic,, antiinflammatory, antipsychotic, anxiolytic, antiulcer, and antitumor, activities. They have also been often used as histamine H 4 receptor (H 4 R) agonist, progesterone receptor agonists, calcium antagonist, PGE 2 antagonist, non‐nucleoside inhibitor of HIV‐1 reverse transcriptase, and PI3Ka selective inhibitor . In addition, 1,4‐oxazepine derivatives have proven to be useful for the treatment of various diseases, including allergic bronchitis, bronchial asthma, breast cancer, epilepsy and trigeminal neuralgia, and psychotic disorders .…”

Section: Introductionmentioning

confidence: 99%

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Zinc Chloride Mediated Synthesis of 1,4‐Oxazepines from N‐Propargylic β‐Enaminones

2017

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An efficient and general method for the synthesis of 1,4‐oxazepines is described. When reacted with ZnCl2 in DCM at 40 °C or CHCl3 at 61 °C, N‐propargylic β‐enaminones undergo 7‐exo‐dig cyclization to afford 2‐methylene‐2,3‐dihydro‐1,4‐oxazepines in good to high yields. This cyclization has been found to be general for a diverse range of N‐propargylic β‐enaminones, and proceeds with high efficiency and with broad functional group tolerance. The reactions in refluxing CHCl3 produced 1,4‐oxazepines in comparatively short reaction times and with better yields that those obtained in refluxing DCM. This operationally easy method may provide rapid access to a library of functionalized 1,4‐oxazepine derivatives of pharmacological interest.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Zinc Chloride Mediated Synthesis of 1,4‐Oxazepines from N‐Propargylic β‐Enaminones

2017

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“…The residue was purified by column chromatography on silica gel to give 2-(1H-indol-2-yl)phenol derivatives. [2] :…”

Section: Synthesis Of Substratesmentioning

confidence: 99%

One-Pot Highly Regioselective Synthesis of Indole-Fused Pyridazino[4,5-b][1,4]benzoxazepin-4(3H)-ones by a Smiles Rearrangement

Jiang

2018

Synlett

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A simple and convenient synthesis of indole-fused pyridazino[4,5-b][1,4]benzoxazepin-4(3H)-ones is described. A range of 2-(1H-indol-2-yl)phenols and 4,5-dichloropyridazin-3-ones are compatible with this reaction. A Smiles rearrangement is proposed as a key step in the highly regioselective construction of the products. The easy availability of the starting materials makes this an appealing method in organic synthesis.

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“…Natural products including wortmannin, myricetin, resveratrol, staurosporine, and viridian have been considered to represent the first generation of PI3K inhibitors . Subsequently, based on the structural scaffolds of these natural products, more potent small‐molecule PI3K inhibitors were deigned . Since then, many kinds of PI3Kβ isoform‐selective inhibitors including TGX221, AZD6482, and GSK2636771 have been developed and most of them have progressed to clinical trials to treat PTEN‐deficient tumors .…”

Section: Introductionmentioning

confidence: 99%

Identification of Natural Products as Novel PI3Kβ Inhibitors Through Pharmacophore‐based Virtual Screening

Jin

Kwon

Kim

et al. 2018

Bulletin Korean Chem Soc

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Phosphatidylinositol 3‐kinase beta (PI3Kβ) is the dominant isoform of PI3K and has been implicated in thrombosis as well as phosphatase and tensin homologue‐loss‐induced tumorigenesis. PI3Kβ has been considered to be an attractive target for anticancer drug discovery, and several PI3Kβ inhibitors have progressed into clinical trials. Here, we disclose the discovery of two natural products (PBY‐0002 and PBY‐0006) that have inhibitory effects on PI3Kβ. These two natural products were identified through pharmacophore‐based virtual screening, molecular docking, and a molecular dynamics simulation. Furthermore, an in vitro assay against human gastric cancer cell lines revealed that these two compounds showed anticancer activity. To identify the binding modes of PBY‐0002 and PBY‐0006 further, we performed a systematical investigation with comparison to the binding mode of GSK2636711, which is a known PI3Kβ inhibitor. The results demonstrated that PBY‐0002 and PBY‐0006 were tightly embedded into the ATP‐binding site via hydrogen bonds and π‐cation interactions. These two natural products can provide a promising starting point for the rational design of potent analogs with inhibitory activity against PI3Kβ.

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6,7-Dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives as selective inhibitors of PI3Kα

Cited by 30 publications

References 23 publications

Zinc Chloride Mediated Synthesis of 1,4‐Oxazepines from N‐Propargylic β‐Enaminones

Zinc Chloride Mediated Synthesis of 1,4‐Oxazepines from N‐Propargylic β‐Enaminones

One-Pot Highly Regioselective Synthesis of Indole-Fused Pyridazino[4,5-b][1,4]benzoxazepin-4(3H)-ones by a Smiles Rearrangement

Identification of Natural Products as Novel PI3Kβ Inhibitors Through Pharmacophore‐based Virtual Screening

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