- Design of a Cyclin G Associated Kinase (GAK)/Epidermal Growth Factor Receptor (EGFR) Inhibitor Set to Interrogate the Relationship of EGFR and GAK in Chordoma
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We describe the design of a set of inhibitors to investigate the relationship between cyclin G associated kinase (GAK) and epidermal growth factor receptor (EGFR) in chordoma bone cancers. These compounds were characterized both in vitro and using in cell
- Asquith, Christopher R. M.,Naegeli, Kaleb M.,East, Michael P.,Laitinen, Tuomo,Havener, Tammy M.,Wells, Carrow I.,Johnson, Gary L.,Drewry, David H.,Zuercher, William J.,Morris, David C.
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supporting information
p. 4772 - 4778
(2019/05/08)
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- Anti-tubercular activity of novel 4-anilinoquinolines and 4-anilinoquinazolines
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We screened a series of 4-anilinoquinolines and 4-anilinoquinazolines and identified novel inhibitors of Mycobacterium tuberculosis (Mtb). The focused 4-anilinoquinoline/quinazoline scaffold arrays yielded compounds with high potency and the identification of 6,7-dimethoxy-N-(4-((4-methylbenzyl)oxy)phenyl)quinolin-4-amine (34) with an MIC90 value of 0.63–1.25 μM. We also defined a series of key structural features, including the benzyloxy aniline and the 6,7-dimethoxy quinoline ring, that are important for Mtb inhibition. Importantly the compounds showed very limited toxicity and scope for further improvement by iterative medicinal chemistry.
- Asquith, Christopher R.M.,Fleck, Neil,Torrice, Chad D.,Crona, Daniel J.,Grundner, Christoph,Zuercher, William J.
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p. 2695 - 2699
(2019/08/07)
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- A novel strategy to the synthesis of 4-anilinoquinazoline derivatives
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A novel approach to prepare 4-anilinoquinazoline derivatives based on the transformation of indoline-2,3-dione to formamidine was developed. The processes with this approach are simple, efficient, and environmentally friendly. The efficiency of this approach was evaluated by synthesizing 17 4-anilinoquinazolines and comparing the obtained yields with those achievable through conventional synthetic methods. It was the first time that compounds 8d, 8e, 8h, and 13b-f were synthesized. The characteristics of the IR and the UV spectra of these compounds and the effects of their substituents on the spectra were observed.
- Wang, Zheng,Wang, Cuiling,Sun, Yanni,Zhang, Ning,Liu, Zhulan,Liu, Jianli
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p. 906 - 913
(2014/01/23)
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- Investigation of quinazolines as inhibitors of breast cancer resistance protein (ABCG2)
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Chemotherapy is one of the major forms of cancer treatment. Unfortunately, tumors are prone to multidrug resistance leading to failure of treatment. Breast cancer resistance protein (BCRP), the second member of ABC transporter subfamily G, has been found to play a major role in drug efflux and hence multidrug resistance. Until now, very few potent and selective BCRP inhibitors like Ko143 have been identified. In the search for more potent and selective BCRP inhibitors, we synthesized and investigated a series of differently substituted quinazoline compounds. Several variations at positions 2, 4, 6 and 7 of the quinazoline scaffold were carried out to develop a structure-activity- relationship analysis for these compounds. It was found that compounds bearing a phenyl substituent at position 2 of the 4-anilinoquinazoline scaffold were most potent. On the aniline ring at position 4 of the quinazoline moiety substituents like NO2, CN, CF3 led to very high BCRP inhibition potencies. The most potent compounds were further investigated for their intrinsic cytotoxicity and their ability to reverse the multidrug resistance. Compound 20, an anilinoquinazoline bearing a phenyl ring at position 2 and meta-nitro substitution on the 4-anilino ring, was found to have the highest therapeutic ratio. The most active compounds from each variation were also investigated for their effect on BCRP expression. It was found that compound 20 has no significant effect on BCRP expression, while compound 31 decreased the surface BCRP expression. The only difference in the two compounds was the presence of a 3,4-dimethoxyphenyl ring in compound 31 instead of phenyl substitution at position 2 of the quinazoline moiety. From the study of all target compounds, compound 20 was the most prominent compound having inhibitory potency even higher than Ko143, the most potent BCRP inhibitor known. Compound 20 was also found to be selective towards BCRP with a very high therapeutic ratio.
- Juvale, Kapil,Gallus, Jennifer,Wiese, Michael
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p. 7858 - 7873
(2014/01/06)
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- Impact of aryloxy-linked quinazolines: A novel series of selective VEGFR-2 receptor tyrosine kinase inhibitors
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Three series of 6,7-dimethoxyquinazoline derivatives substituted in the 4-position by aniline, N-methylaniline and aryloxy entities, targeting EGFR and VEGFR-2 tyrosine kinases, were designed and synthesized. Pharmacological activities of these compounds
- Garofalo, Antonio,Goossens, Laurence,Six, Perrine,Lemoine, Amélie,Ravez, Séverine,Farce, Amaury,Depreux, Patrick
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scheme or table
p. 2106 - 2112
(2011/04/24)
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- A novel approach to quinazolin-4(3H)-one via quinazoline oxidation: an improved synthesis of 4-anilinoquinazolines
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A novel strategy to prepare 4-anilinoquinazoline derivatives based on the oxidation of the quinazoline ring is described. Quinazoline oxidation has been investigated and improved, thus leading to an efficient and high yielding method to quinazolin-4(3H)-ones. Efficiency of this approach has been evaluated synthesizing four well known tyrosine kinase inhibitors and comparing the obtained yields with those achievable through conventional synthetic methods.
- Marzaro, Giovanni,Guiotto, Adriano,Pastorini, Giovanni,Chilin, Adriana
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experimental part
p. 962 - 968
(2010/03/25)
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- Synthesis and biological evaluation of substituted 6-alkynyl-4-anilinoquinazoline derivatives as potent EGFR inhibitors
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A series of C-6 or C-3′ alkynyl-substituted 4-anilinoquinazoline derivatives was prepared straightforwardly by a Sonogashira reaction of the corresponding bromo-substituted 4-anilinoquinazolines. Bioactive assay of these compounds for in vitro EGFR kinase inhibition demonstrated that the novel 6-hydroxypropynyl-4-anilinoquinazoline 5e was a very potent EGFR kinase inhibitor with an IC50 of 14 nM.
- Liu, Lee Tai,Yuan, Ta-Tung,Liu, Hung-Huang,Chen, Shyh-Fong,Wu, Ying-Ta
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p. 6373 - 6377
(2008/03/14)
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- Efficient synthesis of 4-aminoquinazoline and thieno[3,2-d]pyrimidin-4- ylamine derivatives by microwave irradiation
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(Chemical Equation Presented) A simple, efficient, and high-yielding synthesis of quinazolin-4-ylamine and thieno[3,2-d]pyrimidin-4-ylamine derivatives is reported under microwave irradiation conditions. Reaction conditions including temperature, solvent,
- Yoon, David S.,Han, Ying,Stark, Todd M.,Haber, James C.,Gregg, Brian T.,Stankovich, Sara B.
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p. 4775 - 4778
(2007/10/03)
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- Quinazoline formulations and therapeutic use thereof
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Pharmaceutical compositions for parenteral administration of poorly soluble quinazoline compounds in the form of microemulsions or micellar solutions are described. The compositions are useful in treating patients suffering from cancer or having allergic
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- Synthesis and anti-tumor activity of 6,7-dialkoxy-4-phenylamino-quinazolines
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Compounds of the formula: wherein: Rais iodo, (C1-C4)hydroxyalkyl, benzyloxy, OCF3, SCF3, SO3H, SO2F, SO2NR2R3where R2is hydrogen or (
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- Synthesis of [methoxy-11C]PD153035, a selective EGF receptor tyrosine kinase inhibitor
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[Methoxy-11C]PD153035, a potent and specific inhibitor of the EGF receptor tyrosine kinase, was prepared by O-alkylation of O-desmethyl PD153035 with [11C]methyl iodide in DMF. The radiochemical incorporation of [11C]CH3I was on the order of 45%. The mean specific activity obtained at end-of-synthesis (EOS) was 26 GBq/μmol (n=3; range 20-36 GBq/μmol) and total synthesis time was 45-50 minutes including formulation.
- Johnstroem, Peter,Fredriksson, Anna,Thorell, Jan-Olov,Stone-Elander, Sharon
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p. 623 - 629
(2007/10/03)
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- A novel series of 4-phenoxyquinolines: Potent and highly selective inhibitors of PDGF receptor autophosphorylation
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A novel series of 4-phenoxyquinolines some of which showed potent and highly selective inhibitory activities for PDGF receptor autophosphorylation, was discovered. Interestingly, their structures were very similar to those of the selective inhibitors for EGF receptor autophosphorylation.
- Kubo, Kazuo,Shimizu, Toshiyuki,Ohyama, Shin-Ichi,Murooka, Hideko,Nishitoba, Tsuyoshi,Kato, Shinichiro,Kobayashi, Yoshiko,Yagi, Mikio,Isoe, Toshiyuki,Nakamura, Kazuhide,Osawa, Tatsushi,Izawa, Toshio
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p. 2935 - 2940
(2007/10/03)
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- Tyrphostins IV - Highly potent inhibitors of EGF receptor kinase. Structure-activity relationship study of 4-anilidoquinazolines
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Potent 4-anilido-substituted quinazolines which potently inhibit epidermal growth factor receptor (EGFR) kinase were prepared. Structure-activity relationship studies reveal high sensitivity to substitution at the aniline ring.
- Gazit, Aviv,Chen, Jeffrey,Harald, App,McMahon, Gerald,Hirth, Peter,Chen, Irit,Levitzki, Alexander
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p. 1203 - 1207
(2007/10/03)
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