Disease relevance of quinazoline

• Significantly enough, there was no modification of the apoptotic threshold of the androgen-sensitive prostate cancer cells, LNCaP, to either quinazoline-based alpha1-agonist by androgens [1].
• This may have potential therapeutic significance in the use of quinazoline-based alpha1-adrenoceptor antagonists (already in clinical use for the treatment of hypertension and benign prostate hyperplasia) for the treatment of androgen-independent human prostate cancer [1].
• The quinazoline derivatives, trimazosin and prazosin, are also effective vasodilators, which act on both arteries and veins in patients with congestive heart failure [2].
• Prazosin, a quinazoline derivative, is well tolerated and is not associated with chronic toxicity [3].
• 4-(3'-Bromo-4'hydroxylphenyl)-amino-6,7-dimethoxyquinazoline: a novel quinazoline derivative with potent cytotoxic activity against human glioblastoma cells [4].

High impact information on quinazoline

• Trimetrexate, a highly lipid-soluble quinazoline antifolate now undergoing trials as an anticancer agent, was found to be a potent inhibitor of the dihydrofolate reductase (DHFR) isolated from Toxoplasma gondii [5].
• Ketanserin (R 41 468), a quinazoline derivative, has been shown to be a selective blocker of 5-HT2 receptors [6].
• Two of the compound classes, a quinazoline compound series and an indole compound, also increased SMN protein levels and nuclear gem/Cajal body numbers in patient-derived cells [7].
• The novel indole-ether quinazoline AZD2171 is a highly potent (IC50 < 1 nmol/L) ATP-competitive inhibitor of recombinant KDR tyrosine kinase in vitro [8].
• As a strategy for blocking PDGFR signaling, CT52923, a potent selective small molecule piperazinyl quinazoline kinase inhibitor of the PDGFR, was identified [9].

Chemical compound and disease context of quinazoline

• Previous studies documented that the quinazoline-derived alpha1-adrenoceptor antagonist doxazosin affects the attachment and migration of prostate cancer cells [10].
• As selective antagonist inhibition may relieve the symptoms of benign prostatic hyperplasia, we have examined the interactions of antagonists including quinazoline and imidazolidinium/guanidinium compounds complexed with a homology model of the alpha(1A) adrenoceptor [11].
• Two human primary liver cancer cell-lines, PLC/PRF/5 and Hep 3B, grown both in vitro and as xenografts in nude mice were used to evaluate the chemotherapeutic potential of a new quinazoline antifolate CB3717 [12].
• In this study we investigated the effect of the 2 piperazidinyl quinazoline based alpha1-adrenoceptor antagonists and the methoxybenzene sulfonamide alpha1-antagonist tamsulosin on human prostate cancer cell adhesion [13].
• Superimposing the quinazoline moiety upon the pteridine ring of the methotrexate-dihydrofolate reductase (E. coli) complex reveals two orientations of the N3 group in which it can fit the enzyme, making van der Waals contacts [14].

Biological context of quinazoline

• Quinazoline-derived alpha1-adrenoceptor antagonists induce prostate cancer cell apoptosis via an alpha1-adrenoceptor-independent action [1].
• ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tumor cell growth in vitro and in vivo: a new agent for clinical study [15].
• This report combines network thermodynamic modeling and experimental observations to evaluate the effects of direct inhibition of thymidylate synthase at the 5,10-methylenetetrahydrofolate binding site with a potent lipophilic quinazoline antifolate PD130883 on folate oxidation in cells [16].
• Here, we show that the novel quinazoline derivatives 4-(4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P131) and 4-(3'-bromo-4'hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P154) are potent inhibitors of glioblastoma cell adhesion and migration [17].
• The novel quinazoline derivative 4-(3'-bromo-4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P154) exhibited significant cytotoxicity against U373 and U87 human glioblastoma cell lines, causing apoptotic cell death at micromolar concentrations [4].

Anatomical context of quinazoline

• Alfuzosin, a new quinazoline derivative, acts as a selective and competitive antagonist of alpha 1-adrenoceptor-mediated contraction of prostatic, prostatic capsule, bladder base and proximal urethral smooth muscle, thereby reducing the tone of these structures [18].
• Rational design of quinazoline-based irreversible inhibitors of human erythrocyte purine nucleoside phosphorylase [19].
• RESULTS: The quinazoline-based antagonists, doxazosin and terazosin, induce apoptosis, inhibit cell adhesion to the extracellular matrix (by activating anoikis), and prevent cell invasion and migration of prostate tumor epithelial cells and vascular endothelial cells [20].
• Anagrelide, a quinazoline that inhibits cyclic nucleotide phosphodiesterase, inhibits platelet aggregation and has an idiosyncratic effect of inhibiting megakaryocyte maturation and platelet budding at doses below those that affect platelet function [21].
• Prevention of hippocampus neuronal damage in ischemic gerbils by a novel lipid peroxidation inhibitor (quinazoline derivative) [22].

Associations of quinazoline with other chemical compounds

• Time dependence of DNA lesions and growth inhibition by ICI D1694, a new quinazoline antifolate thymidylate synthase inhibitor [23].
• In addition, the cytotoxic activity of CB3717, a specific quinazoline-based inhibitor of thymidylate synthase, was not potentiated by rIFN-alpha 2a [24].
• Biochemical and antitumor effects of 5,8-dideazaisopteroylglutamate, a unique quinazoline inhibitor of thymidylate synthase [25].
• Phosphorothioate p27 oligonucleotides decreased p27 protein in A431 cells and abrogated the quinazoline-mediated G(1) arrest [26].
• ZD1839, a p.o. active, selective quinazoline derivative has demonstrated promising in vitro and in vivo antitumor activity [27].

Gene context of quinazoline

• Quinazoline-treated A431 as well as tumor cells expressing less EGFR (A549, MDA MB 231, and T47D) bound 3- to 6-fold more (125)I-labeled EGF than untreated intact control cells [28].
• Quinazoline-based alpha 1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-beta signalling and I kappa B alpha induction [29].
• Rescue of DeltaF508 and other misprocessed CFTR mutants by a novel quinazoline compound [30].
• The aurora2 structural model provides a rational basis for site-directed mutagenesis of the active site; design of novel H-89, staurosporine, and quinazoline analogues; and the screening of the available chemical database for the identification of other novel, small-molecular entities [31].
• Here we report that two small-molecule, structurally related, quinazoline-type compounds, WHI-131 and WHI-154, directly inhibit enzymatic activity of NPM/ALK as demonstrated by in vitro kinase assays using a synthetic tyrosine-rich oligopeptide and the kinase itself as the substrates [32].

Analytical, diagnostic and therapeutic context of quinazoline

• Quinazoline, pyrido[3,4-d]pyrimidine, and pyrido[3,2-d]pyrimidine 6-acrylamides were all irreversible inhibitors and showed similar high potencies in the enzyme assay (likely due to titration of the available enzyme) [33].
• The minimum inhibitory concentration of quinazoline derivative was determined by the tube dilution method for Cryptococcus neoformans, strain 184 [34].
• Rapid, sensitive, and reproducible radioimmunoassays for TTP pools and immunoreactive dUMP pools have been developed to meet our requirement for the rapid assessment of TS inhibition by quinazoline antifolates [35].
• Determination of the imidazo quinazoline derivative Ro 13-6438 in biological fluids by high-performance liquid chromatography [36].
• Several compounds, including quinazoline ring-containing compounds, have been identified and are currently in clinical trials [37].

References