Synthesis and biological evaluation of N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amines and their pyrido and pyrazino analogues as Ser/Thr kinase inhibitors

Loidreau, Yvonnick; Marchand, Pascal; Dubouilh-Benard, Carole; Nourrisson, Marie-Renée; Duflos, Muriel; Lozach, Olivier; Loaëc, Nadège; Meijer, Laurent; Besson, Thierry

doi:10.1016/j.ejmech.2012.10.006

Cited by 51 publications

(39 citation statements)

References 43 publications

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“…Chemistry The structures of all tested compounds were confirmed by 1 H-NMR, 13 C-NMR and mass spectrometry (electron ionization (EI)-MS). The purities of the tested compounds were determined by elemental analysis.…”

Section: Methodsmentioning

confidence: 99%

“…12) Based on this, the pyridotheinopyrimidine scaffold reported by Loidreau et al as promising CK1 and CLK1 kinases inhibitors could be considered as one of the lead scaffolds that could be modified to provide novel EGFR inhibitors. 13) In a completion of our previous work on the pyridothieno [3,2-d] pyrimidine analogues that have been discovered as promising vascular endothelial growth factor receptor (VEGFR)-2 inhibitors, 14) we initiated this study with the aim of expanding the efficiency of the pyridothieno[3,2-d]-pyrimidine scaffold as ATP-competitive EGFR inhibitors. Our strategy is directed toward the design of a focused library of novel pyridothieno [3,2-d] pyrimidine analogues on the basis of 3 main modifications.…”

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confidence: 99%

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Discovery of Potent Antiproliferative Agents Targeting EGFR Tyrosine Kinase Based on the Pyrido[3′,2′:4,5]thieno[3,2-<i>d</i>]pyrimidin-4-amine Scaffold

Aziz

Said

Shihawy

et al. 2015

CHEMICAL & PHARMACEUTICAL BULLETIN

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A series of pyridothieno[3,2-d]pyrimidin-4-amines was designed and synthesized as congeners to the classical 4-anilinoquinazolines as ATP-competitive epidermal growth factor receptor (EGFR) inhibitors.Compound 5a exhibited the most potent and selective inhibitory activity against EGFR with an IC 50 value of 36.7 nM. Moreover, compounds 4b and 5a showed remarkable cell growth inhibition against leukemia, central nervous system cancer, and non-small cell lung cancer cell lines that overexpress EGFR, with growth inhibition of 50% (GI 50 ) values of around 10 nM in the full U.S. National Cancer Institute 60 cell panel assay. Cell cycle studies indicated that compounds 4b and 5a induced significant cell cycle arrest in the S-phase and G0/G1, respectively, in addition to boosting P27 kip expression. Compound 5a did not alter the viability of placental trophoblasts, which reflects its safety for normal cells. The standard COMPARE analyses demonstrated considerable correlation levels between compounds 4b and 5a and erlotinib, with pyridinium chlorochromate (PCC) values of 0.707 and 0.727, respectively. Key words pyridothieno[3,2-d]pyrimidine; epidermal growth factor receptor (EGFR); inhibitorThe epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase (RTK) that plays a vital role in signaling pathways that regulate cellular growth, proliferation and survival.1) Such signaling pathways are triggered by a tightly regulated protein phosphorylation reaction. This reaction is initiated with the binding of the epidermal growth factor (EGF) to the extracellular domain of EGFR leading to the activation of its intrinsic kinase domain. The latter has the ability to activate proteins by removing phosphate groups from ATP and covalently binding them to tyrosine substrates of the proteins.2) Deregulation of this controlled pathway, through overexpression and/or mutation of EGFR, contributes to the malignant transformations of normal cells. Overexpression of EGFR has been observed in a large number of human cancers including breast, prostate, ovarian, colorectal, kidney, brain and non-small cell lung cancers. 3,4)Examples of clinically approved ATP-competitive EGFR inhibitors including gefitinib, lapatinib and erlotinib, are structurally based on a central 4-anilinoquinazoline scaffold 5) (Fig. 1). However the emerging resistance of cancer cells to current medicines derives our passion to search for novel congeners to the 4-anilinoquinazoline scaffold as a beached for cancer therapy.6,7) Structure-activity relationship studies of 4-anilinoquinazolinederivatives revealed that the quinazoline core fits into the ATP-competitive pocket of EGFR. 8,9) Consistent with this, some investigations showed that the isosteric replacement of the benzene ring of the quinazoline core with five-membered heteroaromatic rings is favorable.10,11) The flexibility of the linking NH group between the heteroaryl core and the aniline ring permits the proper orientation of the aniline ring into the hydrophobic pocket, lying in the b...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Discovery of Potent Antiproliferative Agents Targeting EGFR Tyrosine Kinase Based on the Pyrido[3′,2′:4,5]thieno[3,2-<i>d</i>]pyrimidin-4-amine Scaffold

Aziz

Said

Shihawy

et al. 2015

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…N- (3,pyrido [3 ,2 :4,5]thieno [3,2-d]pyrimidin-4-amine was synthesized as previously described by Loidreau et al [4]. Colourless crystals of title compound suitable for X-ray analysis were obtained by slow evaporation from a dichloromethane-methanol solution 4 : 1 (v/v) at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…Following our search for such Ser/Thr kinases inhibitors of potential therapeutic interest, we previously identified a series of novel N-arylbenzo [b]thieno [3,2-d]pyrimidin-4-amines, synthesized via a Dimroth rearrangement [4,5].…”

Section: Introductionmentioning

confidence: 99%

Structure of N-(3,4-Dimethoxyphenyl)pyrido[3′,2′:4,5]-thieno[3,2-d]pyrimidin-4-amine, a New Inhibitor of CLK1 and DYRK1A Kinases

Guillon

Marchivie

Loidreau

et al. 2013

Journal of Crystallography

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The complete crystal structure of N- (3,4-dimethoxyphenyl)pyrido [3 ,2 :4,5]thieno[3,2-d]pyrimidin-4-amine, synthesized via a Dimroth rearrangement and designed as new inhibitor of CLK1 and DYRK1A kinases, was established by a single-crystal X-ray diffraction. The crystal is orthorhombic, space group Pca2 1 ; = 13.1593 (9), = 13.9823 (10), = 8.5403 (7)Å, = = = 90 ∘ , = 1571.4 (2)Å 3 , and = 4, C 17 H 14 N 4 O 2 S. Solid-state data could be used to enlighten the biological mechanism of action.

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“…图式 2 以烯胺腈为原料合成 4-苯胺基取代嘧啶 Scheme 2 Synthesis of 4-anilino substituted pyrimidine using cyanoenamine as raw material 通过以上方法, 可以得到很多具有生物活性的杂环并嘧啶类化合物, 如吡唑并嘧啶 [5] 、吡咯并嘧啶 [6] 、三唑并嘧啶 [7] 、苯(吡啶、吡嗪)并噻吩并嘧啶 [8] 、苯并呋喃(噻吩)并嘧啶 [9] 、吡啶并呋喃并嘧啶 [10,11] 、呋喃(噻吩)并嘧啶 [12] 等, 其结构如图 2 所示. …”

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Synthesis and Anticancer Activities of Novel Pyranocoumarin Fused Pyrimidine Based on Cyanoenamine

Huang¹,

Liu²

2018

Chin. J. Org. Chem.

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Synthesis and biological evaluation of N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amines and their pyrido and pyrazino analogues as Ser/Thr kinase inhibitors

Cited by 51 publications

References 43 publications

Discovery of Potent Antiproliferative Agents Targeting EGFR Tyrosine Kinase Based on the Pyrido[3′,2′:4,5]thieno[3,2-<i>d</i>]pyrimidin-4-amine Scaffold

Discovery of Potent Antiproliferative Agents Targeting EGFR Tyrosine Kinase Based on the Pyrido[3′,2′:4,5]thieno[3,2-<i>d</i>]pyrimidin-4-amine Scaffold

Structure of N-(3,4-Dimethoxyphenyl)pyrido[3′,2′:4,5]-thieno[3,2-d]pyrimidin-4-amine, a New Inhibitor of CLK1 and DYRK1A Kinases

Synthesis and Anticancer Activities of Novel Pyranocoumarin Fused Pyrimidine Based on Cyanoenamine

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