Synthesis and evaluation of the NSCLC anti-cancer activity and physical properties of 4-aryl- N -phenylpyrimidin-2-amines

Toviwek, Borvornwat; Suphakun, Praphasri; Choowongkomon, Kiattawee; Hannongbua, Supa; Gleeson, M. Paul

doi:10.1016/j.bmcl.2017.08.063

Cited by 11 publications

(10 citation statements)

References 46 publications

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“…The solubility of the compounds under investigation here were assessed in phosphate buffer at pH 7.4 using the equilibrium shake-flask method [27]. The quinazoline analogues displayed solubility ranging from 0.01 to 1.02 mg/mL.…”

Section: Resultsmentioning

confidence: 99%

“…The concentration of sample dissolved in the PBS solution was determined by comparing the peak area of the PBS and DMSO standard using an Agilent 1100 series HPLC with a Sunshell C8 column (Chromanik Technologies Inc., Osaka, Japan). A 100 µL injection of the aqueous sample and 5 µL of DMSO solution (pre-diluted 100 fold using DMSO) were used [27].…”

Section: Methodsmentioning

confidence: 99%

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Elucidation of Vasodilation Response and Structure Activity Relationships of N2,N4-Disubstituted Quinazoline 2,4-Diamines in a Rat Pulmonary Artery Model

et al. 2019

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Pulmonary arterial hypertension (PAH) is a rare and progressive disease arising from various etiologies and pathogenesis. PAH decreases life expectancy due to pulmonary vascular remodeling, elevation of mean pulmonary arterial pressure, and ultimately progresses to heart failure. While clinical treatments are available to reduce the associated symptoms, a complete cure has yet to be found. Phosphodiesterase-5 (PDE-5) inhibition has been identified as a possible intervention point in PAH treatment. The functional vasodilation response to N2,N4-diamino quinazoline analogues with differing PDE-5 inhibitory activities and varying physicochemical properties were assessed in both endothelium-intact and denuded rat pulmonary arteries to gain greater insight into their mode of action. All analogues produced vasorelaxant effects with EC50s ranging from 0.58 ± 0.22 µM to ˃30 µM. It was observed that vasodilation response in intact vessels was highly correlated with that of denuded vessels. The ~10% drop in activity is consistent with a loss of the nitric oxide mediated cyclic guanosine monophosphate (NO/cGMP) pathway in the latter case. A moderate correlation between the vasodilation response and PDE-5 inhibitory activity in the intact vessels was observed. Experimental protocol using the alpha-adrenergic (α1) receptor agonist, phenylephrine (PE), was undertaken to assess whether quinazoline derivatives showed competitive behavior similar to the α1 receptor blocker, prazosin, itself a quinazoline derivative, or to the PDE-5 inhibitor, sildenafil. Competitive experiments with the α1-adrenergic receptor agonist point to quinazoline derivatives under investigation here act via PDE-5 inhibition and not the former. The pre-incubation of pulmonary arterial rings with quinazoline test compounds (10 μM) reduced the contractile response to PE around 40–60%. The most promising compound (9) possessed ~32 folds higher selectivity in terms of vasodilation to its mammalian A549 cell cytotoxicity. This study provides experi0 0mental basis for PDE-5 inhibition as the mode of action for vasodilation by N2,N4-diamino quinazoline analogues along with their safety studies that may be beneficial in the treatment of various cardiovascular pathologies.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Elucidation of Vasodilation Response and Structure Activity Relationships of N2,N4-Disubstituted Quinazoline 2,4-Diamines in a Rat Pulmonary Artery Model

et al. 2019

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“…13f is a new synthetic 3-[(4-phenylpyrimidin-2-yl) amino] benzene-1-sulfonamide and was prepared by us as described previous report (Toviwek et al, 2017). This study aims to confirm 13f as a new EGFR inhibitor using EGFR-kinase inhibiting assay.…”

Section: F As a New Inhibitor Of Egfrmentioning

confidence: 93%

“…This present study was undertaken following earlier hit to lead studies of our group which saw the preparation and antiproliferation assessment of 20 4-aryl-N-phenylpyrimidin-2-amines (Toviwek et al, 2017). The anti-proliferation activity of the set was assessed in the EGFR-overexpressing A549 cell-line leading to the identification of 13f as a sub-micromolar inhibitor with good physico-chemical properties.…”

Section: Research Articlementioning

confidence: 99%

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The Effect of the EGFR - Targeting Compound 3-[(4-Phenylpyrimidin-2-yl) Amino] Benzene-1-Sulfonamide (13f) against Cholangiocarcinoma Cell Lines

Samatiwat

Tabtimmai

Suphakun

et al. 2021

Asian Pac J Cancer Prev

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Preparation, biological & cheminformatics-based assessment of N2,N4-diphenylpyrimidine-2,4-diamine as potential Kinase-targeted antimalarials

Toviwek

Phuangsawai

Konsue

et al. 2021

Bioorganic & Medicinal Chemistry

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Synthesis and evaluation of the NSCLC anti-cancer activity and physical properties of 4-aryl- N -phenylpyrimidin-2-amines

Cited by 11 publications

References 46 publications

Elucidation of Vasodilation Response and Structure Activity Relationships of N2,N4-Disubstituted Quinazoline 2,4-Diamines in a Rat Pulmonary Artery Model

Elucidation of Vasodilation Response and Structure Activity Relationships of N2,N4-Disubstituted Quinazoline 2,4-Diamines in a Rat Pulmonary Artery Model

The Effect of the EGFR - Targeting Compound 3-[(4-Phenylpyrimidin-2-yl) Amino] Benzene-1-Sulfonamide (13f) against Cholangiocarcinoma Cell Lines

Preparation, biological & cheminformatics-based assessment of N2,N4-diphenylpyrimidine-2,4-diamine as potential Kinase-targeted antimalarials

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