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1.
Bioorg Med Chem ; 99: 117608, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38271867

RESUMO

Tropomyosin receptor kinases (TRKs), the superfamily of transmembrane receptor tyrosine kinases, have recently become an attractive method for precision anticancer therapies since the approval of Larotrectinib and Entrectinib by FDA. Herein, we reported the discovery of a series of novel indazolylaminoquinazoline and indazolylaminoindazole as TRK inhibitors. The representative compound 30f exhibited good inhibitory activity against TRKWT, TRKG595R and TRKG667C with IC50 values of 0.55 nM, 25.1 nM and 5.4 nM, respectively. The compound also demonstrated potent superior to Larotrectinib antiproliferative activity against a panel of Ba/F3 cell lines transformed with both NTRK wild type and mutant fusions (IC50 = 10-200 nM). In addition, compound 30f exhibited good in vitro metabolic stability (T1/2 = 73.0 min), indicating that the quinazoline derivatives may have better metabolic stability. Finally, the binding mode of compound 30f predicted by molecular docking well explained the good enzyme inhibitory activity of indazolylaminoquinazoline compounds as TRK inhibitor. Thus, compound 30f can be used as a promising lead molecule for further structural optimization.


Assuntos
Neoplasias , Humanos , Tropomiosina , Simulação de Acoplamento Molecular , Receptores Proteína Tirosina Quinases , Inibidores de Proteínas Quinases/farmacologia
2.
Bioorg Med Chem Lett ; 89: 129309, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37127101

RESUMO

Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) often loses effectiveness against non-small cell lung malignancies (NSCLCs) with ALK gene rearrangements (ALK+). 19 novel imidazo[1,2-b]pyridazine macrocyclic derivatives were designed, synthesized, and tested for their biological activities in an effort to develop ALK inhibitors that would overcome second-generation ALK-TKIs, particularly the G1202R mutation and the lorlatinib-resistant L1196M/G1202R double mutations. Of all the target substances, O-10 had the most effective enzymatic inhibitory activity, with IC50 values for ALKWT, ALKG1202R, and ALKL1196M/G1202R of 2.6, 6.4, and 23 nM, respectively. O-10, on the other hand, reduced the growth of ALK-positive Karpas299, BaF3-EML4-ALKG1202R, and BaF3-EML4-ALKL1196M/G1202R cells with IC50 values of 38, 52, and 64 nM, respectively. This was equally effective to the reference drug Repotrectinib (IC50 = 40, 164, and 208 nM). The kinase selectivity profile, liver microsome stability test and in vivo pharmacokinetic properties in SD rats of compound O-10 were further evaluated. O-10 was regarded as an effective ALK inhibitor for the treatment of mutations overall.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Ratos , Animais , Quinase do Linfoma Anaplásico , Resistencia a Medicamentos Antineoplásicos , Ratos Sprague-Dawley , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Mutação , Lactamas Macrocíclicas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico
3.
Environ Sci Pollut Res Int ; 26(28): 29449-29459, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31401799

RESUMO

Illite/iron nanoparticles (I-nZVI) with different iron contents were synthesized using a liquid-phase reduction method to remove Pb(II) from aqueous solution. The adsorbents were characterized by Lorentz transmission electron microscopy (L-TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and the BET-N2 technique. The composite adsorbents and illite removed Pb(II) from aqueous solution to explore the effect of different reaction conditions, including contact time, concentration, pH, and temperature. The results of batch experiments demonstrated that the removal efficiency mainly depends on the amount of nanoscale zerovalent iron. Under different conditions, the order of the removal efficiency was 30% I-nZVI > 20% I-nZVI > 10% I-nZVI > illite. Reactions between Fe(0) and Pb(II) took place on the surface of the absorbents, and the removal of Pb(II) was based on adsorption and reductive reactions. The adsorption of lead ions by I-nZVI and pure illite conformed to the pseudo-second-order reaction kinetic model, and intraparticle diffusion may not play a remarkable role in removing Pb(II). The adsorption of Pb(II) by 30% I-nZVI, 20% I-nZVI, 10% I-nZVI, and illite was more in line with the Langmuir adsorption model. Thermodynamic studies indicated that the Pb(II) removal process is endothermic in nature, which is in agreement with the experimental results. The high removal efficiency helps to achieve the goal of remediation.


Assuntos
Íons/química , Ferro/química , Chumbo/química , Minerais/química , Nanopartículas/química , Poluentes Químicos da Água/análise , Adsorção , Cinética , Microscopia Eletrônica de Transmissão , Termodinâmica , Difração de Raios X
4.
J Pharm Anal ; 1(1): 8-12, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29403675

RESUMO

A simple, rapid and sensitive liquid chromatography-mass spectrometry (LC-MS) method was developed for the determination of salidroside in rat plasma and study of its pharmacokinetics after oral administration of suspension of Erzhi Wan and Fructus Ligustri lucidi into Wistar rats. Plasma sample of 200 µL was extracted with acetic ether-isopropanol (2:1) and the extraction was performed on a Kromasil C18 column (150 mm × 4. 6 mm, 5 µm) with the mobile phase of methanol-water (41:59, v/v) within a run time of 6.0 min. The analyte was monitored with positive electrospray ionization (ESI) by selected ion monitoring (SIM) mode. The target ions were m/z 323.05 for salidroside and m/z 411.05 for internal Standard (IS) geniposide. A good linear relationship was obtained over the range of 5.0-500.0 ng/mL and the lower limit of quantification was 5.0 ng/mL. The validated method was successfully applied to the pharmacokinetic study of salidroside in rat plasma after oral administration of suspension of Erzhi Wan and Fructus Ligustri lucidi.

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