Objective:To study the anti-ovarian cancer effect and mechanism of Quinazoline derivative(N111)in vitro;Method:Using an online database to predict the therapeutic targets of N111 for ovarian cancer,and conducting biol...Objective:To study the anti-ovarian cancer effect and mechanism of Quinazoline derivative(N111)in vitro;Method:Using an online database to predict the therapeutic targets of N111 for ovarian cancer,and conducting biological functional analysis of the therapeutic targets.The experiment was divided into N111 treatment group(N111 compound group),positive control group(cisplatin group),and negative control group(DMSO group);After grouping,MTT assay was used to detect cell proliferation;Morphological observation was used to observe changes in cell morphology;JC-1 and DCFH-DA probes were used to detect the changes of mitochondrial Membrane potential and intracellular reactive oxygen species;PI,Annexin V-FITC,and DAPI staining were used to detect cell cycle arrest and apoptosis;Clone formation experiments and scratch tests were conducted to detect the cell's ability to form clones and migrate;Western blot method was used to detect the expression level of related proteins.Result:The biological function research results show that the biological function of N111 anti ovarian cancer target protein suggests that the target function aggregates human diseases,inflammation,tumors,and other aspects.Compared with the control group,N111 has a significant inhibitory effect on the proliferation of ovarian cancer cells(IC50=14.62 mmol/L)(P<0.0001);In a concentration dependent manner,it inhibited the formation and migration of single cell colonies,and induced the disorder of mitochondrial Membrane potential,ROS and cell cycle arrest in S phase(P<0.0001);As the concentration of N111 treatment increased,the expression levels of Bcl2,Caspase 3,P-AKT,and SHIP2 decreased,while the expression levels of AKT remained unchanged.The expression levels of Bax and Cleared Caspase 3 increased(P<0.0001).Conclusion:Compound N111 inhibits SHIP2,promotes ROS level disorder,weakens the activation of AKT signaling pathway,and thus inhibits the proliferation,migration,and clone formation of tumor cell A2780,inducing cell apoptosis.展开更多
A three-dimensional quantitative structure-activity relationship （3D-QSAR） study of a series of 7,8-dialkyl-l,3-diaminopyrrolo-[3,2-f] quinazolines with anticancer activity as dihydrofo- late reductase （DHFR） inhi...A three-dimensional quantitative structure-activity relationship （3D-QSAR） study of a series of 7,8-dialkyl-l,3-diaminopyrrolo-[3,2-f] quinazolines with anticancer activity as dihydrofo- late reductase （DHFR） inhibitors was carried out by using the comparative molecular field analysis （CoMFA）, on the basis of our reported 2D-QSAR of these compounds. The es- tablished 3D-QSAR model has good quality of statistics and good prediction ability; the non cross-validation correlation coefficient and the cross-validation value of this model are 0.993 and 0.619, respectively, the F value is 193.4, and the standard deviation SD is 0.208. This model indicates that the steric field factor plays a much more important role than the electrostatic one, in satisfying agreement with the published 2D-QSAR model. However, the 3D-QSAR model offers visual images of the steric field and the electrostatic field. The 3D-QSAR study further suggests the following： to improve the activity, the substituent R^1 should be selected to be a group with an adaptive bulk like Et or i-Pr, and the substituent R should be selected to be a larger alkyl. In particular, based on our present 3D-QSAR as well as the published 2D-QSAR, the experimentMly-proposed hydrophobic binding mechanism on the receptor-binding site of the DHFR can be further explained in theory. Therefore, the QSAR studies help to further understand the ＂hydrophobic binding＂ action mechanism of this kind of compounds, and to direct the molecular design of new drugs with higher activity.展开更多
Quinazoline derivatives were synthesized fromα-iminoesters via a cascade imino-Diels-Alder and then oxidation reaction catalyzed with CuBr_2.This method provided a new strategy for preparing quinazoline derivatives w...Quinazoline derivatives were synthesized fromα-iminoesters via a cascade imino-Diels-Alder and then oxidation reaction catalyzed with CuBr_2.This method provided a new strategy for preparing quinazoline derivatives which may be useful in the synthesis of heterocyclic intermediates.展开更多
Objective: To synthesize inhibitors of the epidermal growth factor receptor tyrosine kinase such as 6-nitro-4-anilinoquinazolines and 6-amino-4-anilinoquinazolines,and to compare their anticancer effects in vitro. Met...Objective: To synthesize inhibitors of the epidermal growth factor receptor tyrosine kinase such as 6-nitro-4-anilinoquinazolines and 6-amino-4-anilinoquinazolines,and to compare their anticancer effects in vitro. Methods: The 4-anilinoquinazolines compounds were prepared by hydrolyzed, ringed, halagenated, substituded in turn from 2-amino-5-nitrobenzylcarbonitril. The synthesized 4- anilinoquinazoline compounds has been rudimentarily screened by using A431 tumor cell line which overexpresses epidermal growth factor receptor as model adopted MTT method. Results: Five 6-nitro-4-halo-sbstituted anilinoquinazolines and five 6-amino-4-halo-substituted anilinoquinazolines have been obtained,and all of them had anticancer activity. The anticancer activity of 6-amino substituted inhibitors was higher than that of 6-nitro substituted inhibitors. However, the difference of anticancer activity between two series of quinazoline was much less than that of their inhibiting EGFR tyrosine kinase activity. Conclusion: The probable reason for 6-nitro-4-anilinoquinazolines having anticancer activity in vitro was that they had been partially transformed to 6-amino-4-anilinoquinazolines through endocellular cytochrome oxidation-reduction system.展开更多
Objective: To prepare six quinazoline schiff bases by six steps of chemistry organic synthesis and test their inhibitory effect on hepatomacellular carcinoma cells HHCC and mammary cancer cell Bcap-37, furthmore,to co...Objective: To prepare six quinazoline schiff bases by six steps of chemistry organic synthesis and test their inhibitory effect on hepatomacellular carcinoma cells HHCC and mammary cancer cell Bcap-37, furthmore,to compare their antitumor activities on these two kinds of cells. Methods: 2-Amino-5-nitro-benzylcarbonitrile was the initial material, and it was under the reaction of hydrolysis, ring-closing, halogenation, addition, reduction and substitution in turn to get the six quinazoline schiff bases, MTT method was adopted to compare their anticancer activities against the two cancer cells. Result and Conclusion: Six 6-imine-4-halo substituted anilinoquinozolines were prepared. The anticancer activities against both HHCC and Bcap-37were found, furthermore, they have more potency that on HHCC than on Bcap-37. In the six compounds, the schiff base Ⅵ is the most potent compound.展开更多
Two new quinazoline derivatives versicomides E(1)and F(2),and 10 known compounds(3-12)were isolated from the moss endophytic fungus Aspergillus sp.Their structures were determined on the basis of extensive spectroscop...Two new quinazoline derivatives versicomides E(1)and F(2),and 10 known compounds(3-12)were isolated from the moss endophytic fungus Aspergillus sp.Their structures were determined on the basis of extensive spectroscopic data analysis and ECD calculations.Among them,the compound 7(6-hydroxy-3-methoxyviridicatin)was first reported as a natural product.Inhibition on LPS-induced NO production in RAW 264.7 murine macrophages found that compounds 5,7 and 8 showed significant inhibitory effects on NO production,with IC50 values of 49.85,22.14 and 46.02μM respectively.展开更多
In silico pharmacokinetics studies can aid the search for molecules with potential ability to be drug candidates. In this paper, a number of quinazoline candidates for epidermal growth factor receptor inhibitors—EGFR...In silico pharmacokinetics studies can aid the search for molecules with potential ability to be drug candidates. In this paper, a number of quinazoline candidates for epidermal growth factor receptor inhibitors—EGFR, important targets for the treatment of cancer, are computationally analyzed. The literature described that 69 quinazoline molecules were synthesized and the respective half maximum inhibitory concentrations (IC50) were obtained. A bilinear parabolic model was built to investigate the druglikeness by correlating the corresponding lipophilicities, which can be represented by the ideal Log P , with the optimal biological activity in terms of pIC50 values. Structural characteristics leading to improved pharmacokinetics parameters were then analyzed. Compound 56 exhibited the lowest IC50 and, therefore, it had the highest ability to inhibit the EGFR. In the present work, the most potent inhibitor 56 is not calculated to be the most promising drug candidate, since it’s out of the parabolic model obtained due to a Log P above 5, which is not within the expected optimum range. Finally, this work is an example of computational prediction that an experimentally, highly active EGFR inhibitor can be unsuccessful as drug candidate because of pitfalls in pharmacokinetics parameters.展开更多
Glioblastoma,the most aggressive form of brain tumor,poses significant challenges in terms of treatment success and patient survival.Current treatment modalities for glioblastoma include radiation therapy,surgical int...Glioblastoma,the most aggressive form of brain tumor,poses significant challenges in terms of treatment success and patient survival.Current treatment modalities for glioblastoma include radiation therapy,surgical intervention,and chemotherapy.Unfortunately,the median survival rate remains dishearteningly low at 12–15 months.One of the major obstacles in treating glioblastoma is the recurrence of tumors,making chemotherapy the primary approach for secondary glioma patients.However,the efficacy of drugs is hampered by the presence of the blood-brain barrier and multidrug resistance mechanisms.Consequently,considerable research efforts have been directed toward understanding the underlying signaling pathways involved in glioma and developing targeted drugs.To tackle glioma,numerous studies have examined kinase-downstream signaling pathways such as RAS-RAF-MEKERK-MPAK.By targeting specific signaling pathways,heterocyclic compounds have demonstrated efficacy in glioma therapeutics.Additionally,key kinases including phosphatidylinositol 3-kinase(PI3K),serine/threonine kinase,cytoplasmic tyrosine kinase(CTK),receptor tyrosine kinase(RTK)and lipid kinase(LK)have been considered for investigation.These pathways play crucial roles in drug effectiveness in glioma treatment.Heterocyclic compounds,encompassing pyrimidine,thiazole,quinazoline,imidazole,indole,acridone,triazine,and other derivatives,have shown promising results in targeting these pathways.As part of this review,we propose exploring novel structures with low toxicity and high potency for glioma treatment.The development of these compounds should strive to overcome multidrug resistance mechanisms and efficiently penetrate the blood-brain barrier.By optimizing the chemical properties and designing compounds with enhanced drug-like characteristics,we can maximize their therapeutic value and minimize adverse effects.Considering the complex nature of glioblastoma,these novel structures should be rigorously tested and evaluated for their efficacy and safety profiles.展开更多
A series of novel 1,2,3-triazole-quinazoline derivatives were synthesized in five steps starting from anthranila- mide by conventional methods. All the title compounds 10a-10r were evaluated for cytotoxic activity aga...A series of novel 1,2,3-triazole-quinazoline derivatives were synthesized in five steps starting from anthranila- mide by conventional methods. All the title compounds 10a-10r were evaluated for cytotoxic activity against four human cancer cell lines （MGC-803, EC-109, MCF-7 and HGC-27） using MTT assay in vitro. Some of the synthe- sized compounds exhibited moderate to potent activity against tested cancer cell lines. Among them, compounds 10h and 10q exhibited excellent growth inhibition against HGC-27 and compound 10m also possessed excellent ac- tivity against MCF-7, with IC50 values less than 1 μmol/L. Especially, compound 10h was more cytotoxic than 5-fluorouracil against all tested four human cancer cell lines.展开更多
Achieving stable deep blue organic light emitting diodes(OLEDs)with narrow full width at half maximum(FWHM)and color gamut in the range of the commission International de L’Eclairage(CIE)ofy≤0.10 is still challengin...Achieving stable deep blue organic light emitting diodes(OLEDs)with narrow full width at half maximum(FWHM)and color gamut in the range of the commission International de L’Eclairage(CIE)ofy≤0.10 is still challenging in display and lighting applications.In this investigation,three donor-acceptor(D-A)deep-blue emitters were designed and synthesized via integrating asymmetric quinazoline(PQ)acceptor with weak donating carbazole(Cz)donor.The effect of the position and number of Cz group in PQunit are investigated,which is also first examples for syste matic research about the effect of different position of asymmetric PQ as acceptor on deep OLEDs.Their bandgaps of 3.12~3.19 eV and the singlet state energy levels of 3.12~3.19 eV were found to be sufficiently large to achieve deep blue light.As expected,these emitters-based OLEDs exhibit deep blue emission with the maximum wavelength≤450 nm and narrow FWHM≈60 nm.Especially,a CIE ofy=0.080 was achieved for 4 PQ-Cz-based OLED.Significantly,the deep blue electroluminescence(EL)spectra of these three emitters-based OLEDs are very stable and the corresponding CIE coordinates deviation(ΔCIE(x,y))can be negligible under the applied voltage ranging from 5 V to 9 V.展开更多
A novel 4-anilinoquinazoline dimer linked by a carbon-carbon bond in the C-7 position was synthesized via a one step Suzuki cross-coupling reaction. All structures of new compounds were characterized by ^1H NMR, ^13C ...A novel 4-anilinoquinazoline dimer linked by a carbon-carbon bond in the C-7 position was synthesized via a one step Suzuki cross-coupling reaction. All structures of new compounds were characterized by ^1H NMR, ^13C NMR, and HRMS. The inhibition rate of the synthetic 4-anilinoquinazoline dimer 8 against epidermal growth factor receptor-tyrosine kinase enzymes （EGFR） in vitro was 44.4% at the concentration of 5.5 μmol/L.展开更多
A novel type of quinazoline derivatives,which were designed by the combination of quinazoline as the back-bone and oxazole scaffold as the substituent,have been synthesized and their biological activities were evaluat...A novel type of quinazoline derivatives,which were designed by the combination of quinazoline as the back-bone and oxazole scaffold as the substituent,have been synthesized and their biological activities were evaluated for anti-proliferative activities and EGFR inhibitory potency.Compound 12b demonstrated the most potent inhibi-tory activity(IC_(50)=0.95μmol/L for EGFR),which could be optimized as a potential EGFR inhibitor in the further study.The structures of the synthesized quinazoline analogs and all intermediates were comfirmed by 1H and 13C NMR,2D NMR spectra,IR spectra and MS spectra.展开更多
A novel copper-catalyzed dual oxidative benzylic C–H aminations of methylarenes with 2-aminobenzoketones in the presence of ammonium acetate was developed. This reaction represents a new avenue for 2-arylquinazolines...A novel copper-catalyzed dual oxidative benzylic C–H aminations of methylarenes with 2-aminobenzoketones in the presence of ammonium acetate was developed. This reaction represents a new avenue for 2-arylquinazolines with good yields. A key intermediate was detected and the kinetics isotope effect（KIE） indicated that C–H bond cleavage was the rate-determining step.展开更多
The quantitative structure-activity relationship （QSAR） studies on a series of 7,8-dialkyl-1,3-diaminopyrrolo-[3,2-f]quinazolines, dihydrofolate reductase （DHFR） inhibitors as potential anticancer agents, have bee...The quantitative structure-activity relationship （QSAR） studies on a series of 7,8-dialkyl-1,3-diaminopyrrolo-[3,2-f]quinazolines, dihydrofolate reductase （DHFR） inhibitors as potential anticancer agents, have been carried out by using the density functional theory （DFT） method, molecular mechanics method （MM＋） and statistical method. Some QSAR models based on their lipophilic and steric parameters were built up via a stepwise regression analysis. It is very interesting to find that the established optimal QSAR equation involves only two descriptors： lipophilicity indexes Clog P and Clog P^2 However, such descriptors can quite well describe a significant statistic quality and have a remarkable predictive activity according to the square of adjusted correlation coefficient （RA^2 = 0.937） and the square of cross-validation coefficient （q^2=0.911） of this equation. The results show that the lipophilicity is a main factor affecting the anticancer activity of this series of antimetastatic agents, and the obtained equation describes a parabolic correlation between pIC50 and Clog P, and indicates a suitable range of Clog P （around 4.43） being very important for optimal pIC50 values. These QSAR studies can offer some useful references for understanding the action mechanism and performing the molecular design or modification of this series of antimetastatic agents.展开更多
[BMIM]Cl catalyzed three component Mannich-type reaction of 4-（quinazolin-4-yloxy）benzenamine and aldehyde with dialkyl phosphite under microwave irradiation has been described. The salient features of the reaction ...[BMIM]Cl catalyzed three component Mannich-type reaction of 4-（quinazolin-4-yloxy）benzenamine and aldehyde with dialkyl phosphite under microwave irradiation has been described. The salient features of the reaction leading to new a-aminophosphonates include shorter reaction time and good yields. The method is environmentally friendly and does not require toxic catalysts or solvents. To the best of our knowledge, this is the first report for [BMIM]Cl induced one-pot synthesis of a-aminophosphonate derivatives.展开更多
A series of novel sorafenib derivatives containing quinazoline moiety were designed and synthesized. Their anti-proliferative activities against HCT116 and HCT115 cell lines were evaluated using MTT assay. Most of the...A series of novel sorafenib derivatives containing quinazoline moiety were designed and synthesized. Their anti-proliferative activities against HCT116 and HCT115 cell lines were evaluated using MTT assay. Most of the synthesized compounds showed significant cytotoxicity against the selected cell lines. These cytotoxicities were consistent with their inhibitory activity against the phosphorylation of c-Raf, MEK1/2 and ERK1/2. Compound GD-09 also showed much stronger anti-tumor activity than that of sorafenib in vivo by B16 melanoma xenograft model test.展开更多
Quinolino[2,1-b]quinazolines 3 and 4, pyrrolo[2,1-b]quinazoline 5 and various substituted 2-(4-chlorostyryl)quinazoline derivatives including: 4-amino derivative 8, 4-hydrazino derivative 9, thiourea derivative 10, th...Quinolino[2,1-b]quinazolines 3 and 4, pyrrolo[2,1-b]quinazoline 5 and various substituted 2-(4-chlorostyryl)quinazoline derivatives including: 4-amino derivative 8, 4-hydrazino derivative 9, thiourea derivative 10, thiosemicarbazide derivative 19, 4-benzylidene hydrazinyl derivative 21, 4-amino thiazolidene derivatives 11, 12, 13, 22, imidazoquinazolines 15, 16, quinazolinium chloride 14, triazino[4,3-c]quinazolines 17, 18, tetrazino[1,6-c]quinazoline 20, 4-amino azetidinyl derivative 23, triazolo[4,3-c]quinazoline 24, 4-amino substituted quinazolines 25, 26, 27, 29 and quinazolino quinazoline 28 were synthesized through different chemical reactions. The obtained compounds were evaluated for their in vitro antitumor activity against HEPG2 and MCF-7 cell lines compared to the reference drug (doxorubicin). Compounds 18, 19, 20, 23 and 24 were found to be the most active against both cell lines exhibiting IC50 values ranging from 10.82 - 29.46 μM/L and 7.09 - 31.85 μM/L against Hep-G2 and MCF-7 cell lines, respectively, in addition to docking study of these five compounds against thymidylate synthase and dihydrofolate reductase enzymes active sites.展开更多
Objective:To evaluate new compounds synthesized by integrating quinoline,quinazoline,and acridine rings with the active moiety of(5-nitroheteroaryl)methylene hydrazine.Methods:A new series of compounds(1a,1b,2a,2b,3a,...Objective:To evaluate new compounds synthesized by integrating quinoline,quinazoline,and acridine rings with the active moiety of(5-nitroheteroaryl)methylene hydrazine.Methods:A new series of compounds(1a,1b,2a,2b,3a,and 3b)were synthesized and evaluated for cytotoxicity against COS-7 cells using the MTT assay.In vitro anti-plasmodial activity of the compounds was measured against CQ-sensitive(3D7)and CQ-resistant(K1)Plasmodium(P.)falciparum strains.β-hematin assay was performed to assess the inhibitory effects ofβ-hematin formation for new compounds.Results:The synthetic compounds had anti-plasmodial activity against blood-stage of 3D7[IC50=(0.328-5.483)μM]and K1[IC50=(0.622-7.746)μM]strains of P.falciparum,with no cytotoxicity against COS-7 cells in effective doses.Compounds 1a,1b,and 2b were the most effective derivatives against P.falciparum 3D7 and K1 strains.Based on theβ-hematin assay,the inhibition ofβ-hematin formation is the main mechanism of the inhibitory effect of these compounds.Conclusions:The synthetic compounds could inhibit the erythrocytic stages of CQ-sensitive and resistant P.falciparum strains without toxicity towards mammalian cells.Compounds 1b,2a,and 2b had comparable anti-plasmodial activity against both CQ-sensitive(3D7)and resistant(K1)P.falciparum strains.These compounds may be promising lead structures for the development of new anti-malarial drugs.展开更多
Ras protein signaling pathways are important in controlling the plight of diferent types of cancer. Here we discussed the paper entitled "Small molecule stabilization of the KSR inactive state antagonizes oncogen...Ras protein signaling pathways are important in controlling the plight of diferent types of cancer. Here we discussed the paper entitled "Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling" published in Nature journal on inactivating the kinase suppressor of Ras(KSR) protein using a small molecule as an inhibitor by Dhawan et al. A biphenyl ether analogue of a quinazoline binds in one of the binding pockets of KSR and results in stabilization of its inactive state. In this inactive state, KSR is unable to take part in the cascade of protein association to perform the signalling process.展开更多
As a group of diversified frameworks, quinazolin derivatives displayed a broad field of biological functions, especially as anticancer. To investigate the quantitative structure-activity relationship, 3D-QSAR models ...As a group of diversified frameworks, quinazolin derivatives displayed a broad field of biological functions, especially as anticancer. To investigate the quantitative structure-activity relationship, 3D-QSAR models were generated with 24 quinazolin scaffold molecules. The experimental and predicted pIC50 values for both training and test set compounds showed good correlation, which proved the robustness and reliability of the generated QSAR models. The most effective CoMFA and CoMSIA were obtained with correlation coefficient2ncv r of 1.00 （both） and leave-one-out coefficient q2 of 0.61 and 0.59, respectively. The predictive abilities of CoMFA and CoMSIA were quite good with the predictive correlation coefficients （2pred r ） of 0.97 and 0.91. In addition, the statis-tic results of CoMFA and CoMSIA were used to design new quinazolin molecules.展开更多
基金Anhui Province University Natural Science Research Project (No.KJ2019A0363)。
文摘Objective:To study the anti-ovarian cancer effect and mechanism of Quinazoline derivative(N111)in vitro;Method:Using an online database to predict the therapeutic targets of N111 for ovarian cancer,and conducting biological functional analysis of the therapeutic targets.The experiment was divided into N111 treatment group(N111 compound group),positive control group(cisplatin group),and negative control group(DMSO group);After grouping,MTT assay was used to detect cell proliferation;Morphological observation was used to observe changes in cell morphology;JC-1 and DCFH-DA probes were used to detect the changes of mitochondrial Membrane potential and intracellular reactive oxygen species;PI,Annexin V-FITC,and DAPI staining were used to detect cell cycle arrest and apoptosis;Clone formation experiments and scratch tests were conducted to detect the cell's ability to form clones and migrate;Western blot method was used to detect the expression level of related proteins.Result:The biological function research results show that the biological function of N111 anti ovarian cancer target protein suggests that the target function aggregates human diseases,inflammation,tumors,and other aspects.Compared with the control group,N111 has a significant inhibitory effect on the proliferation of ovarian cancer cells(IC50=14.62 mmol/L)(P<0.0001);In a concentration dependent manner,it inhibited the formation and migration of single cell colonies,and induced the disorder of mitochondrial Membrane potential,ROS and cell cycle arrest in S phase(P<0.0001);As the concentration of N111 treatment increased,the expression levels of Bcl2,Caspase 3,P-AKT,and SHIP2 decreased,while the expression levels of AKT remained unchanged.The expression levels of Bax and Cleared Caspase 3 increased(P<0.0001).Conclusion:Compound N111 inhibits SHIP2,promotes ROS level disorder,weakens the activation of AKT signaling pathway,and thus inhibits the proliferation,migration,and clone formation of tumor cell A2780,inducing cell apoptosis.
基金This work was supported by the National Natural Science Foundation of China （No.20673148）. We also heartily thank the College of Life Sciences, Sun Yat-Sen University for the SYBYL 6.9 computation environment support.
文摘A three-dimensional quantitative structure-activity relationship （3D-QSAR） study of a series of 7,8-dialkyl-l,3-diaminopyrrolo-[3,2-f] quinazolines with anticancer activity as dihydrofo- late reductase （DHFR） inhibitors was carried out by using the comparative molecular field analysis （CoMFA）, on the basis of our reported 2D-QSAR of these compounds. The es- tablished 3D-QSAR model has good quality of statistics and good prediction ability; the non cross-validation correlation coefficient and the cross-validation value of this model are 0.993 and 0.619, respectively, the F value is 193.4, and the standard deviation SD is 0.208. This model indicates that the steric field factor plays a much more important role than the electrostatic one, in satisfying agreement with the published 2D-QSAR model. However, the 3D-QSAR model offers visual images of the steric field and the electrostatic field. The 3D-QSAR study further suggests the following： to improve the activity, the substituent R^1 should be selected to be a group with an adaptive bulk like Et or i-Pr, and the substituent R should be selected to be a larger alkyl. In particular, based on our present 3D-QSAR as well as the published 2D-QSAR, the experimentMly-proposed hydrophobic binding mechanism on the receptor-binding site of the DHFR can be further explained in theory. Therefore, the QSAR studies help to further understand the ＂hydrophobic binding＂ action mechanism of this kind of compounds, and to direct the molecular design of new drugs with higher activity.
基金the financial support from National Natural Science Foundation of China(No.20972198).
文摘Quinazoline derivatives were synthesized fromα-iminoesters via a cascade imino-Diels-Alder and then oxidation reaction catalyzed with CuBr_2.This method provided a new strategy for preparing quinazoline derivatives which may be useful in the synthesis of heterocyclic intermediates.
文摘Objective: To synthesize inhibitors of the epidermal growth factor receptor tyrosine kinase such as 6-nitro-4-anilinoquinazolines and 6-amino-4-anilinoquinazolines,and to compare their anticancer effects in vitro. Methods: The 4-anilinoquinazolines compounds were prepared by hydrolyzed, ringed, halagenated, substituded in turn from 2-amino-5-nitrobenzylcarbonitril. The synthesized 4- anilinoquinazoline compounds has been rudimentarily screened by using A431 tumor cell line which overexpresses epidermal growth factor receptor as model adopted MTT method. Results: Five 6-nitro-4-halo-sbstituted anilinoquinazolines and five 6-amino-4-halo-substituted anilinoquinazolines have been obtained,and all of them had anticancer activity. The anticancer activity of 6-amino substituted inhibitors was higher than that of 6-nitro substituted inhibitors. However, the difference of anticancer activity between two series of quinazoline was much less than that of their inhibiting EGFR tyrosine kinase activity. Conclusion: The probable reason for 6-nitro-4-anilinoquinazolines having anticancer activity in vitro was that they had been partially transformed to 6-amino-4-anilinoquinazolines through endocellular cytochrome oxidation-reduction system.
文摘Objective: To prepare six quinazoline schiff bases by six steps of chemistry organic synthesis and test their inhibitory effect on hepatomacellular carcinoma cells HHCC and mammary cancer cell Bcap-37, furthmore,to compare their antitumor activities on these two kinds of cells. Methods: 2-Amino-5-nitro-benzylcarbonitrile was the initial material, and it was under the reaction of hydrolysis, ring-closing, halogenation, addition, reduction and substitution in turn to get the six quinazoline schiff bases, MTT method was adopted to compare their anticancer activities against the two cancer cells. Result and Conclusion: Six 6-imine-4-halo substituted anilinoquinozolines were prepared. The anticancer activities against both HHCC and Bcap-37were found, furthermore, they have more potency that on HHCC than on Bcap-37. In the six compounds, the schiff base Ⅵ is the most potent compound.
基金the National Natural Science Foundation of China(Nos.81874293 and 81630093)for financial support and Major Basic Research Program of Shandong Province(ZR2019ZD26).
文摘Two new quinazoline derivatives versicomides E(1)and F(2),and 10 known compounds(3-12)were isolated from the moss endophytic fungus Aspergillus sp.Their structures were determined on the basis of extensive spectroscopic data analysis and ECD calculations.Among them,the compound 7(6-hydroxy-3-methoxyviridicatin)was first reported as a natural product.Inhibition on LPS-induced NO production in RAW 264.7 murine macrophages found that compounds 5,7 and 8 showed significant inhibitory effects on NO production,with IC50 values of 49.85,22.14 and 46.02μM respectively.
基金The authors are thankful to Program to Support Publishing(PROPESQ)of Federal University of Juiz de Fora—UFJF and FAPEMIG.
文摘In silico pharmacokinetics studies can aid the search for molecules with potential ability to be drug candidates. In this paper, a number of quinazoline candidates for epidermal growth factor receptor inhibitors—EGFR, important targets for the treatment of cancer, are computationally analyzed. The literature described that 69 quinazoline molecules were synthesized and the respective half maximum inhibitory concentrations (IC50) were obtained. A bilinear parabolic model was built to investigate the druglikeness by correlating the corresponding lipophilicities, which can be represented by the ideal Log P , with the optimal biological activity in terms of pIC50 values. Structural characteristics leading to improved pharmacokinetics parameters were then analyzed. Compound 56 exhibited the lowest IC50 and, therefore, it had the highest ability to inhibit the EGFR. In the present work, the most potent inhibitor 56 is not calculated to be the most promising drug candidate, since it’s out of the parabolic model obtained due to a Log P above 5, which is not within the expected optimum range. Finally, this work is an example of computational prediction that an experimentally, highly active EGFR inhibitor can be unsuccessful as drug candidate because of pitfalls in pharmacokinetics parameters.
基金The authors are thankful to Dr.Mayur Yergeri and Science and Engineering Research Board(SERB),Government of India,New Delhi,(CRG/2019/001452).
文摘Glioblastoma,the most aggressive form of brain tumor,poses significant challenges in terms of treatment success and patient survival.Current treatment modalities for glioblastoma include radiation therapy,surgical intervention,and chemotherapy.Unfortunately,the median survival rate remains dishearteningly low at 12–15 months.One of the major obstacles in treating glioblastoma is the recurrence of tumors,making chemotherapy the primary approach for secondary glioma patients.However,the efficacy of drugs is hampered by the presence of the blood-brain barrier and multidrug resistance mechanisms.Consequently,considerable research efforts have been directed toward understanding the underlying signaling pathways involved in glioma and developing targeted drugs.To tackle glioma,numerous studies have examined kinase-downstream signaling pathways such as RAS-RAF-MEKERK-MPAK.By targeting specific signaling pathways,heterocyclic compounds have demonstrated efficacy in glioma therapeutics.Additionally,key kinases including phosphatidylinositol 3-kinase(PI3K),serine/threonine kinase,cytoplasmic tyrosine kinase(CTK),receptor tyrosine kinase(RTK)and lipid kinase(LK)have been considered for investigation.These pathways play crucial roles in drug effectiveness in glioma treatment.Heterocyclic compounds,encompassing pyrimidine,thiazole,quinazoline,imidazole,indole,acridone,triazine,and other derivatives,have shown promising results in targeting these pathways.As part of this review,we propose exploring novel structures with low toxicity and high potency for glioma treatment.The development of these compounds should strive to overcome multidrug resistance mechanisms and efficiently penetrate the blood-brain barrier.By optimizing the chemical properties and designing compounds with enhanced drug-like characteristics,we can maximize their therapeutic value and minimize adverse effects.Considering the complex nature of glioblastoma,these novel structures should be rigorously tested and evaluated for their efficacy and safety profiles.
文摘A series of novel 1,2,3-triazole-quinazoline derivatives were synthesized in five steps starting from anthranila- mide by conventional methods. All the title compounds 10a-10r were evaluated for cytotoxic activity against four human cancer cell lines （MGC-803, EC-109, MCF-7 and HGC-27） using MTT assay in vitro. Some of the synthe- sized compounds exhibited moderate to potent activity against tested cancer cell lines. Among them, compounds 10h and 10q exhibited excellent growth inhibition against HGC-27 and compound 10m also possessed excellent ac- tivity against MCF-7, with IC50 values less than 1 μmol/L. Especially, compound 10h was more cytotoxic than 5-fluorouracil against all tested four human cancer cell lines.
基金supports from the National Key Research and Development Plan(No.2016YFB0401004)supports from the Open Fund of Beijing National Laboratory for Molecular Sciences(BNLMS,No.BNLMS20160131)the Fundamental Research Funds for the Central Universities(Harbin Institute of Technology)。
文摘Achieving stable deep blue organic light emitting diodes(OLEDs)with narrow full width at half maximum(FWHM)and color gamut in the range of the commission International de L’Eclairage(CIE)ofy≤0.10 is still challenging in display and lighting applications.In this investigation,three donor-acceptor(D-A)deep-blue emitters were designed and synthesized via integrating asymmetric quinazoline(PQ)acceptor with weak donating carbazole(Cz)donor.The effect of the position and number of Cz group in PQunit are investigated,which is also first examples for syste matic research about the effect of different position of asymmetric PQ as acceptor on deep OLEDs.Their bandgaps of 3.12~3.19 eV and the singlet state energy levels of 3.12~3.19 eV were found to be sufficiently large to achieve deep blue light.As expected,these emitters-based OLEDs exhibit deep blue emission with the maximum wavelength≤450 nm and narrow FWHM≈60 nm.Especially,a CIE ofy=0.080 was achieved for 4 PQ-Cz-based OLED.Significantly,the deep blue electroluminescence(EL)spectra of these three emitters-based OLEDs are very stable and the corresponding CIE coordinates deviation(ΔCIE(x,y))can be negligible under the applied voltage ranging from 5 V to 9 V.
基金the financial support of Key International S&T Cooperation Projects(No.2008DFA31040 and No.2009DFA32080) of Ministry of Science and Technology of the People's Republic of China
文摘A novel 4-anilinoquinazoline dimer linked by a carbon-carbon bond in the C-7 position was synthesized via a one step Suzuki cross-coupling reaction. All structures of new compounds were characterized by ^1H NMR, ^13C NMR, and HRMS. The inhibition rate of the synthetic 4-anilinoquinazoline dimer 8 against epidermal growth factor receptor-tyrosine kinase enzymes （EGFR） in vitro was 44.4% at the concentration of 5.5 μmol/L.
基金We are grateful for the financial support from the National Natural Science Foundation of China(Project No.81172937)as well as surpport from the Education Department of Henan Province Science and Technology Research Projects(No.14A150052)the Scientific Research Plan of Zhenzhou(No.121PPTGG509-2).
文摘A novel type of quinazoline derivatives,which were designed by the combination of quinazoline as the back-bone and oxazole scaffold as the substituent,have been synthesized and their biological activities were evaluated for anti-proliferative activities and EGFR inhibitory potency.Compound 12b demonstrated the most potent inhibi-tory activity(IC_(50)=0.95μmol/L for EGFR),which could be optimized as a potential EGFR inhibitor in the further study.The structures of the synthesized quinazoline analogs and all intermediates were comfirmed by 1H and 13C NMR,2D NMR spectra,IR spectra and MS spectra.
基金the National Nature Science Foundation of China (Nos. 2127222, 91213303, 21172205, 21432009, 21472177)
文摘A novel copper-catalyzed dual oxidative benzylic C–H aminations of methylarenes with 2-aminobenzoketones in the presence of ammonium acetate was developed. This reaction represents a new avenue for 2-arylquinazolines with good yields. A key intermediate was detected and the kinetics isotope effect（KIE） indicated that C–H bond cleavage was the rate-determining step.
基金Project supported by the Natural Science Foundation of Guangdong Province （No. 05003264）.
文摘The quantitative structure-activity relationship （QSAR） studies on a series of 7,8-dialkyl-1,3-diaminopyrrolo-[3,2-f]quinazolines, dihydrofolate reductase （DHFR） inhibitors as potential anticancer agents, have been carried out by using the density functional theory （DFT） method, molecular mechanics method （MM＋） and statistical method. Some QSAR models based on their lipophilic and steric parameters were built up via a stepwise regression analysis. It is very interesting to find that the established optimal QSAR equation involves only two descriptors： lipophilicity indexes Clog P and Clog P^2 However, such descriptors can quite well describe a significant statistic quality and have a remarkable predictive activity according to the square of adjusted correlation coefficient （RA^2 = 0.937） and the square of cross-validation coefficient （q^2=0.911） of this equation. The results show that the lipophilicity is a main factor affecting the anticancer activity of this series of antimetastatic agents, and the obtained equation describes a parabolic correlation between pIC50 and Clog P, and indicates a suitable range of Clog P （around 4.43） being very important for optimal pIC50 values. These QSAR studies can offer some useful references for understanding the action mechanism and performing the molecular design or modification of this series of antimetastatic agents.
基金Project supported by the National Key Program for Basic Research （Nos. 2010CB126105, 2010CB134504） and the National Natural Science Foundation of China （No. 20872021）.
文摘[BMIM]Cl catalyzed three component Mannich-type reaction of 4-（quinazolin-4-yloxy）benzenamine and aldehyde with dialkyl phosphite under microwave irradiation has been described. The salient features of the reaction leading to new a-aminophosphonates include shorter reaction time and good yields. The method is environmentally friendly and does not require toxic catalysts or solvents. To the best of our knowledge, this is the first report for [BMIM]Cl induced one-pot synthesis of a-aminophosphonate derivatives.
基金Supported by the National Natural Science Foundation of China(81202038)Science and Technology Innovation Foundation in Yantai University(01081)
文摘A series of novel sorafenib derivatives containing quinazoline moiety were designed and synthesized. Their anti-proliferative activities against HCT116 and HCT115 cell lines were evaluated using MTT assay. Most of the synthesized compounds showed significant cytotoxicity against the selected cell lines. These cytotoxicities were consistent with their inhibitory activity against the phosphorylation of c-Raf, MEK1/2 and ERK1/2. Compound GD-09 also showed much stronger anti-tumor activity than that of sorafenib in vivo by B16 melanoma xenograft model test.
文摘Quinolino[2,1-b]quinazolines 3 and 4, pyrrolo[2,1-b]quinazoline 5 and various substituted 2-(4-chlorostyryl)quinazoline derivatives including: 4-amino derivative 8, 4-hydrazino derivative 9, thiourea derivative 10, thiosemicarbazide derivative 19, 4-benzylidene hydrazinyl derivative 21, 4-amino thiazolidene derivatives 11, 12, 13, 22, imidazoquinazolines 15, 16, quinazolinium chloride 14, triazino[4,3-c]quinazolines 17, 18, tetrazino[1,6-c]quinazoline 20, 4-amino azetidinyl derivative 23, triazolo[4,3-c]quinazoline 24, 4-amino substituted quinazolines 25, 26, 27, 29 and quinazolino quinazoline 28 were synthesized through different chemical reactions. The obtained compounds were evaluated for their in vitro antitumor activity against HEPG2 and MCF-7 cell lines compared to the reference drug (doxorubicin). Compounds 18, 19, 20, 23 and 24 were found to be the most active against both cell lines exhibiting IC50 values ranging from 10.82 - 29.46 μM/L and 7.09 - 31.85 μM/L against Hep-G2 and MCF-7 cell lines, respectively, in addition to docking study of these five compounds against thymidylate synthase and dihydrofolate reductase enzymes active sites.
基金supported by the grant(No.852)from Pasteur Institute of Iran to A.A.Mehrizi
文摘Objective:To evaluate new compounds synthesized by integrating quinoline,quinazoline,and acridine rings with the active moiety of(5-nitroheteroaryl)methylene hydrazine.Methods:A new series of compounds(1a,1b,2a,2b,3a,and 3b)were synthesized and evaluated for cytotoxicity against COS-7 cells using the MTT assay.In vitro anti-plasmodial activity of the compounds was measured against CQ-sensitive(3D7)and CQ-resistant(K1)Plasmodium(P.)falciparum strains.β-hematin assay was performed to assess the inhibitory effects ofβ-hematin formation for new compounds.Results:The synthetic compounds had anti-plasmodial activity against blood-stage of 3D7[IC50=(0.328-5.483)μM]and K1[IC50=(0.622-7.746)μM]strains of P.falciparum,with no cytotoxicity against COS-7 cells in effective doses.Compounds 1a,1b,and 2b were the most effective derivatives against P.falciparum 3D7 and K1 strains.Based on theβ-hematin assay,the inhibition ofβ-hematin formation is the main mechanism of the inhibitory effect of these compounds.Conclusions:The synthetic compounds could inhibit the erythrocytic stages of CQ-sensitive and resistant P.falciparum strains without toxicity towards mammalian cells.Compounds 1b,2a,and 2b had comparable anti-plasmodial activity against both CQ-sensitive(3D7)and resistant(K1)P.falciparum strains.These compounds may be promising lead structures for the development of new anti-malarial drugs.
文摘Ras protein signaling pathways are important in controlling the plight of diferent types of cancer. Here we discussed the paper entitled "Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling" published in Nature journal on inactivating the kinase suppressor of Ras(KSR) protein using a small molecule as an inhibitor by Dhawan et al. A biphenyl ether analogue of a quinazoline binds in one of the binding pockets of KSR and results in stabilization of its inactive state. In this inactive state, KSR is unable to take part in the cascade of protein association to perform the signalling process.
基金financial supports from the National Natural Science Foundation of China (Nos. 50673085, 20677053)the National High-Tech Research and Development Programme of China (No. 2010AA09Z203)
文摘As a group of diversified frameworks, quinazolin derivatives displayed a broad field of biological functions, especially as anticancer. To investigate the quantitative structure-activity relationship, 3D-QSAR models were generated with 24 quinazolin scaffold molecules. The experimental and predicted pIC50 values for both training and test set compounds showed good correlation, which proved the robustness and reliability of the generated QSAR models. The most effective CoMFA and CoMSIA were obtained with correlation coefficient2ncv r of 1.00 （both） and leave-one-out coefficient q2 of 0.61 and 0.59, respectively. The predictive abilities of CoMFA and CoMSIA were quite good with the predictive correlation coefficients （2pred r ） of 0.97 and 0.91. In addition, the statis-tic results of CoMFA and CoMSIA were used to design new quinazolin molecules.
