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根据骨架迁跃原理,设计并合成了一系列具有酪氨酸激酶抑制剂拉帕替尼(Lapatinib)和诺拉替尼(Neratinib)结构片段的水杨酰芳胺类化合物,其结构均经IR,1H NMR,13C NMR和MS确证.采用四甲基偶氮唑盐(MTT)法考察所合成化合物的体外抗肿瘤细胞(A549,MCF-7,SGC-7901,Bel-7402)活性.结果表明,所合成的化合物对4种肿瘤细胞增殖均有一定的抑制活性,部分化合物的活性强于阳性对照药吉非替尼(Gefitinib). 相似文献
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采用共价键法将表皮生长因子受体固定在毛细管内壁,制备了一种毛细管电泳酶微反应器。结合毛细管电泳高效分离技术,以三磷酸腺苷为底物,吉非替尼为抑制剂,利用表皮生长因子受体酶微反应器在线测定了吉非替尼对皮生长因子受体的抑制性能。结果显示,吉非替尼可竞争性的抑制三磷酸腺苷与表皮生长因子受体的结合,从而影响三磷酸腺苷与表皮生长因子受体的结合量以及产物二磷酸腺苷的生成量。根据不同浓度吉非替尼下三磷酸腺苷峰面积的变化计算了吉非替尼对表皮生长因子受体的抑制率。同时绘制了抑制曲线,得到IC50值为32.44±0.82μmol/L。实验表明该酶微反应器可实际用于酪氨酸激酶抑制剂的抑制率的快速测定。 相似文献
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利用气相色谱-质谱法在电子电离源下对用于治疗肺癌的药物泰瑞沙(Tagrisso)进行分析,对主成分奥斯替尼(Osimertinib)在质谱中产生的主要的碎片离子进行归属,推测其可能的质谱裂解途径。参考主成分奥斯替尼的质谱裂解方式,由质谱裂解机理的角度出发对该药物中的4个未知的关键杂质的结构进行有效解析。此外,发现奥斯替尼及其个别杂质在质谱裂解过程中出现了显著的违背偶电子规则的碎片离子。通过对药物泰瑞沙的质谱分析期望能够提供一些分析、解析药物中未知杂质的思路和方法。 相似文献
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《理化检验(化学分册)》2019,(11)
<正>甲磺酸伊马替尼是一种小分子酪氨酸激酶抑制剂,该药在2001年获得美国食品药品监督管理局的认证,被批准在美国用于治疗干扰素治疗失败的慢性粒细胞性白血病。甲磺酸伊马替尼还被美国食品药品监督管理局、欧盟专利药品评审委员会批准用于胃肠道间质肿瘤的治疗[1-2]。甲磺酸伊马替尼合成过程中用到的甲醇、乙醇,可能在成盐时与甲磺酸 相似文献
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The well-known proto-oncogene rearrangement during transfection (RET), also known as ret proto-oncogene Homo sapiens (human), is a rare gene that is involved in the physiological development of some organ systems and can activate various cancers, such as non-small cell lung cancer, thyroid cancer, and papillary thyroid cancer. In the past few years, cancers with RET alterations have been treated with multikinase inhibitors (MKIs). However, because of off-target effects, these MKIs have developed drug resistance and some unacceptable adverse effects. Therefore, these MKIs are limited in their clinical application. Thus, the novel highly potent and RET-specific inhibitors selpercatinib and pralsetinib have been accelerated for approval by the Food and Drug Administration (FDA), and clinical trials of TPX-0046 and zetletinib are underway. It is well tolerated and a potential therapeutic for RET-altered cancers. Thus, we will focus on current state-of-the-art therapeutics with these novel RET inhibitors and show their efficacy and safety in therapy. 相似文献
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Rearranged during transfection (RET) is an oncogenic driver receptor that is overexpressed in several cancer types, including non-small cell lung cancer. To date, only multiple kinase inhibitors are widely used to treat RET-positive cancer patients. These inhibitors exhibit high toxicity, less efficacy, and specificity against RET. The development of drug-resistant mutations in RET protein further deteriorates this situation. Hence, in the present study, we aimed to design novel drug-like compounds using a fragment-based drug designing strategy to overcome these issues. About 18 known inhibitors from diverse chemical classes were fragmented and bred to form novel compounds against RET proteins. The inhibitory activity of the resultant 115 hybrid molecules was evaluated using molecular docking and RF-Score analysis. The binding free energy and chemical reactivity of the compounds were computed using MM-GBSA and density functional theory analysis, respectively. The results from our study revealed that the developed hybrid molecules except for LF21 and LF27 showed higher reactivity and stability than Pralsetinib. Ultimately, the process resulted in three hybrid molecules namely LF1, LF2, and LF88 having potent inhibitory activity against RET proteins. The scrutinized molecules were then subjected to molecular dynamics simulation for 200 ns and MM-PBSA analysis to eliminate a false positive design. The results from our analysis hypothesized that the designed compounds exhibited significant inhibitory activity against multiple RET variants. Thus, these could be considered as potential leads for further experimental studies. 相似文献
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本研究的目的是分析声速匹配技术对甲状腺癌的诊断价值。选取了159例甲状腺病变患者设为甲状腺病变组,健康志愿者40例设为甲状腺正常组,行声速匹配技术检查,分析特征并对比ZSI值,评估了声速匹配技术对甲状腺癌的诊断价值。结果显示,甲状腺癌组ZSI值较高(P<0.05)。ZSI值预测甲状腺癌的ROC曲线下面积(AUC)为0.867(0.729~1.004),灵敏度为86.67%,特异度为60.00%,似然比为2.167,ZSI值临界值为50.42 m/s。预后不良组甲状腺癌患者ZSI值高于预后良好组(P<0.05)。由本文结果可知声速匹配技术对不同类型甲状腺癌的诊断准确性均较高,可准确测出患者甲状腺声速值,稳定性良好,可用于临床甲状腺癌的诊断和预后预测。 相似文献
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Fragment‐Based Discovery of a Dual pan‐RET/VEGFR2 Kinase Inhibitor Optimized for Single‐Agent Polypharmacology
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Brendan Frett Francesca Carlomagno Maria Luisa Moccia Annalisa Brescia Giorgia Federico Valentina De Falco Brittany Admire Zhongzhu Chen Wenqing Qi Massimo Santoro Hong‐yu Li 《Angewandte Chemie (International ed. in English)》2015,54(30):8717-8721
Oncogenic conversion of the RET (rearranged during transfection) tyrosine kinase is associated with several cancers. A fragment‐based chemical screen led to the identification of a novel RET inhibitor, Pz‐1. Modeling and kinetic analysis identified Pz‐1 as a type II tyrosine kinase inhibitor that is able to bind the “DFG‐out” conformation of the kinase. Importantly, from a single‐agent polypharmacology standpoint, Pz‐1 was shown to be active on VEGFR2, which can block the blood supply required for RET‐stimulated growth. In cell‐based assays, 1.0 nM of Pz‐1 strongly inhibited phosphorylation of all tested RET oncoproteins. At 1.0 mg kg?1 day?1 per os, Pz‐1 abrogated the formation of tumors induced by RET‐mutant fibroblasts and blocked the phosphorylation of both RET and VEGFR2 in tumor tissue. Pz‐1 featured no detectable toxicity at concentrations of up to 100.0 mg kg?1, which indicates a large therapeutic window. This study validates the effectiveness and usefulness of a medicinal chemistry/polypharmacology approach to obtain an inhibitor capable of targeting multiple oncogenic pathways. 相似文献
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Elisa Alvarez-Curto John D. Pediani Graeme Milligan 《Analytical and bioanalytical chemistry》2010,398(1):167-180
The role of G protein coupled receptors (GPCRs) in numerous physiological processes that may be disrupted or modified in disease
makes them key targets for the development of new therapeutic medicines. A wide variety of resonance energy transfer (RET)
techniques such as fluorescence RET and bioluminescence RET have been developed in recent years to detect protein–protein
interactions in living cells. Furthermore, these techniques are now being exploited to screen for novel compounds that activate
or block GPCRs and to search for new, previously undiscovered signaling pathways activated by well-known pharmacologically
classified drugs. The high resolution that can be achieved with these RET methods means that they are well suited to study
both intramolecular conformational changes in response to ligand binding at the receptor level and intermolecular interactions
involving protein translocation in subcellular compartments resulting from external stimuli. In this review we highlight the
latest advances in these technologies to illustrate general principles. 相似文献
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Hai-Yan Zhang Zhen-Xian Du Bao-Qin Liu Yan-Yan Gao Xin Meng Yifu Guan Wei-Wei Deng Hua-Qin Wang 《Experimental & molecular medicine》2009,41(5):362-369
TNF-related apoptosis-inducing ligand (TRAIL) has been proposed as a promising cancer therapy that preferentially induces apoptosis in cancer cells, but not most normal tissues. However, many cancers are resistant to TRAIL by mechanisms that are poorly understood. In this study, we showed that tunicamycin, a naturally occurring antibiotic, was a potent enhancer of TRAIL-induced apoptosis through downregulation of survivin. The tunicamycin-mediated sensitization to TRAIL was efficiently reduced by forced expression of survivin, suggesting that the sensitization was mediated at least in part through inhibition of survivin expression. Tunicamycin also repressed expression of cyclin D1, a cell cycle regulator commonly overexpressed in thyroid carcinoma. Furthermore, silencing cyclin D1 by RNA interference reduced survivin expression and sensitized thyroid cancer cells to TRAIL; in contrast, forced expression of cyclin D1 attenuated tunicamycin-potentiated TRAIL-induced apoptosis via over-riding downregulation of survivin. Collectively, our results demonstrated that tunicamycin promoted TRAIL-induced apoptosis, at least in part, by inhibiting the expression of cyclin D1 and subsequent survivin. Of note, tunicamycin did not sensitize the differentiated thyroid epithelial cells to TRAIL-induced apoptosis. Thus, combined treatment with tunicamycin and TRAIL may offer an attractive strategy for safely treating resistant thyroid cancers. 相似文献
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Recent experiments on resonance energy transfer (RET) in photosynthetic systems have found evidence of quantum coherence between the donor and the acceptor. Under these conditions, Fo?rster's theory of RET is no longer applicable and no theory of coherent RET advanced to date rivals the intuitive simplicity of Fo?rster's theory. Here, we develop a framework for understanding RET that is based on classical electrodynamics but still captures the essence of the quantum coherence between the molecules. Our theory requires only a knowledge of the complex polarizabilities of the two molecules participating in the transfer as well as the distance between them. We compare our results to quantum mechanical calculations and show that the results agree quantitatively. 相似文献
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The rotational energy transfer (RET) by Ar collisions within the SH X?(2)Π (v' = 0, J' = 0.5-10.5) state is characterized. The integral cross sections as a function of collision energy for each rotational transition are calculated using a quantum scattering method in which the constructed potential energy functions are based on a ground state potential energy surface (PES) reported previously. On the other hand, a laser-induced excitation fluorescence technique is employed to monitor the relaxation of the rotational population as a function of photolysis-probe delay time following the photodissociation of H(2)S at 248 nm. The rotational population evolution is comparable to its theoretical counterpart based on calculated Λ-resolved RET rate constants. The propensity in Λ-resolved RET transitions is found to approximately resemble the case of OH(X?(2)Π, v' = 0) + Ar. The Λ-averaged RET collisions are also analyzed and result in several propensity rules in the transitions. Most propensity rules are similar to those observed in the collisions of SH(A?(2)Σ(+)) by Ar. However, the behavior of the conserving ratio, defined as rate constants for spin-orbit conserving transition divided by those for spin-orbit changing transition, shows distinct difference from those described by Hund's case (b). 相似文献
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Sissa C Manna AK Terenziani F Painelli A Pati SK 《Physical chemistry chemical physics : PCCP》2011,13(28):12734-12744
Resonance Energy Transfer (RET) is investigated in pairs of charge-transfer (CT) chromophores. CT chromophores are an interesting class of π conjugated chromophores decorated with one or more electron-donor and acceptor groups in polar (D-π-A), quadrupolar (D-π-A-π-D or A-π-D-π-A) or octupolar (D(-π-A)(3) or A(-π-D)(3)) structures. Essential-state models accurately describe low-energy linear and nonlinear spectra of CT-chromophores and proved very useful to describe spectroscopic effects of electrostatic interchromophore interactions in multichromophoric assemblies. Here we apply the same approach to describe RET between CT-chromophores. The results are quantitatively validated by an extensive comparison with time-dependent density functional theory (TDDFT) calculations, confirming that essential-state models offer a simple and reliable approach for the calculation of electrostatic interchromophore interactions. This is an important result since it sets the basis for more refined treatments of RET: essential-state models are in fact easily extended to account for molecular vibrations in truly non-adiabatic approaches and to account for inhomogeneous broadening effects due to polar solvation. Optically forbidden (dark) states of quadrupolar and octupolar chromophores offer an interesting opportunity to verify the reliability of the dipolar approximation. In striking contrast with the dipolar approximation that strictly forbids RET towards or from dark states, our results demonstrate that dark states can take an active role in RET with interaction energies that, depending on the relative orientation of the chromophores, can be even larger than those relevant to allowed states. Essential-state models, whose predictions are quantitatively confirmed by TDDFT results, allow us to relate RET interaction energies towards allowed and dark states to the supramolecular symmetry of the RET-pair, offering reliable design strategies to optimize RET-interactions. 相似文献
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State-to-state rotational energy transfer (RET) rate coefficients for NO (A 2Sigma+, v'=0, J=5.5, 11.5, 17.5) were measured for N2 and O2 at room temperature using a pump-probe method. The NO A 2Sigma+ state is prepared by 226 nm light and the RET is monitored by fluorescence from the D 2Sigma+ v'=0 state, following excitation by a time-delayed laser at approximately 1.1 microm. Additionally, total collisional removal and final state distributions were measured exciting in the Q1+P21 band head, to simulate an NO laser-induced fluorescence atmospheric monitoring scheme. Time-resolved modeling is used to understand relaxation mechanisms and predict relaxation times in ambient air. H2O at atmospherically relevant concentrations does not affect the degree of RET in ambient air. 相似文献