295330-61-9

Upstream product

• 153436-54-5 PD153035 
• 295330-64-2 4-[(3-bromo-phenyl)amino]-6-methylcarbonyloxy-7-methoxy-quinazoline 
• 591-19-5 m-Bromoaniline 
• 179688-53-0 (4-hydroxy-7-methoxyquinazolin-6-yl) acetate 
• 179688-52-9 4,6-dihydroxy-7-methoxyquinazoline 
• 179688-52-9 6-hydroxy-7-methoxyquinazolin-4(3H)-one 
• 13794-72-4 3H-6,7-dimethoxyquinazolin-4-one 
• 230955-75-6 6-acetoxy-4-chloro-7-methoxyquinazoline 
• 93-07-2 Veratric acid 
• 3943-77-9 ethyl veratrate 
• 100905-33-7 ethyl 2-nitro-4,5-dimethoxybenzoate 
• 20323-74-4 2-carboethoxy-4,5-dimethoxyaniline 
• 179688-54-1 4-chloro-7-methoxyquinazolin-6-yl acetate hydrochloride salt 
• 13794-72-4 6,7-dimethoxy-4-hydroxyquinazoline 

Downstream Products

• 295330-57-3 4-[(3-bromo-phenyl)amino]-6-(2-bromoethoxy)-7-methoxy-quinazoline 
• 1165931-33-8 1-{3-[4-(3-bromophenylamino)-7-methoxyquinazolin-6-yloxy]propyl}-2-butyl-4-chloro-1H-imidazole-5-carboxaldehyde 
• 1389355-17-2 C₁₇H₁₅BrFN₃O₂ 
• 1389355-33-2 N-(3-bromophenyl)-6-(2-[18F]fluoroethoxy)-7-methoxyquinazolin-4-amine 
• 295330-67-5 4-[(3-bromophenyl)amino]-6-oxiranylmethoxyl-7-methoxyquinazoline 

Relevant academic research and scientific papers

Design, synthesis and biological evaluation of sulfamoylphenyl-quinazoline derivatives as potential EGFR/CAIX dual inhibitors

Multi-target, especially dual-target, drug design has become a popular research field for cancer treatment. Development of small molecule dual-target inhibitors through hybridization strategy can provide highly potent and selective anticancer agents. In this study, three series of quinazoline derivatives bearing a benzene-sulfonamide moiety were designed and synthesized as dual EGFR/CAIX inhibitors. All the synthesized compounds were evaluated against epidermoid carcinoma (A431) and non-small cell lung cancer (A549 and H1975) cell lines, which displayed weak to potent anticancer activity. In particular, compound 8v emerged as the most potent derivative against mutant-type H1975 cells, which exhibited comparable activity to osimertinib. Importantly, 8v exhibited stronger anti-proliferative activity than osimertinib against H1975 cells under hypoxic condition. Kinase inhibition studies indicated that 8v showed excellent inhibitory effect on EGFRT790M enzyme, which was 41 times more effective than gefitinib and almost equal to osimertinib. Mechanism studies revealed that 8v exhibited remarkable CAIX inhibitory effect comparable to acetazolamide and significantly inhibited the expression of p-EGFR as well as its downstream p-AKT and p-ERK in H1975 cells. Notably, 8v was found to inhibit the expression of CAIX and its upstream HIF-1α in H1975 cells under hypoxic condition. Molecular docking was also performed to gain insights into the ligand-binding interactions of 8v inside EGFRWT, EGFRT790M and CAIX binding sites.

Design and Evaluation of Potent EGFR Inhibitors through the Incorporation of Macrocyclic Polyamine Moieties into the 4-Anilinoquinazoline Scaffold

Adenosine triphosphate (ATP)-competitive inhibitors of the epidermal growth factor receptor (EGFR) have provided a significant improvement in the disease outcome of nonsmall cell lung cancer (NSCLC). Unfortunately, some marketed drugs affect a transient beneficial response in EGFR mutant NSCLC patients. We reported a series of potential EGFR inhibitors through incorporation of macrocyclic polyamine into 4-anilinoquinazoline scaffold. It is expected that anilinoquinazoline part effectively bind to EGFR domain, while ATP molecules are captured by a macrocyclic polyamine moiety. In vitro experiments exhibited that most of tested compounds suppressed tumor cell proliferation more strongly than Gefitinib and Lapatinib (dual inhibitor of EGFR/HER2) as controls. In kinase assays, the compound 1f showed excellent dual inhibition activity toward EGFRWT (IC50 = 1.4 nM) and HER2 (IC50 = 2.1 nM). In vivo pharmacology evaluation of 1f showed significant antitumor activity (TGI = 44.2%) in A549 xenografts mice. The current work provided a feasible solution to optimize anilinoquinazoline-based inhibitors.

Facile Synthesis of Novel Perfluorocarbon-Modulated 4-Anilinoquinazoline Analogues

4-Anilinoquinazoline analogues stand out among many kinds of small molecules that inhibit the tyrosine kinase activities of epidermal growth factor receptor (EGFR), thus serving as significant molecular targets for anticancer drug design. Herein, a series of novel perfluorocarbon (PFC) modulated 4-anilinoquinazolines were designed and prepared straightforwardly by nucleophilic substitution reaction of various anilinoquinazolines and PFC-derived methanesulfonate. In the presence of base, the reaction proceeded smoothly to afford a wide range of 4-anilinoquinazolines with different substituents on aniline moiety in good to high yields. Furthermore, the PFC-modified analogues of gefitinib and erlotinib were also obtained in 93% and 90% respectively, which may have potential for developing new inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase and fluorinated contrast agents (CA) for 19F MRI.

Quinazoline derivative and application thereof

The invention belongs to the field of medical chemistry, and particularly relates to 4-anilino quinazoline derivative with 1-methyl-2-nitro-5-methylene imidazole. The structure of the 4-anilino quinazoline derivative is shown as a graph, wherein an R represents a compound shown as a graph or -(CH)R, the n is equal to 2 or 3 or 4 or 5 or 6, and an R represents morpholino or piperidyl or pyrrolidyl or piperazinyl or dimethylamino; an R represents a compound shown as a graph or hydrogen; an R, an R and an R respectively independently selectively represent hydrogen or chlorine or fluorine or bromine or acetenyl or trifluoromethylphenol. The 4-anilino quinazoline derivative has the advantage that as shown by pharmacological experiments, effects of inhibiting tumor cell proliferation can be realized by the 4-anilino quinazoline derivative which is a compound and pharmaceutically acceptable salt of the 4-anilino quinazoline derivative.

Design, synthesis and biological evaluation of quinazoline–phosphoramidate mustard conjugates as anticancer drugs

A series of novel compounds with phosphoramide mustard functionality incorporated into the quinazoline scaffold of EGFR/HER2 inhibitors were designed and synthesized as multi-target-directed ligands against tumor cells. In?vitro assays showed that tumor cell lines with high HER2 level were more sensitive to the compounds than tumor cells with low HER2 level. Compound 10d (EMB-3) was one of the most potent inhibitors with IC50of 7.4?nM and 82?nM against EGFR and HER2, respectively. The mechanism studies were also supported by the effect of 10d-induced DNA damage in MDA-MB-468?cells. In?vivo efficacy study showed that 10d could significantly inhibit H522 tumor xenograft model with a TGI of 68% at dose of 100?mg/kg (QDx28, p.o.) and no significant body weight loss was observed. MTD study indicated that compound 10d had no acute toxicity to mice at doses up to 900?mg/kg (single dose).

Model 18 F mark 4-amino-quinazoline derivatives and its preparation method and tumor PET imaging applications

The invention provides novel F marked 4-aminoquinazoline compounds. The novel F marked 4-aminoquinazoline compounds are characterized in that one end of each of the novel F marked 4-aminoquinazoline compounds has a F substituted alkyloxy structure; the other end of each of the compounds has a 6,7-substituted quinazoline structure, and a substituent R1 is positioned in the 3 position of a 4-aminobenzene ring which is the quinazoline maternal, and is H, F, Cl, Br, I, a trifluoromethyl group or an acetenyl group; a substituent R2 is positioned in the 4 position of the 4-aminobenzene ring which is the quinazoline maternal, and is H, F, Cl, Br, a methyl group, a methoxy group, a 3-fluorophenoxyl group, or a 2-pyridyloxy group; and n is 1-5. The structural formula of the compounds is shown as A in the specification. Results of experiments show that the precursor of the marker of the compounds is easy to synthesize, marks through using a two-step method and has a high marking rate. The compounds have a good bioactivity, for example, the compounds have high absorption and slow removal in tumor tissues and low intake and fast removal in normal tissues and blood, so the compounds have a high tumor/background ratio, and especially have a high tumor/blood ratio, a high tumor/flesh ratio and a high tumor/brain ration, are in favor of the PET tumor development, and perform a huge potential as a brain tumor developer.

Design, synthesis and biological evaluation of 6-(nitroimidazole-1 H -alkyloxyl)-4-anilinoquinazolines as efficient EGFR inhibitors exerting cytotoxic effects both under normoxia and hypoxia

A series of novel 6-(nitroimidazole-1H-alkyloxyl)-4-anilinoquinazoline derivatives (15a-15r) were designed, synthesized and evaluated as efficient EGFR inhibitors through introduction of hypoxia activated nitroimidazole moiety into the quinazoline scaffold of EGFR inhibitors. The majority of these newly synthesized compounds exhibited comparable EGFR inhibitory activities to gefitinib and moderate to excellent anti-proliferative activities against HT-29 cells under normoxia and hypoxia. The most promising compound 15c displayed the IC50 value of 0.47 nM against EGFR kinase and excellent cytotoxic effect against HT-29 cells under normoxia and hypoxia with the IC50 values of 2.21 μM and 1.62 μM, respectively. The mimic reductive activation study revealed that compound 15c exerted reductive activation properties under hypoxia, which were consistent with the in vitro metabolic study, wherein 15c was easily reductive activated under hypoxia and much more stable under normoxia. All these results suggested that 15c was a potential cancer therapeutic agent both under normoxia and hypoxia and was worth of further development.

Hybrids from 4-anilinoquinazoline and hydroxamic acid as dual inhibitors of vascular endothelial growth factor receptor-2 and histone deacetylase

A series of hybrids derived from 4-anilinoquinazoline and hydroxamic acid were designed, synthesized, and evaluated as dual inhibitors of vascular endothelia growth factor receptor-2 (VEGFR-2) tyrosine kinase and histone deacetylase (HDAC). Most of these compounds exhibited potent HDAC inhibition and moderate VEGFR-2 inhibition. Among them, compound 6l exhibited the most potent inhibitory activities against VEGFR-2 (IC50 = 84 nM) and HDAC (IC50 = 2.8 nM). It also showed the most potent antiproliferative ability against MCF-7, a human breast cancer line, with IC50 of 1.2 μM. Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction of compound 6l at the active binding sites of VEGFR-2 and HDAC.

Synthesis and evaluation of novel F-18 labeled 4-aminoquinazoline derivatives: Potential PET imaging agents for tumor detection

Three novel 18F-labeled 4-aminoquinazoline derivatives, N-(3-chloro-4-fluorophenyl)-6-(2-[18F]fluoroethoxy)-7- methoxyquinazolin-4-amine([18F]1), N-(3-ethynylphenyl)-6-(2-[ 18F]fluoroethoxy)-7-methoxyquinazolin-4-amine([18F]2), and N-(3-bromophenyl)-6-(2-[18F]fluoroethoxy)-7-methoxyquinazolin-4- amine([18F]3) were synthesized and radiolabeled by two-step reaction with overall radiochemical yield of 21-24% (without decay corrected). Then we carried out their biodistribution experiments in S180 tumor-bearing mice. Results showed that they had certain concentration accumulation in tumor and fast clearance from muscle and blood. It was encouraging that [18F]3 was competitive among three 18F-labeled 4-aminoquinazoline derivatives in some aspects such as tumor/muscle uptake ratio reaching 7.70 at 60 min post-injection, tumor/blood uptake ratio reaching 6.61 at 120 min post-injection. So we compared radioactivity characteristics of [ 18F]3 with those of [18F]-FDG and L-[18F]-FET in the same animal model. The absolute radioactivity uptake of [18F]3 in tumor reached 3.31 at 60 min p.i., which was slightly higher than [ 18F]-FDG (2.16) and L-[18F]-FET (2.75) at the same time phase. For [18F]3, tumor/muscle uptake ratio peaked 7.70 at 60 min, which was obviously superior to those of [18F]-FDG and L-[ 18F]-FET at all time points. The tumor/brain uptake ratios of [ 18F]3 were 10.36, 17.42, 41.11 at 30 min, 60 min and 120 min post-injection, respectively, and are much higher than those of L-[ 18F] FET (2.54, 2.92 and 2.95) and [18F]-FDG (0.61, 1.02 and 1.33) at the same time points. All these results indicate that [ 18F]3 is promising to become a potential PET tumor imaging agent.

Synthesis and in vitro antitumor activities of novel 4-anilinoquinazoline derivatives

A series of 6, 7-dialkoxy-4-anilinoquinazolines were designed, synthesized by substituting different heterocycles on 6-position and a variety of anilines on 4-position of the quinazoline. These novel quinazoline compounds were screened for their cytotoxic effect on epidermal growth factor receptor overexpressing skin epidermoid carcinoma cell line (A431), by using nonoverexpressing tumor cells as negative control (breast adeno carcinoma cell line MCF-7). 2-Butyl-4-chloro-1-{3-[7-methoxy-4-(3-(trifluoromethyl)phenylamino)quinazolin-6-yloxy]-propyl}-1H-imidazole-5-carboxaldehyde (30) and 2-butyl-4-chloro-1-{3-[4-(3-iodophenyl amino)-7-methoxyquinazolin-6-yloxy]propyl}-1H-imidazole-5-carboxaldehyde (33) were found to be more potent against A431 cell line (IC50 3.5 and 3 μM) and their activities are comparable to gefitinib. Insilico docking experiments with human EGFR Tyrosine kinase domain (PDB id-2gs2) indicated that 33 docks at the same position as that of gefitinib involving Val702, Ala719, Ser696, and Lys721.