Design, synthesis and biological evaluation of novel 4-alkynyl-quinoline derivatives as PI3K/mTOR dual inhibitors

Lv, Xiaoqing; Huang, Ying; Ma, Xiaodong; Qiu, Ni; Wu, Peng; Yang, Bo; Hu, Yongzhou

doi:10.1016/j.ejmech.2015.05.025

Cited by 26 publications

(11 citation statements)

References 26 publications

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“…This molecule shows the high inhibition effect of both PI3K and mTOR with an acceptable oral bioavailability [ 67 , 68 ]. Several omipalisib-like derivatives, characterized by a N-{5-[6-quinolinyl]-3-pyridinyl}benzenesulfonamide scaffold, have been synthesized and biologically evaluated for their PI3K/mTOR inhibition capability (biological data of omipalisib and compounds 31 – 34 are reported in Table 2 ) [ 69 , 70 , 71 , 72 ].…”

Section: Quinolines As Inhibitors Of Carcinogenic Pathwaysmentioning

confidence: 99%

“…Crystallography and in silico studies highlight some recurrent and crucial interactions between these ligands and the ATP-binding site of PI3Kγ: the backbone NH of Val 882 (Val 851 in PI3Kα) forms a hydrogen bond with quinoline nitrogen; Lys 883 interacts, through a charged bond, with the sulfonamide group; and the C-4 quinoline substituent frequently stabilizes the ligand-protein complex, accommodating itself in the ribose pocket physiologically occupied by ATP. In Figure 11 it is reported the co-crystal structure of omipalisib in complex with the catalytic subunit of PI3Kγ, [ 67 , 69 , 70 , 71 , 72 ].…”

Section: Quinolines As Inhibitors Of Carcinogenic Pathwaysmentioning

confidence: 99%

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Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

2020

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The quinoline ring system has long been known as a versatile nucleus in the design and synthesis of biologically active compounds. Currently, more than one hundred quinoline compounds have been approved in therapy as antimicrobial, local anaesthetic, antipsychotic, and anticancer drugs. In drug discovery, indeed, over the last few years, an increase in the publication of papers and patents about quinoline derivatives possessing antiproliferative properties has been observed. This trend can be justified by the versatility and accessibility of the quinoline scaffold, from which new derivatives can be easily designed and synthesized. Within the numerous quinoline small molecules developed as antiproliferative drugs, this review is focused on compounds effective on c-Met, VEGF (vascular endothelial growth factor), and EGF (epidermal growth factor) receptors, pivotal targets for the activation of important carcinogenic pathways (Ras/Raf/MEK and PI3K/AkT/mTOR). These signalling cascades are closely connected and regulate the survival processes in the cell, such as proliferation, apoptosis, differentiation, and angiogenesis. The antiproliferative biological data of remarkable quinoline compounds have been analysed, confirming the pivotal importance of this ring system in the efficacy of several approved drugs. Furthermore, in view of an SAR (structure-activity relationship) study, the most recurrent ligand–protein interactions of the reviewed molecules are summarized.

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Section: Quinolines As Inhibitors Of Carcinogenic Pathwaysmentioning

confidence: 99%

Section: Quinolines As Inhibitors Of Carcinogenic Pathwaysmentioning

confidence: 99%

Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

2020

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“…In 2015, Lv et al [81] synthesized novel 4-alkynyl-quinoline derivatives (232-234) as PI3K/mTOR dual inhibitors (PI3Kα IC 50 ~1.63-300nM) by modification of GSK2126458 (143). “To improve the water solubility and explore potential interactions with residues in the ribose pocket (e.g.…”

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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“…When the experiment began, test compounds were serially diluted to the desired concentrations and then 1 μL of each of them was added to a 384-well plate (Corning, New York, NY, USA) as assay plate [23]. Four microliters of PIP2:3PS lipid kinase substrate working solution was added to each well of the assay plate.…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of Novel Benzothiazole Derivatives as Selective PI3Kβ Inhibitors

Cao

Cao²,

Liu

et al. 2016

Molecules

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Abstract:A novel series of PI3Kβ (Phosphatidylinositol-3-kinases beta subunit) inhibitors with the structure of benzothiazole scaffold have been designed and synthesized. All the compounds have been evaluated for inhibitory activities against PI3Kα, β, γ, δ and mTOR (Mammalian target of rapamycin). Two superior compounds have been further evaluated for the IC 50 values against PI3Ks/mTOR. The most promising compound 11 displays excellent anti-proliferative activity and selectivity in multiple cancer cell lines, especially in the prostate cancer cell line. Docking studies indicate the morpholine group in 2-position of benzothiazole is necessary for the potent antitumor activity, which confirms our design is reasonable.

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Design, synthesis and biological evaluation of novel 4-alkynyl-quinoline derivatives as PI3K/mTOR dual inhibitors

Cited by 26 publications

References 26 publications

Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

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

Design, Synthesis and Biological Evaluation of Novel Benzothiazole Derivatives as Selective PI3Kβ Inhibitors

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