Study on the in vitro anti ovarian cancer effect and mechanism of quinazoline derivative(N111)

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.

Two New Quinazoline Derivatives from the Moss Endophytic Fungus Aspergillus sp. and Their Anti-inflammatory Activity

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.

In Silico Pharmacokinetics Studies for Quinazolines Proposed as EGFR Inhibitors

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.

A review on potential heterocycles for the treatment of glioblastoma targeting receptor tyrosine kinases

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.

Synthesis, Cytotoxic Activity Evaluation of Novel 1,2,3-Triazole Linked Quinazoline Derivatives

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.

Stable deep blue organic light emitting diodes with CIE of y<0.10 based on quinazoline and carbazole units

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.

Efficient synthesis of 2-arylquinazolines via copper-catalyzed dual oxidative benzylic C–H aminations of methylarenes

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.

QSAR Studies on a Series of 7,8-Dialkyl-1,3-diaminopyrrolo-[3,2-f]quinazolines with Anticancer Activity

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.

[BMIM]CI Catalyzed One-Pot Synthesis of a-Aminophospho- nate Derivatives Containing a 4-Phenoxyquinazoline Moiety under Microwave Irradiation

[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.

Design,Synthesis and Bioactivities Evaluation of Novel Quinazoline Analogs Containing Oxazole Units

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.

Design,Synthesis and Biological Activities of Quinazoline Containing Sorafenib Analogs as Antitumor Agents

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.

Utility of 2-Methyl-quinazolin-4(3H)-one in the Synthesis of Heterocyclic Compounds with Anticancer Activity

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.

In vitro anti-plasmodial activity of new synthetic derivatives of 1-(heteroaryl)-2-((5-nitroheteroaryl)methylene) hydrazine

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.

Arresting kinase suppressor of Ras in an inactive state

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.

Synthesis and Crystal Structure of 2,6-Bis(benzimidazo(1,2-c)-quinazolin-6-yl)pyridine Tetrahydrate

The title compound, 2,6-bis（benzimidazo（1,2-c）quinazolin-6-yl）pyridine tetrahydrate, was synthesized by simple condensation of 2-（2-sminophenyl） benzimidazole with pyfidine- 2,6-dicarboxylic acid and characterized by elemental analysis, IR spectra and single-crystal X-ray diffraction. The crystal belongs to the monoclinic system, space group C2/c with a = 22.226（8）, b = 16.730（7）, c = 16.820（5）A, β = 115.796（13）°, V = 5631（4）A^3, C33H27NTO4, Mr = 585.62, Z = 8, Dc = 1.381 g/cm^3, λ（MoKα） = 0.71073 A, F（000） = 2448 and μ = 0.09 mm^-1. The structure was refined to the final R = 0.0730 and wR = 0.1573 for 6346 independent reflections （Rint = 0.0801） and 3384 observed reflections （I 〉 2σ（I））. In the crystal, the molecules are linked through intermolecular O-H…O and O-H…N hydrogen bonds. Intermolecular π-π interactions （with distances of about 3.45 A） are pronounced in the crystal structure.

Boron-based Drug Design for Cancer Therapy

1 Results Selective inhibition of protein tyrosine kinases is gaining importance as an effective therapeutic approach for the treatment of a wide range of human cancers.The epidermal growth factor receptor (EGFR) protein tyrosine kinase is one of the important kinases that play a fundamental role in cell growth signal pathways.We focused on the 4-anilinoquinazoline framework,which is observed in both compounds as a common structure.A boron atom has a vacant orbital and interconverts with ease between th...