- Design, synthesis and biological evaluation of novel histone deacetylase inhibitors incorporating 4-aminoquinazolinyl systems as capping groups
-
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.
- Zhang, Qingwei,Li, Yang,Zhang, Baoyin,Lu, Bingliu,Li, Jianqi
-
-
Read Online
- Pure red phosphorescent iridium(iii) complexes containing phenylquinazoline ligands for highly efficient organic light-emitting diodes
-
Two novel heteroleptic iridium complexes containing 4-phenylquinazoline (pqz) as a cyclometalating ligand, namelyIr1andIr2, are designed and synthesized. Methoxy groups are incorporated into the 6- and 7-sites of pqz rings to tune the physical properties
- Tian, Houru,Liu, Di,Li, Jiuyan,Ma, Mengyao,Lan, Ying,Wei, Wenkui,Niu, Rui,Song, Kai
-
-
Read Online
- 6,7-Dimethoxy-Quinazolin-4-yl-Amino-Nicotinamide Derivatives as Potent Inhibitors of VEGF Receptor II
-
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).
- Ashok, Abhishek,Thanukrishnan, Kannan,Bhojya Naik, Halehatty S.,Ghosh, Soma
-
-
Read Online
- Pro-apoptotic activity of novel 4-anilinoquinazoline derivatives mediated by up-regulation of bax and activation of poly(ADP-ribose) phosphatase in ehrlich ascites carcinoma cells
-
Quinazolines are very important class of heterocyclic compounds with antitumor properties. In search of novel anti-tumour agents, a series of 4-anilinoquinazolines were synthesized and characterized using proton and 13C NMR, Fourier transform infrared and mass spectroscopic techniques. These compounds were evaluated for their cytotoxic effect on ehrlich ascites carcinoma cells using MTT assay. Among the tested compounds, compound N-(3-((6,7-dimethoxyquinazoline-4-yl)amino)phenyl)-4-nitrobenzene sulfonamide exhibited more potent activity with an IC50 value of 10.29 ± 1.14 μM against ehrlich ascites carcinoma cell line. in vivo studies using compound N-(3-((6,7-dimethoxyquinazoline-4-yl)amino)phenyl)-4-nitrobenzene sulfonamide (4G) showed that there was reduction in the mice body weight, ascites volume and decrease in cell number. Mice treated with compound 4G showed higher survivability compared with that of control mice. The cells treated with compound 4G also exhibited typical morphological changes of apoptotic damages. Further, compound 4G induced tumour cell death by activating pro-apoptotic protein Bax which activates caspase-3 which in turn cleaves poly (ADP- ribose) polymerase and causes DNA fragmentation. Thus, our results strongly conclude that our compound 4G acts as a antincancer agent by inducing apoptosis in ehrlish ascites carcinoma cells.
- Devegowda, Preethi Saligrama,Balaji, Kyathegowdanadoddi Srinivas,Prasanna, Doddakunche Shivaramu,Swaroop, Toreshettahally Ramesh,Jayarama, Shankar,Siddalingaiah, Lokesh,Rangappa, Kanchugarakoppal Subbegowda
-
-
Read Online
- Synthesis of [methoxy-11C]PD153035, a selective EGF receptor tyrosine kinase inhibitor
-
[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
-
-
Read Online
- Synthesis and biological evaluation of novel triazolyl 4-anilinoquinazolines as anticancer agents
-
The synthesis of novel triazolyl 4-anilinoquinazolines in five sequential synthetic steps via copper-catalyzed click chemistry and their anticancer biological evaluation is described.
- Hassan, Hani Mutlak A.,Denetiu, Iuliana,Khan, Salman A.,Rehan, Mohd,Sakkaf, Kaltoom,Gauthaman, Kalamegam
-
-
Read Online
- Syntheses, antiviral activities and induced resistance mechanisms of novel quinazoline derivatives containing a dithioacetal moiety
-
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.
- Xie, Dandan,Shi, Jing,Zhang, Awei,Lei, Zhiwei,Zu, Guangcheng,Fu, Yun,Gan, Xiuhai,Yin, Limin,Song, Baoan,Hu, Deyu
-
-
Read Online
- The preparation and SAR of 4-(anilino), 4-(phenoxy), and 4-(thiophenoxy)-quinazolines: Inhibitors of p56(lck) and EGF-R tyorsine kinase activity
-
We report herein our preliminary results of a SAR study of quinazoline-based inhibitors of p56(lck) and EGF-R tyrosine kinase activity. The most potent inhibitor of p56(lck) identified, RPR-108518A (10), has an IC50 of 0.50 μM. The 3-chlorophenoxy- and 3-chlorothiophenoxy- derivatives 5 and 6 were also shown to be extremely potent EGF-R inhibitors.
- Myers, Michael R.,Setzer, Natalie N.,Spada, Alfred P.,Zulli, Allison L.,Hsu, Chin-Yi J.,Zilberstein, Asher,Johnson, Susan E.,Hook, Linda E.,Jacoski, Mary V.
-
-
Read Online
- 6-Aryl substituted 4-(4-cyanomethyl) phenylamino quinazolines as a new class of isoform-selective PI3K-alpha inhibitors
-
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.
- 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.
-
-
Read Online
- Epidermal growth factor receptor tyrosine kinase: Structure-activity relationships and antitumour activity of novel quinazolines
-
Investigation of structure-activity relationships of novel quinazolines has identified 4-(4-isoquinolylamino)-quinazoline and a 4-(trans-2-phenylcyclopropylamino)-quinazoline as potent inhibitors of EGF-receptor tyrosine kinase in vitro. Further modificatons of the latter compound have identified a derivative which shows anti-tumour activity against a tumour xenograft model when dosed orally once per day.
- Gibson,Grundy,Godfrey,Woodburn,Ashton,Curry,Scarlett,Barker,Brown
-
-
Read Online
- 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
-
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.
- 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
-
-
Read Online
- Targeting epidermal growth factor receptor with ferrocene-based kinase inhibitors
-
A series of ferrocene analogues based on a 6,7-dimethoxy-N- phenylquinazolin-4-amine template has been synthesized, and two compounds were characterized in the solid state by X-ray crystallography. The compounds have been tested for in vitro anticancer activity, against epidermal growth receptor (EGFR), and submicromolar IC50 values have been determined.
- Amin, Jahangir,Chuckowree, Irina,Tizzard, Graham J.,Coles, Simon J.,Wang, Minghua,Bingham, John P.,Hartley, John A.,Spencer, John
-
-
Read Online
- Synthesis and biological evaluation of substituted 6-alkynyl-4-anilinoquinazoline derivatives as potent EGFR inhibitors
-
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
-
-
Read Online
- Novel 4-[5-(substituted-1,2,4-oxadiazol-3-yl)phenylamine] derivatives of 6,7-dimethoxy-quinazolines as potent inhibitors of VEGF receptors I and II
-
A series of novel 4-[5-(substituted-1,2,4-oxadiazol-3-yl)phenylamine] derivatives at C-4 position of 6,7-dimethoxy-quinazolines were synthesized through multistep synthesis. The new compounds were tested for inhibition of vascular endothelial growth factor receptor II (VEGFR-2). Many compounds display VEGFR-2 inhibitory activity with an IC50 as low as 0.017 μM in an HTRF enzymatic assay. Compound 8j exhibited good antibacterial activity by inhibiting the growth of methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA) and ATCC 35218 Escherichia coli (MIC: 0.25-16.00 μg/mL).
- Ashok, Abhishek,Thanukrishnan, Kannan,Naik, Halehatty S. Bhojya,Ghosh, Soma
-
-
Read Online
- 6,7-Dimethoxy-quinazolin-4-yl-amino-thiophene-2-carboxamides as Potent Inhibitors of VEGF Receptors 1 and 2
-
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.
- Ashok, Abhishek,Thanukrishnan, Kannan,Bhojya Naik, Halehatty S.,Shaik, Abdul Gaffar
-
-
Read Online
- Synthesis and biological evaluation of some novel thiophene-bearing quinazoline derivatives as EGFR inhibitors
-
Background: With the approval of gefitinib, erlotinib, afatinib, and osimertinib for clinical use, targeting Epidermal Growth Factor Receptor (EGFR) has been intensively pursued. Similar to most therapies, challenges related to the treatment resistance against these drugs have emerged over time, so new EGFR Tyrosine Kinase Inhibitors (TKIs) need to be developed. This study aimed to investigate the potential use of a series of thiophene-bearing quinazoline derivatives as EGFR inhibitors. We designed and synthesized nine quinazolin derivatives, among which five compounds (5e, 5f, 5g, 5h, and 5i) were reported for the first time. Methods: Two cancer cell lines, A431 (overexpressing EGFR) and A549 (EGFR wild-type and K-ras mutation), were treated by these compounds and subjected to MTT assay. The A431 cells were selected for further treatment (5e) and Western blot analysis. Results: Although the compounds exerted no obvious effects on the proliferation of A549 cells, seven out of the nine compounds significantly inhibited the growth of A431 cells. In particular, the IC50 values of 5e and erlotinib were nearly equal. Western blot results showed that 5e significantly inhibited EGFR autophosphorylation in A431 cells. Structure-activity relationships indicated that quinazolines bearing 6,7-side chains were more potent than those unsubstituted at the 6,7-positions. Moreover, electron-withdrawing hydrophobic groups on the 5-position of the thiophene were preferred, such as chlorine or bromine atom. Conclusion: Nine 4-aminoquinazolin derivatives were designed, synthesized, and evaluated against A431 and A549 cell lines. Seven compounds significantly inhibited the growth of A431 cells. In particular, 5e possessed similar antitumor potency to that of erlotinib.
- Zou, Min,Jin, Bo,Liu, Yanrong,Chen, Huiping,Zhang, Zhuangli,Zhang, Changzheng,Zhao, Zhihong,Zheng, Liyun
-
-
Read Online
- Quinazoline compound and application thereof
-
The invention relates to a quinazoline-containing compound as shown in a general formula (I), and a pharmaceutically acceptable salt, a solvate and a prodrug thereof, wherein substituent groups R1, R2, R3, R4, R5, R6, p, m and n are defined in the specification. The invention also relates to application of the compound shown in the general formula (I) in preparation of antitumor drugs, and also relates to application of the compound, the pharmaceutically acceptable salt, the solvate and the prodrug thereof in preparation and/or prevention and alleviation of cancers caused by tumor cells of human tissues or organs, wherein the cancers are preferably colon cancer, liver cancer, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, skin cancer, ovarian cancer, cervical cancer, kidney cancer, leukemia, prostate cancer, pancreatic cancer, bladder cancer, rectal cancer, osteosarcoma, nasopharyngeal cancer or gastric cancer and the like.
- -
-
Paragraph 0105-016; 0108
(2021/05/12)
-
- Discovery of New 4-Indolyl Quinazoline Derivatives as Highly Potent and Orally Bioavailable P-Glycoprotein Inhibitors
-
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.
- 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)
-
- Discovery of quinazolinyl-containing benzamides derivatives as novel HDAC1 inhibitors with in vitro and in vivo antitumor activities
-
A series of quinazolinyl-containing benzamide derivatives were designed, synthesized and evaluated for their in vitro histone deacetylase 1 (HDAC1) inhibitory activities. Compounds 11a surpassed the known class I selective HDAC inhibitor MS-275 in both HDAC1 enzymatic inhibitory activity and cellular anti-proliferative activity against a selected set of cancer cell types (Hut78, K562, Hep3B and HCT116 cells) with no observed effects on human normal cells. In particular, compound 11a inhibited HDAC1 over the other tested HDACs isoforms (HDAC2, HDAC6 and HDAC8) with acceptable safety profiles. Moreover, compound 11a displayed favorable oral pharmacokinetic properties and showed significant antitumor activity in the A549 tumor xenograft model in vivo.
- Zhang, Zixue,Zhang, Qingwei,Zhang, Hao,Jiao, Minru,Guo, Zheng,Peng, Xinyan,Fu, Lei,Li, Jianqi
-
-
- Discovery of BPR1R024, an Orally Active and Selective CSF1R Inhibitor that Exhibits Antitumor and Immunomodulatory Activity in a Murine Colon Tumor Model
-
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.
- 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
-
p. 14477 - 14497
(2021/10/20)
-
- Method suitable for industrial production and preparation of gefitinib
-
The invention discloses a method suitable for industrial production and preparation of gefitinib, which takes 6, 7-dimethoxy-3H-quinazoline-4-one as a raw material, and gefitinib is obtained through four steps of chlorination, amination, demethylation and reaction with N-(3-chloropropyl) morpholine, so as to solve the problems that the existing synthetic route is complex and long, the total yield is low, a large number of environment-unfriendly reagents are used, and the technology cannot be amplified. According to the method, pyridine hydrochloride/DMSO is utilized to remove 6-position methyl in a high-selectivity manner, a key intermediate N-(3-chloro-4-fluorophenyl)-6-hydroxy-7-methoxyquinazoline-4-amine is obtained in a high yield manner, and convenient synthesis of the intermediate is realized. The synthesis method has the advantages of cheap and easily available raw materials and short route, and gefitinib and derivatives modified by different 6-site groups can be rapidly obtained. The preparation method solves the bottleneck problem of large-scale production of the active pharmaceutical ingredient gefitinib.
- -
-
Paragraph 0022-0029
(2021/08/19)
-
- Discovery of quinazoline derivatives as a novel class of potent and in vivo efficacious LSD1 inhibitors by drug repurposing
-
Histone lysine-specific demethylase 1 (LSD1) is an important epigenetic modulator, and is implicated in malignant transformation and tumor pathogenesis in different ways. Therefore, the inhibition of LSD1 provides an attractive therapeutic target for cancer therapy. Based on drug repurposing strategy, we screened our in-house chemical library toward LSD1, and found that the EGFR inhibitor erlotinib, an FDA-approved drug for lung cancer, possessed low potency against LSD1 (IC50 = 35.80 μM). Herein, we report our further medicinal chemistry effort to obtain a highly water-soluble erlotinib analog 5k (>100 mg/mL) with significantly enhanced inhibitory activity against LSD1 (IC50 = 0.69 μM) as well as higher specificity. In MGC-803 cells, 5k suppressed the demethylation of LSD1, indicating its cellular activity against the enzyme. In addition, 5k had a remarkable capacity to inhibit colony formation, suppress migration and induce apoptosis of MGC803 cells. Furthermore, in MGC-803 xenograft mouse model, 5k treatment resulted in significant reduction in tumor size by 81.6% and 96.1% at dosages of 40 and 80 mg/kg/d, respectively. Our findings indicate that erlotinib-based analogs provide a novel structural set of LSD1 inhibitors with potential for further investigation, and may serve as novel candidates for the treatment of LSD1-overexpressing cancers.
- Li, Zhonghua,Qin, Tingting,Li, Zhongrui,Zhao, Xuan,Zhang, Xinhui,Zhao, Taoqian,Yang, Nian,Miao, Jinxin,Ma, Jinlian,Zhang, Zhenqiang
-
-
- Synthesis and in vitro anti-bladder cancer activity evaluation of quinazolinyl-arylurea derivatives
-
Based on the structural modification of molecular-targeted agent sorafenib, a series of quinazolinyl-arylurea derivatives were synthesized and evaluated for their anti-proliferative activities against six human cancer cell lines. Compared with other cell lines tested, T24 was more sensitive to most compounds. Compound 7j exhibited the best profile with lower IC50 value and favorable selectivity. In this study, we focused on 7j-induced death forms of T24 cells and tried to elucidate the reason for its potent proliferative inhibitory activity. Compound 7j treatment could trigger three different cell death forms including apoptosis, ferroptosis, and autophagy; which form would occur depended on the concentrations and incubation time of 7j: (1) Lower concentrations within the initial 8 h of 7j treatment led to apoptosis-dependent death. (2) Ferroptosis and autophagy occurred in the case of higher concentrations combining with extended incubation time through effectively regulating the Sxc?/GPx4/ROS and PI3K/Akt/mTOR/ULK1 pathways, respectively. (3) The above death forms were closely associated with intracellular ROS generation and decreased mitochondrial membrane potential induced by 7j. In molecular docking and structure-activity relationship analyses, 7j could bind well to the active site of the corresponding receptor glutathione peroxidase 4 (GPx4). Compound 7j could be a promising lead for molecular-targeted anti-bladder cancer agents’ discovery.
- Chen, Jia-Nian,Li, Ting,Cheng, Li,Qin, Tai-Sheng,Sun, Ye-Xiang,Chen, Chu-Ting,He, Yue-Zhen,Liu, Guang,Yao, Di,Wei, Ying,Li, Qiu-Yin,Zhang, Guang-Ji
-
-
- Discovery and Characterization of the Potent and Highly Selective (Piperidin-4-yl)pyrido[3,2- d]pyrimidine Based in Vitro Probe BAY-885 for the Kinase ERK5
-
The availability of a chemical probe to study the role of a specific domain of a protein in a concentration- and time-dependent manner is of high value. Herein, we report the identification of a highly potent and selective ERK5 inhibitor BAY-885 by high-throughput screening and subsequent structure-based optimization. ERK5 is a key integrator of cellular signal transduction, and it has been shown to play a role in various cellular processes such as proliferation, differentiation, apoptosis, and cell survival. We could demonstrate that inhibition of ERK5 kinase and transcriptional activity with a small molecule did not translate into antiproliferative activity in different relevant cell models, which is in contrast to the results obtained by RNAi technology.
- Nguyen, Duy,Lemos, Clara,Wortmann, Lars,Eis, Knut,Holton, Simon J.,Boemer, Ulf,Moosmayer, Dieter,Eberspaecher, Uwe,Weiske, Joerg,Lechner, Christian,Prechtl, Stefan,Suelzle, Detlev,Siegel, Franziska,Prinz, Florian,Lesche, Ralf,Nicke, Barbara,Nowak-Reppel, Katrin,Himmel, Herbert,Mumberg, Dominik,Von Nussbaum, Franz,Nising, Carl F.,Bauser, Marcus,Haegebarth, Andrea
-
p. 928 - 940
(2019/01/30)
-
- Virtual Screening Identifies Irreversible FMS-like Tyrosine Kinase 3 Inhibitors with Activity toward Resistance-Conferring Mutations
-
The use of covalent irreversible binding inhibitors is an established concept for drug development. Usually, the discovery of new irreversible kinase inhibitors occurs serendipitously, showing that efficient rational approaches for the rapid discovery of new drugs are needed. Herein, we report a virtual screening strategy that led to the discovery of irreversible inhibitors of FMS-like tyrosine kinase 3 (FLT3) involved in the pathogenesis of acute myeloid leukemia. A virtual screening library was designed to target the highly conserved Cys828 residue preceding the DFG motif by modification of reported reversible inhibitors with chemically reactive groups. Prospective covalent docking allowed the identification of two lead series, resulting in a massive increase in inhibition of kinase activity and cell viability by irreversible inhibitors compared to the corresponding reversible scaffolds. Lead compound 4b (BSc5371) displays superior cytotoxicity in FLT3-dependent cell lines to compounds in recent clinical trials and overcomes drug-resistant mutations.
- Bensinger, Dennis,Stubba, Daniel,Cremer, Anjali,Kohl, Vanessa,Wa?mer, Theresa,Stuckert, Johanna,Engemann, Victoria,Stegmaier, Kimberly,Schmitz, Katja,Schmidt, Boris
-
p. 2428 - 2446
(2019/03/11)
-
- IDENTIFICATION AND USE OF ERK5 INHIBITORS
-
The present invention covers heterocyclic compounds of general formula (I) in which T, U, Y, Z, R1 and R3 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of cancer disorders, as a sole agent or in combination with other active ingredients.
- -
-
-
- Novel quinazoline EGFR inhibitor, and preparation method and application thereof
-
A novel quinazoline EGFR inhibitor, and a preparation and an application thereof belong to the field of synthesis of medicines. The novel quinazoline EGFR inhibitor has a general formula shown in thedescription; and in the general formula, R is one from H, F, Cl, Br, and I, and R1 and R2 are same to or different from each other, and are respectively selected from H, a nitro group, an amino group,a hydroxyl group, a 2-methoxyethoxy group, a C1-C4 alkoxy group and a C1-C4 alkyl group. The novel quinazoline EGFR inhibitor is different from existing quinazoline inhibitors with the 4-position substituted with various anilines, and is designed and synthesized by substituting the 4-position of a quinazoline skeleton with a broadly bioactive thienylmethylamine and reasonably modifying the 6-position and the 7-position with groups not including an electrophilic acrylamide bond in order to avoid covalent bonds with EGFR. Compared with existing antitumor drugs, the above compound can significantly inhibit EGFR phosphorylation, and has excellent anti-proliferative activity against EGFR overexpressing tumor cells (such as A431 and MCF-7).
- -
-
Paragraph 0036
(2019/10/01)
-
- PHARMACEUTICAL COMPOSITION AND APPLICATION REPLACING QUINOLONE DERIVATIVE, PHARMACEUTICAL ACCEPTABLE SALT, OR STEREOISOMER
-
Provided are a substituted quinolone derivative as shown by formula (I), or a pharmaceutically acceptable salt and a prodrug molecule thereof, and a pharmaceutical composition thereof, as well as the use of same in preparing drugs for the prevention and treatment of a tumor. The quinolone derivative, salt, prodrug molecule, and pharmaceutical composition thereof can be used as a protein kinase inhibitor, which is effective in inhibiting the activity of AXL protein kinase, and is capable of inhibiting the proliferation, migration and invasion of various tumor cells; and can be used in the preparation of anti-tumor drugs, especially drugs for treating hyperproliferative diseases such as a tumor in human beings and other mammals.
- -
-
-
- Design and discovery of quinazoline- and thiourea-containing sorafenib analogs as EGFR and VEGFR-2 dual TK inhibitors
-
Both EGFR and VEGFR-2 play a critical role in tumor growth, angiogenesis and metastasis, and targeting EGFR and VEGFR-2 simultaneously represents a promising approach to cancer treatment. In this work, a series of novel quinazoline- and thiourea-containing sorafenib analogs (10a–v) were designed and synthesized as EGFR and VEGFR-2 dual TK inhibitors. Their in vitro enzymatic inhibitory activities against EGFR and VEGFR-2, and antiproliferative activities against HCT-116, MCF-7 and B16 cell lines were evaluated and described. Most of the compounds showed potent activities against both cell lines and TK kinases. Compounds 10b and 10q which exhibited the most potent inhibitory activities against EGFR (IC50 = 0.02 μM and 0.01 μM, respectively), VEGFR-2 (IC50 = 0.05 μM and 0.08 μM, respectively), and good antiproliferative activities, also displayed competitive anti-tumor activities than sorafenib in vivo by B16 melanoma xenograft model test.
- Sun, Shaofeng,Zhang, Jingwen,Wang, Ningning,Kong, Xiangkai,Fu, Fenghua,Wang, Hongbo,Yao, Jianwen
-
-
- Novel hybrid molecules of quinazoline chalcone derivatives: Synthesis and study of In Vitro cytotoxic activities
-
Background: A new series of quinazoline linked chalcone conjugates were synthesized and evaluated for their in vitro cytotoxicity. Methods: The quinazoline-chalcone derivatives (13a-r) have been prepared by the Claisen-Schmidt condensation of various substituted benzaldehydes (12a-r) with substituted l-(4-(3,4- dihydroquinazolin-4-ylamino)phenyl)ethanone (11a-b) in the presence of aqueous NaOH. Three potential compounds 13f, 13g and 13h exhibited cytotoxicity against leukemia (GI50 value of 1.07, 0.26 and 0.24 μM), Non-small lung (GI50 values of 2.05,1.32 and 0.23 μM), colon (GI50 values of 0.54, 0.34 and 0.34 μM) and breast (GI50 values of 2.17, 1.84 and 0.22 μM) cell line, respectively. Results and Conclusion: Based on these biological results, it is evident that compound 13h has the potential to be considered for further detailed studies either alone or in combination with existing therapies as potential anticancer agents.
- Thiriveedhi, Arunkumar,Nadh, Ratnakaram Venkata,Srinivasu, Navuluri,Kaushal, Kishore
-
p. 757 - 765
(2018/06/26)
-
- Erlotinib derivative with antitumor activity, and preparation method and application thereof
-
The invention discloses an erlotinib derivative with antitumor activity, and a preparation method and application thereof, and belongs to the technical field of synthesis of antitumor active medicine. The method has the main technical scheme that the erlotinib derivative with antitumor activity has a structure formula shown as the accompanying drawing, wherein R is phenyl, p-methylphenyl, m-nitrophenyl, o-chlorphenyl or o-hydroxy benzon phenyl. The invention also discloses a concrete synthesis process of the erlotinib derivative with antitumor activity and application of the erlotinib derivative with antitumor activity to preparation of liver cancer treatment medicine. The erlotinib molecules are modified and are structurally connected with a series of different 1,2,3-triazole groups; the synthesized erlotinib derivative is subjected to anti-tumor activity test; the test result shows that the compound has high inhibition activity on liver cancer HepG2 cells.
- -
-
-
- Dioxolone structure containing 4 - N substituted quinazoline derivatives and its preparation and use (by machine translation)
-
The invention discloses a dioxolone structure containing 4 -NSubstituted quinazoline derivatives, its structure such as shown in I. This invention has introduced to substituted benzoic acid, methanol, nitric acid, formamide, trichloro oxygen phosphorus chlorine, nitrobenzene formaldehyde, acetone, stannous chloride, substituted aromatic aldehyde as raw material, by the multi-step reaction to synthesize the target compound. The compounds can be used as anti-tumor, anti-bacterial plant and anti-plant-virus of the drug. (1 E, 4 E) - 1 - substituted phenyl - 5 - (4 - (substituted quinazoline - 4 - amino) phenyl) - 1, 4 - pentadiene - 3 - one. (by machine translation)
- -
-
-
- Erlotinib-1,2,3-triazole compound with antineoplastic activity and preparation method as well as application thereof
-
The invention discloses an erlotinib-1,2,3-triazole compound with antineoplastic activity and a preparation method as well as application thereof, which belong to the technical field of synthesis of antineoplastic active medicines. The point of the technical solution of the invention is that the structural formula of the erlotinib-1,2,3-triazole compound with antineoplastic activity is shown in the description. The invention further discloses a specific synthesis process for the erlotinib-1,2,3-triazole compound with antineoplastic activity and application thereof in the preparation of medicines for treating or preventing lung cancer. The structure of the compound synthesized by the invention is novel, moreover, the synthesis process is simple, the synthesized erlotinib-1,2,3-triazole compound is combined with the action target EGFR (epidermal growth factor receptor) in the same way as erlotinib, and the compound has a good inhibition effect on both lung cancer A549 cells and NCI-H1299 cells.
- -
-
-
- Model 18 F mark substituted [...] compound and its preparation method and tumor PET imaging applications
-
The invention provides a novel F marked substituted quinazoline compound. The novel F marked substituted quinazoline compound is characterized in that one end of the novel F marked substituted quinazoline compound has a F substituted alkyloxy structure; the other end of the compound has a 6,7-substituted quinazoline structure, and a substituent R1 is positioned in the 4 position of a quinazoline maternal, and is a 2-, 3-, 4-F substituted alkyloxy group; and a substituent R2 is positioned in the 6 position of the quinazoline maternal, and is a methoxyethoxy group, a methoxy group, or a morpholinepropanolato group. The structural formula of the compound is shown as A in the specification. Results of experiments show that the compound has the advantages of good bioactivity, good serum stability, low intake in tissues of the liver and the like, and high enrichment and slow removal rate in tumors, and the marking precursor of the compound has the advantages of easy synthesis, extremely high marking rate and the like, so the compound has a huge potential for the tumor PET development.
- -
-
-
- Discovery of potent c-MET inhibitors with new scaffold having different quinazoline, pyridine and tetrahydro-pyridothienopyrimidine headgroups
-
Cellular mesenchymal-epithelial transition factor (c-MET) is closely linked to human malignancies, which makes it an important target for treatment of cancer. In this study, a series of 3-methoxy-N-phenylbenzamide derivatives, N-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl) benzamide derivatives and N1-(3-fluoro-4-methoxyphenyl)-N3-(4-fluorophenyl) malonamide derivatives were designed and synthesized, some of them were identified as c-MET inhibitors. Among these compounds with new scaffolds having different quinazoline, pyridine and tetrahydro-pyridothienopyrimidine head groups, compound 11c, 11i, 13b, 13h exhibited both potent inhibitory activities against c-MET and high anticancer activity against tested cancer cell lines in vitro. In addition, kinase selectivity assay further demonstrated that both 13b and 13h are potent and selective c-MET inhibitors. Molecular docking supported that they bound well to c-MET and VEGFR2, which demonstrates that they are potential c-MET RTK inhibitors for cancer therapy.
- Jiang, Yingnan,Zhang, Ke,Gao, Suyu,Wang, Guihua,Huang, Jian,Wang, Jinhui,Chen, Lixia
-
-
- 4-aminobenzene quinazoline derivatives containing 1,2,3-triazole and preparation method
-
The invention relates to a 4-aminobenzene quinazoline derivatives containing 1,2,3-triazole and a preparation method. The preparation method comprises adding 4-(3-amino)phenyl-6,7-dimethoxyquinazoline and 1,2,3-triazole into a reactor, adding a reaction solvent and a catalyst, stirring uniformly, and reacting at 80-140 DEG C; and after reaction is finished, cooling the product to room temperature, performing reduced-pressure distillation to remove the solvent, recrystallizing the obtained solid by ethanol, and performing vacuum drying to obtain an off-white solid. The provided 4-aminobenzene quinazoline derivatives organically combines quinazoline, Schiff base and triazole group, possesses certain anti-tumor effect, and possesses possibility of helping to reducing drug resistance of tumor cells. The synthesis route possesses advantages that the raw materials are easy to obtain, operation is simple, the solvent is saved, pollution is reduced and the like, and is easy for industrialized production.
- -
-
-
- The combination of quinazoline and chalcone moieties leads to novel potent heterodimeric modulators of breast cancer resistance protein (BCRP/ABCG2)
-
During the last decade it has been found that chalcones and quinazolines are promising inhibitors of ABCG2. The combination of these two scaffolds offers a new class of heterocyclic compounds with potentially high inhibitory activity against ABCG2. For this purpose we investigated 22 different heterodimeric derivatives. In this series only methoxy groups were used as substituents as these had been proven superior for inhibitory activity of chalcones. All compounds were tested for their inhibitory activity, specificity and cytotoxicity. The most potent ABCG2 inhibitor in this series showed an IC50 value of 0.19 μM. It possesses low cytotoxicity (GI50 = 93 μM), the ability to reverse MDR and is nearly selective toward ABCG2. Most compounds containing dimethoxy groups showed slight activity against ABCB1 too. Among these three compounds (17, 19 and 24) showed even higher activity toward ABCB1 than ABCG2. All inhibitors were further screened for their effect on basal ATPase activity. Although the basal ATPase activity was partially stimulated, the compounds were not transported by ABCG2. Thus, quinazoline-chalcones are a new class of effective ABCG2 inhibitors.
- Kraege, Stefanie,Stefan, Katja,Juvale, Kapil,Ross, Thomas,Willmes, Thomas,Wiese, Michael
-
p. 212 - 229
(2016/04/26)
-
- Molecular targeting anticancer photosensitizer AKT - phthalocyanine conjugates
-
The invention discloses a molecularly targeted anticancer photosensitizer erlotinib-phthalocyanine conjugate and application thereof. An erlotinib structural unit with a long alkoxy chain is introduced into the periphery of a metal phthalocyanine big ring, so that the amphipathicity, biocompatibility and targeting property of the photosensitizer can be improved. The conjugate is difficult to aggregate, and the cellular uptake ratio is improved; and meanwhile, the compounds are simple in structure, an isomer does not exist, and the product is easy to purify. According to the compound, the targeting property of the photosensitizer in photodynamics therapy is expected to be improved, and the activity of the photosensitizer in photodynamics therapy is enhanced. The synthetic method is simple, fewer side reactions are carried out, the yield is high, the raw materials are readily available, the cost is low, and the industrial production is realized.
- -
-
-
- Design, synthesis, and biological evaluation of novel quinazolinyl-diaryl urea derivatives as potential anticancer agents
-
Through a structure-based molecular hybridization approach, a series of novel quinazolinyl-diaryl urea derivatives were designed, synthesized, and screened for their in vitro antiproliferative activities against three cancer cell lines (HepG2, MGC-803, and A549). Six compounds (7g, 7m, 7o, 8e, 8g, and 8m) showed stronger activity against a certain cell line compared with the positive reference drugs sorafenib and gefitinib. Among the six compounds, 8g exhibited the strongest activity. In particular, compound 8g induced A549 apoptosis, arrested cell cycle at the G0/G1 phase, elevated intracellular reactive oxygen species level, and decreased mitochondrial membrane potential. This compound can also effectively regulate the expression of apoptosis- and cell cycle-related proteins, and influence the Raf/MEK/ERK pathway. Molecular docking and structure-activity relationship analyses revealed that it can bind well to the active site of the receptor c-Raf, which was consistent with the biological data. Therefore, compound 8g may be a potent antitumor agent, representing a promising lead for further optimization.
- Chen, Jia-Nian,Wang, Xian-Fu,Li, Ting,Wu, De-Wen,Fu, Xiao-Bo,Zhang, Guang-Ji,Shen, Xing-Can,Wang, Heng-Shan
-
-
- With anti-tumor effect of a quinazoline-urea derivative and its application (by machine translation)
-
The present invention relates to a of the general formula (II) anti-tumor function of said quinazoline-urea derivative and its application. The definition of the substituent in the general formula (II) in the specification. This invention, in order to SUO draw non-Buddhist nun and Geftinat compounds as the precursor, retention of SUO draw non-Buddhist nun the pharmocology-carbamido; at the same time, such as in reserved [...] EGFR-TKIs Geftinat, synthesis, and obtain a series of quinazoline-urea derivatives, by the in vitro activity tests, some compounds exhibit excellent anti-tumor activity, such derivatives have high research and utility value. (II). (by machine translation)
- -
-
-
- Ferulic acid ester derivative containing quinazoline, as well as preparation method and purpose of ferulic acid ester derivative
-
The invention discloses a ferulic acid ester derivative containing quinazoline, as well as a preparation method and a purpose of the ferulic acid ester. A structural general formula (I) of the ferulic acid ester derivative containing the quinazoline is as follows: R1 is methyl, ethyl, n-propyl, isopropyl and normal-butyl; R2 is hydrogen, 6,7-dimethoxy and 6,7-bis-methoxyethoxy. The ferulic acid ester derivative containing the quinazoline can resist the cucumber mosaic virus, the tobacco mosaic virus, the southern rice black-streaked dwarf virus and the rice stripe virus.The structural general formula (I) is shown in the specification.
- -
-
Paragraph 0015; 0033; 0037; 0041; 0045; 0049
(2016/10/09)
-
- Quinazoline derivatives and their use
-
The present invention provides a quinazoline compound shown in formula (I), or pharmaceutically acceptable salt thereof. R1, R2 and R7 are independently and respectively selected from hydrogen, C1-6 alkyl, C1-6 alkoxy, halogenate C1-6 alkyl, halogenate C1
- -
-
Paragraph 0242; 0243
(2016/10/08)
-
- QUINAZOLINE DERIVATIVE AND APPLICATION THEREOF
-
This invention provides a class of quinazoline compounds, as represented by formula (I), and their pharmaceutically acceptable salts, wherein: each of R1 and R2 independently, is selected from H, C1-C6 alkoxy, h
- -
-
Paragraph 0036
(2014/07/22)
-
- QUINAZOLINE DERIVATIVE AND APPLICATION THEREOF
-
This invention provides a class of quinazoline compounds, as represented by formula (I), and their pharmaceutically acceptable salts, wherein: each of R1 and R2 independently, is selected from H, C1-C6 alkoxy, h
- -
-
Paragraph 0110
(2014/08/19)
-
- Novel [99mTcN]2+ labeled EGFR inhibitors as potential radiotracers for single photon emission computed tomography (SPECT) tumor imaging
-
The epidermal growth factor receptor (EGFR) is overexpressed in many cancers, including breast, ovarian, endometrial and non-small cell lung cancer. An EGFR-specific imaging agent could facilitate clinical evaluation of primary tumors or metastases. To achieve this goal, 4-(2-aminoethylamino)-6,7- dimethoxyquinazoline (ADMQ) was synthesized based on a 4-aminoquinazoline core and then conjugated with N-mercapto-acetylglycine (MAG) and N- mercaptoacetyltriglycine (MAG3), respectively, to give compounds 1 and 2. The final complexes [99mTcN]-1 and [99mTcN]-2 were successfully obtained with radiochemical purities of >99% and >98% as measured by radio-HPLC. No decomposition of the two complexes at room temperature was observed over a period of 2 h. Their partition coefficients indicated they were hydrophilic and the electrophoresis results showed they were negatively charged. Biodistribution in tumor-bearing mice demonstrated that the two new complexes showed tumor accumulation, high tumor-tomuscle (T/M) ratios and fast clearance from blood and muscle. Between the two compounds, the 99mTcN-MAG3-ADMQ ([99mTcN]-2) showed the better characteristics, with the tumor/muscle and tumor/blood ratios reached 2.11 and 1.90 at 60 min post-injection, 4.20 and 1.10 at 120 min post-injection, suggesting it could be a promising radiotracer for SPECT tumor imaging.
- Zhao, Mingxia,Ning, Hongyu,Feng, Man,Li, Shilei,Chang, Jin,Qi, Chuanmin
-
p. 5508 - 5521
(2014/06/10)
-
- Discovery of new HER2/EGFR dual kinase inhibitors based on the anilinoquinazoline scaffold as potential anti-cancer agents
-
Herein, we designed and synthesized certain anilinoquinazoline derivatives bearing bulky arylpyridinyl, arylpropenoyl and arylpyrazolyl moieties at the 4′ position of the anilinoquinazoline, as potential dual HER2/EGFR kinase inhibitors. A detailed molecular modeling study was performed by docking the synthesized compounds in the active site of the epidermal growth factor receptor (EGFR). The synthesized compounds were further tested for their inhibitory activity on EGFR and HER2 tyrosine kinases. The aryl 2-imino-1,2-dihydropyridine derivatives 5d and 5e displayed the most potent inhibitory activity on EGFR with IC50 equal to 2.09 and 1.94 μM, respectively, and with IC50 equal to 3.98 and 1.04 μM on HER2, respectively. Furthermore, the anti-proliferative activity of these most active compounds on MDA-MB-231 breast cancer cell lines, known to overexpress EGFR, showed an IC50 range of 2.4 and 2.5 μM, respectively.
- Sadek, Maiada M.,Serrya, Rabah A.,Kafafy, Abdel-Hamid N.,Ahmed, Marawan,Wang, Feng,Abouzid, Khaled A. M.
-
p. 215 - 222
(2014/04/03)
-
- Small-molecule phosphodiesterase probes: Discovery of potent and selective CNS-penetrable quinazoline inhibitors of PDE1
-
PDE1 is a family of calcium-activated, dual substrate phosphodiesterases expressed in both the CNS and periphery that play a role in the integration of intracellular calcium and cyclic nucleotide signaling cascades. Exploration of the potential in targeting this family of enzymes to treat neuropsychiatric disorders has been hampered by a lack of potent, selective, and brain penetrable PDE1 inhibitors. To identify such compounds we used high-throughput screening, structure-based design, and targeted synthetic chemistry to discover the 4-aminoquinazoline 7a (PF-04471141) and the 4-indanylquinazoline 27 (PF-04822163) each of which are PDE1 inhibitors that readily cross the blood brain barrier. These quinazoline-based PDE1-selective inhibitors represent valuable new tools to study the biological processes regulated by PDE1 and to begin to determine the potential therapeutic utility of such compounds to treat neuropsychiatric disorders.
- Humphrey, John M.,Yang, Eddie,Ende, Christopher W. Am,Arnold, Eric P.,Head, Jenna L.,Jenkinson, Stephen,Lebel, Lorraine A.,Liras, Spiros,Pandit, Jayvardhan,Samas, Brian,Vajdos, Felix,Simons, Samuel P.,Evdokimov, Artem,Mansour, Mahmoud,Menniti, Frank S.
-
p. 1290 - 1296
(2014/10/15)
-
- Discovery of a 4-aryloxy-1H-pyrrolo[3,2-c]pyridine and a 1-aryloxyisoquinoline series of TRPA1 antagonists
-
A series of TRPA1 antagonists is described having a 4-aryloxy-1H-pyrrolo[3,2-c]pyridine or a 1-aryloxyisoquinoline scaffold. These compounds have high ligand efficiency and favorable physical properties and may thus serve as scaffolds for further optimization.
- Hu, Yun-Jin,St.-Onge, Miguel,Laliberté, Sébastien,Vallée, Frédéric,Jin, Shujuan,Bedard, Leanne,Labrecque, Jean,Albert, Jeffrey S.
-
supporting information
p. 3199 - 3203
(2015/02/19)
-
- Design and synthesis of novel quinazoline nitrogen mustard derivatives as potential therapeutic agents for cancer
-
Thirteen novel quinazoline nitrogen mustard derivatives were designed, synthesized and evaluated for their anticancer activities in vitro and in vivo. Cytotoxicity assays were carried out in five cancer cell lines (HepG2, SH-SY5Y, DU145, MCF-7 and A549) and one normal human cell line (GES-1), in which compound 22b showed very low IC50 to HepG2 (the IC50 value is 3.06 μM), which was lower than Sorafenib. Compound 22b could inhibit cell cycle at S and G2/M phase and induce cell apoptosis. In the HepG2 xenograft model, 22b exhibited significant cancer growth inhibition with low host toxicity in vivo.
- Li, Shilei,Wang, Xiao,He, Yong,Zhao, Mingxia,Chen, Yurong,Xu, Jingli,Feng, Man,Chang, Jin,Ning, Hongyu,Qi, Chuanmin
-
p. 293 - 301
(2013/10/01)
-
- Novel dual use of formamide-POCl3 mixture for the efficient, one-pot synthesis of condensed 2 H-pyrimidin-4-amine libraries under microwave irradiation
-
The novel dual use of formamide-POCl3 mixture for the incorporation of a C-N fragment to form the pyrimidine nucleus and its subsequent chlorination in an efficient, one-pot synthesis of potentially bioactive condensed 2H-pyrimidin-4-amine libraries under
- Jain, Kishore S.,Kathiravan, Muthu K.,Bariwal, Jitender B.,Chaskar, Pratip K.,Tompe, Santosh S.,Arya, Nikhilesh
-
p. 719 - 727
(2013/01/15)
-
- Investigation of quinazolines as inhibitors of breast cancer resistance protein (ABCG2)
-
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
-
p. 7858 - 7873
(2014/01/06)
-
- Inhibition studies on Mycobacterium tuberculosis N-acetylglucosamine-1- phosphate uridyltransferase (GlmU)
-
Peptidoglycan is an essential component of the cell wall of bacteria, including Mycobacterium tuberculosis, that provides structural strength and rigidity to enable internal osmotic pressure to be withstood. The first committed step in the biosynthesis of peptidoglycan involves the formation of uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) from uridine triphosphate (UTP) and GlcNAc-1-phosphate. This reaction is catalysed by N-acetylglucosamine- 1-phosphate uridyltransferase (GlmU), a bifunctional enzyme with two independent active sites that possess acetyltransferase and uridyltransferase activities. Herein, we report the first inhibition study targeted against the uridyltransferase activity of M. tuberculosis GlmU. A number of potential inhibitors were initially prepared leading to the discovery of active aminoquinazoline-based compounds. The most potent inhibitor in this series exhibited an IC50 of 74 μM against GlmU uridyltransferase activity and serves as a promising starting point for the discovery of more potent inhibitors.
- Tran, Anh Thu,Wen, Daying,West, Nicholas P.,Baker, Edward N.,Britton, Warwick J.,Payne, Richard J.
-
p. 8113 - 8126
(2013/12/04)
-
- Cl3CCN/PPh3 and CBr4/PPh3: Two efficient reagent systems for the preparation of N-heteroaromatic halides
-
Cl3CCN/PPh3 and CBr4/PPh3 are two highly reactive reagent systems for the conversion of N-heteroaromatic hydroxy compounds into N-heteroaromatic chlorides or bromides in moderate to excellent yields under mild and acid-free conditions.
- Kijrungphaiboon, Woranun,Chantarasriwong, Oraphin,Chavasiri, Wainthorn
-
scheme or table
p. 674 - 677
(2012/02/15)
-
- Synthesis and antitumor activity of novel quinazoline derivatives containing thiosemicarbazide moiety
-
Series of novel derivatives of quinazoline containing thiosemicarbazide moiety 5 and 9 have been synthesized and tested for their antitumor activities in vitro against a panel of five human cancer cell lines. Bioassay results indicated that most of the prepared compounds exhibited cytotoxicity against various cancer cells. From the structure-activity relationships it was found that unsubstituted quinazoline ring and benzene ring or halogen substituted benzene ring in quinazoline derivatives 5 and 9 would be the most favorable for their antitumor activity.
- He, Junbo,Wang, Xiaoguo,Zhao, Xiaoqin,Liang, Yongju,He, Hongwu,Fu, Liwu
-
p. 925 - 930
(2012/09/08)
-