13790-39-1Relevant articles and documents
Design, synthesis and biological evaluation of novel histone deacetylase inhibitors incorporating 4-aminoquinazolinyl systems as capping groups
Zhang, Qingwei,Li, Yang,Zhang, Baoyin,Lu, Bingliu,Li, Jianqi
, p. 4885 - 4888 (2017)
A series of hydroxamic acid-based HDACIs with 4-aminoquinazolinyl moieties as capping groups was profiled. Most compounds showed more potent HDACs inhibition activity than clinically used drug SAHA. Among them, compounds 5f and 5h selectively inhibited HDAC 1,2 over HDAC8, and showed strong activity in several cellular assays, not possessing significant toxicity to primary human cells and hERG inhibition. Strikingly, 5f possessed acceptable pharmacokinetic characteristics and exhibited significant antitumor activity in an A549 xenograft model study at well tolerated doses.
6,7-Dimethoxy-Quinazolin-4-yl-Amino-Nicotinamide Derivatives as Potent Inhibitors of VEGF Receptor II
Ashok, Abhishek,Thanukrishnan, Kannan,Bhojya Naik, Halehatty S.,Ghosh, Soma
, p. 1723 - 1728 (2017)
The sprouting of new blood vessels, or angiogenesis, is necessary for any solid tumor to grow large enough to cause life-threatening disease. Vascular endothelial growth factor (VEGF) is one of the key promoters of tumor-induced angiogenesis. Inhibition of the VEGF signaling pathway has emerged as one of the most promising new approaches for cancer therapy. A series of 6,7-dimethoxy-quinazolin-4-yl-amino-nicotinamides were synthesized and evaluated as antagonists of VEGF receptor II (VEGFR-2). Many compounds display VEGFR-2 inhibitory activity, and compound 7a was found to be a potent inhibitor of VEGFR-2 in an homogeneous time-resolved fluorescence enzymatic assay with an IC50 as low as 48 nM (comparable activity to ZD-6474).
Synthesis of [methoxy-11C]PD153035, a selective EGF receptor tyrosine kinase inhibitor
Johnstroem, Peter,Fredriksson, Anna,Thorell, Jan-Olov,Stone-Elander, Sharon
, p. 623 - 629 (1998)
[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.
Syntheses, antiviral activities and induced resistance mechanisms of novel quinazoline derivatives containing a dithioacetal moiety
Xie, Dandan,Shi, Jing,Zhang, Awei,Lei, Zhiwei,Zu, Guangcheng,Fu, Yun,Gan, Xiuhai,Yin, Limin,Song, Baoan,Hu, Deyu
, p. 433 - 443 (2018)
A series of novel quinazoline derivatives containing a dithioacetal moiety were designed and synthesized, and their structures were characterized by 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, and high-resolution mass spectrometry. Bioassay results indicated that compound 4b exhibited remarkable protective activity against cucumber mosaic virus (CMV, EC50 = 248.6 μg/mL) and curative activity against potato virus Y (EC50 = 350.5 μg/mL), which were better than those of ningnanmycin (357.7 μg/mL and 493.7 μg/mL, respectively). Moreover, compound 4b could increase the chlorophyll content in plants, improve photosynthesis, and effectively induce tobacco anti-CMV activity.
6-Aryl substituted 4-(4-cyanomethyl) phenylamino quinazolines as a new class of isoform-selective PI3K-alpha inhibitors
Yadav, Rammohan R.,Guru, Santosh K.,Joshi, Prashant,Mahajan, Girish,Mintoo, Mubashir J.,Kumar, Vikas,Bharate, Sonali S.,Mondhe, Dilip M.,Vishwakarma, Ram A.,Bhushan, Shashi,Bharate, Sandip B.
, p. 731 - 743 (2016)
Isoform-selective inhibition of PI3K-α has been identified as one of the important strategy to discover effective and safer anticancer agents. Herein, we report discovery of ‘quinazoline’ as a new chemotype for isoform-selective PI3K-α inhibitors. The indolyl substituted quinazoline 9u displayed selective inhibition of PI3K-α with IC50value of 0.201?μM with >49.7 over PI3K-β, and δ-isoforms. Quinazoline 9u also inhibited PI3K-γ with IC50value of 0.750 μM (3.7 fold selective for α-versus γ-isoform). The isoform-selective inhibition was also demonstrated at protein-expression level by western-blot analysis in MCF-7 and PC-3?cells. The isoform-selective inhibitor 9u also showed inhibition of phospho-Akt levels in these cells. Quinazoline 9u showed in-vitro cytotoxicity in MCF-7?cells with GI50of 7?μM, which was highly selective for cancer cells, as it was non-toxic to normal cells fR2, HEK293 and hGF (GI50?>?50?μM). Compound 9u at 25?mg/kg dose showed 62 and 37% TGI in Ehrlich Ascites Carcinoma and Ehrlich Solid Tumor mice models. In nutshell, our efforts to identify potent and efficacious PI3K inhibitors resulted in the discovery of a new class of isoform-selective PI3K-α inhibitors possessing promising in-vivo anticancer activity.
Design, Synthesis and Bioevaluation of Two Series of 3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-ones and N-(1-Benzylpiperidin-4-yl)quinazolin-4-amines
Lan, Ta Thu,Anh, Duong Tien,Pham-The, Hai,Dung, Do Thi Mai,Park, Eun Jae,Jang, Sun Dong,Kwon, Joo Hee,Kang, Jong Soon,Thuan, Nguyen Thi,Han, Sang-Bae,Nam, Nguyen-Hai
, (2020)
Two series of 3-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-ones and N-(1-benzylpiperidin-4-yl)quinazolin-4-amines were designed initially as potential acetylcholine esterase inhibitors. Biological evaluation demonstrated that N-(1-benzylpiperidin-4-yl)quinazolin-4-amines significantly inhibited AChE activity. Especially, two compounds of them were found to be the most potent with relative AChE inhibition percentages of 87 percent in comparison to donepezil. The docking studies with AChE showed similar interactions between donepezil and four derivatives. N-(1-Benzylpiperidin-4-yl)quinazolin-4-amines also exhibited significant DPPH scavenging effects. The two series of compound also exerted moderate to good cytotoxicity against three human cancer cell lines, including SW620 (human colon cancer), PC-3 (prostate cancer), and NCI?H23 (lung cancer), with 3-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-one being the most cytotoxic agent. 3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-one significantly induced early apoptosis and arrested the SW620 cells at G2/M phase. From this study, two compounds of N-(1-benzylpiperidin-4-yl)quinazolin-4-amines could serve as new leads for further design and AChE inhibitors, while 3-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-one could serve as a new lead for the design and development of more potent anticancer agents.
Synthesis and biological evaluation of substituted 6-alkynyl-4-anilinoquinazoline derivatives as potent EGFR inhibitors
Liu, Lee Tai,Yuan, Ta-Tung,Liu, Hung-Huang,Chen, Shyh-Fong,Wu, Ying-Ta
, p. 6373 - 6377 (2007)
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.
6,7-Dimethoxy-quinazolin-4-yl-amino-thiophene-2-carboxamides as Potent Inhibitors of VEGF Receptors 1 and 2
Ashok, Abhishek,Thanukrishnan, Kannan,Bhojya Naik, Halehatty S.,Shaik, Abdul Gaffar
, p. 1065 - 1070 (2017)
The identification of agents with antiproliferative activity against endothelial cells has significant value for the treatment of many angiogenesis-dependent pathologies. The vascular endothelial growth factor (VEGF) and its receptors have been implicated as key factors in tumor angiogenesis and are major targets in cancer therapy. A series of novel 6,7-dimethoxy-quinazolin-4-yl-amino-thiophene-2-carboxamides were synthesized and evaluated as antagonists of VEGFR-1 and VEGFR-2. More specifically, several analogues exhibited low micromolar to nanomolar potency in the inhibition of VEGFR-1 and VEGFR-2. The most potent compound in this series, compound 7b, was found to be a potent inhibitor of VEGFR-2 in a homogeneous time-resolved fluorescence enzymatic assay with an IC50 as low as 87 nm.
Discovery of New 4-Indolyl Quinazoline Derivatives as Highly Potent and Orally Bioavailable P-Glycoprotein Inhibitors
Chen, Zhe-Sheng,Dai, Qing-Qing,Li, Guo-Bo,Liu, Hong-Min,Liu, Hui,Wang, Bo,Wang, Shaomeng,Yu, Bin,Yuan, Shuo,Zhang, Jing-Ya,Zhang, Xiao-Nan,Zuo, Jia-Hui
, p. 14895 - 14911 (2021/10/12)
The major drawbacks of P-glycoprotein (P-gp) inhibitors at the clinical stage make the development of new P-gp inhibitors challenging and desirable. In this study, we reported our structure-activity relationship studies of 4-indolyl quinazoline, which led to the discovery of a highly effective and orally active P-gp inhibitor, YS-370. YS-370 effectively reversed multidrug resistance (MDR) to paclitaxel and colchicine in SW620/AD300 and HEK293T-ABCB1 cells. YS-370 bound directly to P-gp, did not alter expression or subcellular localization of P-gp in SW620/AD300 cells, but increased the intracellular accumulation of paclitaxel. Furthermore, YS-370 stimulated the P-gp ATPase activity and had moderate inhibition against CYP3A4. Significantly, oral administration of YS-370 in combination with paclitaxel achieved much stronger antitumor activity in a xenograft model bearing SW620/Ad300 cells than either drug alone. Taken together, our data demonstrate that YS-370 is a promising P-gp inhibitor capable of overcoming MDR and represents a unique scaffold for the development of new P-gp inhibitors.
Discovery of BPR1R024, an Orally Active and Selective CSF1R Inhibitor that Exhibits Antitumor and Immunomodulatory Activity in a Murine Colon Tumor Model
Chang, Chun-Yu,Chen, Chiung-Tong,Chou, Ling-Hui,Hsieh, Hsing-Pang,Huang, Yu-Chen,Lai, You-Liang,Lee, Kun-Hung,Lin, Wen-Hsing,Shih, Chuan,Su, Yu-Chieh,Wang, Pei-Chen,Wu, Cai-Syuan,Yang, Chen-Ming,Yeh, Teng-Kuang,Yen, Wan-Ching
supporting information, p. 14477 - 14497 (2021/10/20)
Colony-stimulating factor-1 receptor (CSF1R) is implicated in tumor-associated macrophage (TAM) repolarization and has emerged as a promising target for cancer immunotherapy. Herein, we describe the discovery of orally active and selective CSF1R inhibitors by property-driven optimization of BPR1K871 (9), our clinical multitargeting kinase inhibitor. Molecular docking revealed an additional nonclassical hydrogen-bonding (NCHB) interaction between the unique 7-aminoquinazoline scaffold and the CSF1R hinge region, contributing to CSF1R potency enhancement. Structural studies of CSF1R and Aurora kinase B (AURB) demonstrated the differences in their back pockets, which inspired the use of a chain extension strategy to diminish the AURA/B activities. A lead compound BPR1R024 (12) exhibited potent CSF1R activity (IC50 = 0.53 nM) and specifically inhibited protumor M2-like macrophage survival with a minimal effect on antitumor M1-like macrophage growth. In vivo, oral administration of 12 mesylate delayed the MC38 murine colon tumor growth and reversed the immunosuppressive tumor microenvironment with the increased M1/M2 ratio.
