Synthesis and biological evaluation of novel 2-arylamino-3-(arylsulfonyl)quinoxalines as PI3Kα inhibitors

Wu, Peng; Su, Yi; Liu, Xiaowen; Zhang, Lei; Ye, Yong; Xu, Jinbao; Weng, Shaoyu; Li, Yani; Liu, Tao; Huang, Shufang; Yang, Bo; He, Qiaojun; Hu, Yongzhou

doi:10.1016/j.ejmech.2011.09.015

Cited by 32 publications

(15 citation statements)

References 23 publications

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“…In 2011, Wu et al [82] synthesized a series of novel 2-arylamino-3-(arylsulfonyl)quinoxalines (238) through a newly developed approach from XL-765 (236, PI3K α/β/δ/γ IC 50 =39/113/43 /9 nM ) and XL-147 (237, PI3K α/β/δ/γ IC 50 = 39/383/36 /23 nM).The most potent compound (239, PI3Kα IC 50 = 0.07 µM) validated the potential of 2-arylamino- 3- (arylsulfonyl) quinoxaline series for cancer treatment by targeting PI3Kα.…”

Section: Pyridines Quinolines Indoles and Indazolesmentioning

confidence: 99%

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

Liu

Wan

et al. 2016

Oncotarget

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Section: Pyridines Quinolines Indoles and Indazolesmentioning

confidence: 99%

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

Liu

Wan

et al. 2016

Oncotarget

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“…2-Chloro-3-arylsulfonylquinoxalines 55–59 were synthesized using the same materials and procedures as reported [13].…”

Section: Resultsmentioning

confidence: 99%

“…In our efforts to identify novel inhibitors of PI3K [13], we established a pharmacophore model based on reported PI3K inhibitors and identified the morpholinoquinoxaline derivative WR1 ( 1 ) as an initial hit with good potency against PI3Kα (IC 50 : 0.44 µM) [14], which is equivalent to that of the extensively studied tool compound LY294002 ( 2 , PI3Kα, IC 50 : 0.63 µM) (Fig. 1) [15], [16].…”

Section: Introductionmentioning

confidence: 99%

Identification of Novel Piperazinylquinoxaline Derivatives as Potent Phosphoinositide 3-Kinase (PI3K) Inhibitors

Guan

et al. 2012

PLoS ONE

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BackgroundDevelopment of small-molecule inhibitors targeting phosphoinositide 3-kinase (PI3K) has been an appealing strategy for the treatment of various types of cancers.Methodology/Principal FindingOur approach was to perform structural modification and optimization based on previously identified morpholinoquinoxaline derivative WR1 and piperidinylquinoxaline derivative WR23 with a total of forty-five novel piperazinylquinoxaline derivatives synthesized. Most target compounds showed low micromolar to nanomolar antiproliferative potency against five human cancer cell lines using MTT method. Selected compounds showed potent PI3Kα inhibitory activity in a competitive fluorescent polarization assay, such as compound 22 (IC50 40 nM) and 41 (IC50: 24 nM), which induced apoptosis in PC3 cells. Molecular docking analysis was performed to explore possible binding modes between target compounds and PI3K.Conclusions/SignificanceThe identified novel piperazinylquinoxaline derivatives that showed potent PI3Kα inhibitory activity and cellular antiproliferative potency may be promising agents for potential applications in cancer treatment.

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“…65 The amines used in this case were cyclic aliphatic amines rather than aromatic amines but the synthetic route used was analogous to their earlier report. 60 The most potent compounds inhibited Akt phosphorylation in PC3 cells at 10µM.…”

Section: Pyrazines and Quinoxalinesmentioning

confidence: 97%

“…60 The synthetic route used started with benzene-1,2-diamine ( 194 ) which was condensed with diethyl oxalate. A quinoxaline dione was produced which was chlorinated with SOCl 2 to produce 195 .…”

Section: Pyrazines and Quinoxalinesmentioning

confidence: 99%

Recent syntheses of PI3K/Akt/mTOR signaling pathway inhibitors

Welker

Kulik

2013

Bioorganic & Medicinal Chemistry

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This review focuses on the syntheses of PI3K/Akt/mTOR inhibitors that have been reported outside of the patent literature in the last 5 years but is largely centered on synthetic work reported in 2011 and 2012. While focused on syntheses of inhibitors, some information on in vitro and in vivo testing of compounds is also included. Many of these reported compounds are reversible, competitive adenosine triphosphate (ATP) binding inhibitors, so given the structural similarities of many of these compounds to the adenine core, this review presents recent work on inhibitors based on where the synthetic chemistry was started, i.e. inhibitor syntheses which started with purines/pyrimidines are followed by inhibitor syntheses which began with pyridines, pyrazines, azoles, and triazines then moves to inhibitors which bear no structural resemblance to adenine: liphagal, wortmannin and quercetin analogs. The review then finishes with a short section on recent syntheses of phosphotidyl inositol (PI) analogs since competitive PI binding inhibitors represent an alternative to the competitive ATP binding inhibitors which have received the most attention.

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Synthesis and biological evaluation of novel 2-arylamino-3-(arylsulfonyl)quinoxalines as PI3Kα inhibitors

Cited by 32 publications

References 23 publications

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

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

Identification of Novel Piperazinylquinoxaline Derivatives as Potent Phosphoinositide 3-Kinase (PI3K) Inhibitors

Recent syntheses of PI3K/Akt/mTOR signaling pathway inhibitors

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