- UiO-66-NH2as an effective solid support for quinazoline derivatives for antibacterial agents against Gram-negative bacteria
-
Nanomaterials have been widely used as a class of antibacterial drugs. However, the bottlenecks of this class of materials are their significant aggregation and accumulation, as well as toxicity resulting from excessive metal leaching. Metal-organic frameworks (MOFs) have inspired researchers owing to their distinct characteristics of robust architecture and tunable pore structures, which may help overcome the above challenges. We, herein, synthesize UiO-66-NH2 and use it as a solid support for loading quinazoline derivatives that are specifically designed and active against Gram-negative bacteria. The quinazoline derivatives were adsorbed on UiO-66-NH2 nanoparticles to form new UiO-66-NH2-quinazoline formulations which have a large inhibitory zone against Gram-negative bacteria, compared to that of free quinazoline compounds. This work has the potential for increasing antibacterial activity while also broadening the antibacterial range, and thus opens a pathway for new medical applications using MOFs. This journal is
- Al Blooshi, Afra G.,Al Neyadi, Shaikha S.,Alnaqbi, Mohamed. A.,Nguyen, Ha L.
-
p. 20386 - 20395
(2021/12/02)
-
- 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
-
supporting information
p. 14477 - 14497
(2021/10/20)
-
- 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
-
-
- 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)
-
- SUBSTITUTED IMIDAZOLES FOR THE INHIBITION OF TGF-BETA AND METHODS OF TREATMENT
-
This disclosure relates to low molecular weight substituted imidazoles that inhibit the TGF-b signaling pathway. More specifically, this disclosure relates to methods of using said imidazoles for the treatment of diseases related to the TGF-b signaling pathways including, but not limited to, atherosclerosis, Marfan syndrome, Loeys-Dietz syndrome, obesity, diabetes, multiple sclerosis, keratoconus, idiopathic pulmonary fibrosis, Alzheimer's Disease, chronic kidney disease, and scleroderma.
- -
-
Paragraph 00119
(2020/03/15)
-
- Design, synthesis, and anticancer activities of sodium quinazolin-4-diselenide compounds
-
Substituted 4-chloroquinazoline reacted with sodium diselenide to give novel sodium quinazoline-4-diselenide compounds. The reaction provides an efficient and facile approach to the synthesis of sodium quinazoline-4-diselenide compounds. Structures of title compounds were confirmed by IR, 1H NMR, 13C NMR, and elemental analysis. MTT assay was adopted to show anticancer activities of the compounds. Compounds 5a and 5h showed good activities against cancer-cell lines MDA-MB-435, MDA-MB-231, A549, SiHa, and HeLa. In addition, 5a exhibited quite good anticancer effects on relative above cell lines with 10μM concentration compared with oxaliplatin and gefitinib of the commercial anticancer drugs.
- Zhang, Yuchun,Niu, Pengpeng,Wen, Quanwu,Sun, Lin,Wang, Weili,Xu, Shengguang,Liu, Gang
-
p. 497 - 502
(2019/11/03)
-
- 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
-
-
- Discovery of novel quinazoline derivatives as potent PI3Kδ inhibitors with high selectivity
-
Inhibition of PI3Kδ has been proved to be an efficacious strategy for the treatment of hematological malignancies where the PI3K/Akt signaling pathway is hyperactive. Herein, a series of quinazoline derivatives bearing acrylamide fragment were prepared using skeleton-deconstruction strategy. The preliminary bioactivity evaluation resulted in the discovery of lead compound 15c. Compound 15c exhibited excellent enzyme activity against PI3Kδ (IC50 = 27.5 nM) compared with BEZ235 as well as the significant anti-proliferation activities. With the high selectivity over other PI3K isoforms and potent effects on PI3K/Akt pathway, 15c can be identified as a promising PI3Kδ inhibitor worthy of further profiling.
- Teng, Yu,Li, Xinyu,Ren, Shengnan,Cheng, Yu,Xi, Kun,Shen, Hongtao,Ma, Wenzhuo,Luo, Guoshun,Xiang, Hua
-
-
- QUINAZOLINE COMPOUND FOR EGFR INHIBITION
-
Disclosed is a novel quinazoline compound. Specifically, disclosed are a compound represented by the formula (I) and a pharmacologically acceptable salt.
- -
-
Paragraph 0136; 0139; 0203; 0205
(2019/11/21)
-
- Synthesis and mode of action studies of novel {2-(3-R-1H-1,2,4-triazol-5-yl)phenyl}amines to combat pathogenic fungi
-
Due to their high specificity and efficacy, triazoles have become versatile antifungals to treat fungal infections in human healthcare and to control phytopathogenic fungi in agriculture. However, azole resistance is an emerging problem affecting human health as well as food security. Here we describe the synthesis of 10 novel {2-(3-R-1H-1,2,4-triazol-5-yl)phenyl}amines. Their structure was ascertained by liquid chromatography–mass spectrometry, 1H and 13C NMR, and elemental analysis data. Applying an in vitro growth assay, these triazoles show moderate to significant antifungal activity against the opportunistic pathogen Aspergillus niger, 12 fungi (Fusarium oxysporum, Fusarium fujikuroi, Colletotrichum higginsianum, Gaeumannomyces graminis, Colletotrichum coccodes, Claviceps purpurea, Alternaria alternata, Mucor indicus, Fusarium graminearum, Verticillium lecanii, Botrytis cinerea, Penicillium digitatum) and three oomycetes (Phytophtora infestans GL-1, P. infestans 4/91; R+ and 4/91; R?) in the concentration range from 1 to 50 μg/ml (0.003–2.1 μM). Frontier molecular orbital energies were determined to predict their genotoxic potential. Molecular docking calculations taking into account six common fungal enzymes point to 14α-demethylase (CYP51) and N-myristoyltransferase as the most probable fungal targets. With respect to effectiveness, structure–activity calculations revealed the strong enhancing impact of adamantyl residues. The shown nonmutagenicity in the Salmonella reverse-mutagenicity assay and no violations of drug-likeness parameters suggest the good bioavailability and attractive ecotoxicological profile of the studied triazoles.
- Antypenko, Lyudmyla,Sadykova, Zhanar,Shabelnyk, Kostiantyn,Meyer, Fatuma,Kovalenko, Sergiy,Meyer, Vera,Garbe, Leif-Alexander,Steffens, Karl
-
-
- Alkylsulfonamide-containing quinazoline derivatives as potent and orally bioavailable PI3Ks inhibitors
-
Phosphoinositide 3-kinases (PI3Ks) are regarded as promising targets for treatment of various cancers due to their roles in regulating cell proliferation, differentiation, migration, and survival. Here we report our efforts to develop potent and orally bioavailable PI3K inhibitors for the treatment of cancers. The alkylsulfonamide-containing quinazoline derivatives A1–A18 significantly inhibited PI3Kα, and cell proliferation among HCT-116, MCF-7 and SU-DHL-6 cell lines. The optimal compound A1 displayed potent inhibitory activity against PI3Kα (IC50 = 4.5 nM), PI3Kβ (IC50 = 4.5 nM), PI3Kγ (IC50 = 4.5 nM), PI3Kδ (IC50 = 4.5 nM) and significantly inhibited the growth of HCT-116, MCF-7 and SU-DHL-6 cell lines with IC50 values of 0.82 μM, 0.99 μM and 0.19 μM, respectively. Western blot analysis demonstrated A1 significantly suppressed the phosphorylation of AKTS473 in a dose-dependent manner. Furthermore, A1 could markedly inhibit cancer growth at the dose of 25 mg/kg in nude mouse HCT-116 xenograft model in vivo without causing significant weight loss or toxicity.
- Hei, Yuan-Yuan,Zhang, San-Qi,Feng, Yifan,Wang, Jin,Duan, Weiming,Zhang, Hao,Mao, Shuai,Sun, Haopeng,Xin, Minhang
-
-
- Benzopyrimidine compound, preparation method, and applications thereof
-
The invention provides a benzopyrimidine compound, and a pharmaceutically acceptable salt and an isotope labeled product thereof, and applications of the benzopyrimidine compound and the derivatives of the benzopyrimidine compound in preparation of Btk or PI3K kinases inhibitors used in treatment or prevention of diseases related with the activity of protein kinase, for example, diseases such as tumor including leukemia and lymphoma can be treated through inhibiting Btk or PI3K.
- -
-
Paragraph 0040; 0041; 0063-0065
(2019/11/04)
-
- Synthesis and in vitro cytotoxicity of the 4-(Halogenoanilino)-6-bromoquinazolines and their 6-(4-fluorophenyl) substituted derivatives as potential inhibitors of epidermal growth factor receptor tyrosine kinase
-
Series of the 2-unsubstituted and 2-(4-chlorophenyl)–substituted 4-anilino-6-bromoquinazolines and their 6-(4-fluorophenyl)–substituted derivatives were evaluated for in vitro cytotoxicity against MCF-7 and HeLa cells. The 2-unsubstituted 4-anilino-6-brom
- Mphahlele, Malose Jack,Paumo, Hugues K.,Choong, Yee Siew
-
-
- Design and synthesis of novel 6-aryl substituted 4-anilinequinazoline derivatives as potential PI3Kδ inhibitors
-
In this study, a series of new 6-aryl substituted 4-anilinequinazolines was designed and synthesized as PI3Kδ inhibitors based on our reported chemical structures. The preliminary structure-activity relationship (SAR) was established, and compounds 13h an
- Xin, Minhang,Hei, Yuan-Yuan,Zhang, Hao,Shen, Ying,Zhang, San-Qi
-
p. 1972 - 1977
(2017/04/10)
-
- Discovery of 6-benzamide containing 4-phenylquinazoline derivatives as novel PI3Kδ inhibitors
-
In the present study, a series of new 6-benzamide containing 4-phenylquinazoline derivatives were designed and synthesized as PI3Kδ inhibitors. The preliminary SAR for this series of compounds was established. PI3Kδ inhibitory assay showed that most of th
- Xin, Minhang,Hei, Yuan-Yuan,Zhang, Hao,Xie, Xiao-Xiao,Mao, Shuai,Zuo, Sai-Jie,Zhang, San-Qi
-
p. 167 - 174
(2018/04/12)
-
- 6-pyrromonazole substituted quinazoline compound, and derivative, synthetic method and application thereof
-
The invention discloses a compound as shown in the formula (I), (II) or (III), or salt of the compound acceptable in pharmacy, aquo-complex, a solvate, a polymorphic substance, a tautomer or a prodrug; a synthetic method of the formula (I) comprises the f
- -
-
Paragraph 0104; 0106; 0220; 0222
(2017/08/28)
-
- 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.
-
p. 731 - 743
(2016/08/02)
-
- Discovery and Pharmacological Characterization of Novel Quinazoline-Based PI3K Delta-Selective Inhibitors
-
Inhibition of the lipid kinase PI3Kδ is a promising principle to treat B and T cell driven inflammatory diseases. Using a scaffold deconstruction-reconstruction strategy, we identified 4-aryl quinazolines that were optimized into potent PI3Kδ isoform selective analogues with good pharmacokinetic properties. With compound 11, we illustrate that biochemical PI3Kδ inhibition translates into modulation of isoform-dependent immune cell function (human, rat, and mouse). After oral administration of compound 11 to rats, proximal PD markers are inhibited, and dose-dependent efficacy in a mechanistic plaque forming cell assay could be demonstrated.
- Hoegenauer, Klemens,Soldermann, Nicolas,Stauffer, Frédéric,Furet, Pascal,Graveleau, Nadege,Smith, Alexander B.,Hebach, Christina,Hollingworth, Gregory J.,Lewis, Ian,Gutmann, Sascha,Rummel, Gabriele,Knapp, Mark,Wolf, Romain M.,Blanz, Joachim,Feifel, Roland,Burkhart, Christoph,Zécri, Frédéric
-
supporting information
p. 762 - 767
(2016/08/24)
-
- QUINAZOLINE COMPOUNDS AS KINASE INHIBITORS AND USES THEREOF
-
A compound for treating protein kinase-related disease or disorder having a structure of formula (A): wherein X is N or CH; Y is NH, O, or CH2; Z is an aryl or a heteroaryl; and R1, R2, R3, and R4 are
- -
-
Page/Page column 48; 49; 83
(2017/04/25)
-
- Design, synthesis, anti-tumor activity, and molecular modeling of quinazoline and pyrido[2,3-d]pyrimidine derivatives targeting epidermal growth factor receptor
-
Three series of novel quinazoline and pyrido[2,3-d]pyrimidine derivatives were designed, synthesized and evaluated for their ability to inhibit EGFR tyrosine kinase and a panel of five human cancer cell lines (MCF-7, A549, BT-474, SK-BR-3, and MDA-MB-231)
- Hou, Ju,Wan, Shanhe,Wang, Guangfa,Zhang, Tingting,Li, Zhonghuang,Tian, Yuanxin,Yu, Yonghuan,Wu, Xiaoyun,Zhang, Jiajie
-
p. 276 - 289
(2016/05/10)
-
- Combination of mTOR inhibitors and P13-kinase inhibitors, and uses thereof
-
The present invention provides for a method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject. In yet another aspect, a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell is set forth.
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Page/Page column 354
(2016/04/26)
-
- 6-ARYL-4-PHENYLAMINO-QUINAZOLINE ANALOGS AS PHOSPHOINOSITIDE-3-KINASE INHIBITORS
-
The present invention relates to 6-aryl-4-phenylamino quinazolines of formula I wherein, R and R′ are as herein described. The present invention particularly relates to synthesis and anticancer and phoshpoinositide-3-kinase-α (PI3K-α ) inhibitory activity. In addition, the invention relates to methods of using compounds for treating or preventing various cancers such as pancreatic, prostate, breast and melanoma.
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-
-
- Use of Inhibitors of the Activity or Function of PI3K
-
The invention relates to new uses of PI3K inhibitors, wherein said inhibitors have an inhibitory action on the PI3K isoform delta for the treatment of immunopathology in a subject suffering from a disease or disorder selected from malaria, leishmaniasis, trypanosomiasis, toxoplasmosis and/or neurocysticercosis, via functional inhibition of TLR9 of the infected subject.
- -
-
Paragraph 0974-0975
(2016/01/09)
-
- IRAK INHIBITORS AND USES THEREOF
-
The present invention provides quinazoline and quinoline compounds, compositions thereof, and methods of using the same. Also disclosed is the activity of such compounds as inhibitors of IRAK enzymes.
- -
-
Paragraph 00274; 00275
(2015/11/16)
-
- COMBINATION OF KINASE INHIBITORS AND USES THEREOF
-
The present invention provides for a method for treating a disease condition associated with PI3-kinase a and/or a receptor tyrosine kinase (RTK) in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase α and/or an RTK in a subject. In yet another aspect, a method of inhibiting phosphorylation of Akt (S473) in a cell is set forth.
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Page/Page column 73
(2015/02/19)
-
- Synthesis of Lapatinib via direct regioselective arylation of furfural
-
A new synthesis of Lapatinib, an orally active drug for breast cancer, is described. The synthesis involves a palladium catalyzed regioselective arylation of furfural with 6-bromo-N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)quinazolin-4-amine. This key step replaces an atom inefficient Suzuki cross coupling reaction used in a previously disclosed route and significantly shortens the synthesis.
- Erickson, Greg,Guo, Jiasheng,McClure, Mike,Mitchell, Mark,Salaun, Marie-Catherine,Whitehead, Andrew
-
supporting information
p. 6007 - 6010
(2015/01/08)
-
- Discovery of 2-methoxy-3-phenylsulfonamino-5-(quinazolin-6-yl or quinolin-6-yl)benzamides as novel PI3K inhibitors and anticancer agents by bioisostere
-
2-Substituted-3-sulfonamino-5-(quinazolin-6-yl or quinolin-6-yl)benzamides have been proposed as novel structures of PI3K inhibitors and anticancer agents based on bioisostere. In the present study, 2-substituted-3-sulfonamino-5-(4- morpholinoquinazolin-6-yl)benzamides and 2-methoxy-3-sulfonamino-5-(4- morpholinoquinolin-6-yl)benzamides were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against four human cancer cell lines, including A549, HCT-116, U-87 MG and KB. The SAR of the title compounds was preliminarily discussed. Compound 1a with potent antiproliferative activity was tested for its inhibitory activity against PI3K and mTOR and its effect on the AKT and p-AKT473. The anticancer effect of 1a was evaluated in established nude mice U-87 MG xenograft model. The results suggest that compound 1a can significantly inhibit PI3K/AKT/mTOR pathway and tumor growth. These findings strongly support the assumption that title compounds are potent PI3K inhibitors and anticancer agents.
- Shao, Teng,Wang, Juan,Chen, Jian-Gang,Wang, Xiao-Meng,Li, Huan,Li, Yi-Ping,Li, Yan,Yang, Guang-De,Mei, Qi-Bing,Zhang, San-Qi
-
-
- COMBINATION OF KINASE INHIBITORS AND USES THEREOF
-
The present invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In yet another aspect, a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell is set forth. The present invention also provides a pharmaceutical kit effective for treating a disease condition associated with PI3 -kinase α and/or mTOR in a subject.
- -
-
Paragraph 00641
(2014/10/04)
-
- QUINAZOLINE DERIVATIVES AS PI3K MODULATORS
-
The invention relates to substituted quinazoline derivative of the formula (I), wherein A, X1, X2, X3, X4 and R5 are as defined in the description. Such compounds are suitable for the treatment of a disorder or disease which is mediated by the activity of the PI3K enzymes.
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-
Page/Page column 57
(2013/05/09)
-
- Use of inhibitors of the activity or function of PI3K
-
The invention relates to new uses of PI3K inhibitors, wherein said inhibitors have an inhibitory action on the PI3K isoform delta for the treatment of immunopathology in a subject suffering from a disease or disorder selected from malaria, leishmaniasis, trypanosomiasis, toxoplasmosis and/or neurocysticercosis, via functional inhibition of TLR9 of the infected subject.
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-
Page/Page column 186
(2013/07/05)
-
- 4,6-DL- AND 2,4,6-TRISUBSTITUTED QUINAZOLINE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS USEFUL FOR TREATING VIRAL INFECTIONS
-
This invention provides the treatment of viral infections with a 4,6- disubstituted or 2,4,6-trisubstituted quinazoline derivative represented by the structural formula [(I)] wherein: R2 is selected from the group consisting of hydrogen, NR'R"
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-
Page/Page column 94-95
(2008/06/13)
-
- 2,4-SUBSTITUTED QUINAZOLINES AS LIPID KINASE INHIBITORS
-
The invention relates to compounds of the formula (I), which are appropriate for the treatment of kinase, e.g. PI3K-related, diseases, such as proliferative diseases, inflammatory diseases, obstructive airways disorders and transplantation related disease
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-
Page/Page column 60
(2008/06/13)
-
- METHODS AND COMPOSITIONS FOR THE TREATMENT OF PAIN, INFLAMMATION AND CANCER
-
This invention relates to methods of treating, managing and preventing pain, inflammation, cancer, and ocular diseases and disorders, and to compounds and pharmaceutical compositions useful in such methods.
- -
-
Page/Page column 44-45
(2008/12/07)
-
- METHODS AND COMPOSITIONS FOR THE TREATMENT OF BODY COMPOSITION DISORDERS
-
This invention relates to methods of treating, managing and preventing body composition disorders, and to compounds and pharmaceutical compositions useful in such methods.
- -
-
Page/Page column 47
(2008/12/07)
-
- 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
-
p. 6373 - 6377
(2008/03/14)
-
- COMPOUND HAVING TGF-BETA INHIBITORY ACTIVITY AND PHARMACEUTICAL COMPOSITION CONTAINING SAME
-
The present invention provides compounds of formula (I) or compounds of formula (II) and pharmaceutically acceptable salts or solvates thereof. An objective of the present invention is to provide compounds having TGF2 inhibitory activity.
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Page/Page column 49
(2010/11/24)
-
- Anilinoquinazaolines as protein tyrosine kianse inhibitors
-
Heteroaromatic compounds are described, methods for their preparation, pharmaceutical compositions containing them, methods of use, and their use in medicines. In particular, the invention relates to quinazoline and pyridopyrimidine derivatives which exhibit protein tyrosine kinase inhibition.
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Page/Page column 45
(2008/06/13)
-
- AKT PROTEIN KINASE INHIBITORS
-
The present invention provides compounds, including resolved enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof, comprising the Formula: A-L-CR where CR is a cyclical core group, L is a linking group and A is as defined herein. Also provided are methods of using the compounds of this invention as AKT protein kinase inhibitors and for the treatment of hyperproliferative diseases such as cancer.
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Page/Page column 64
(2008/06/13)
-
- MORPHOLINYLANILINOQUINAZO- LINE DERIVATIVES FOR USE AS ANTIVIRAL AGENTS
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Compounds of formula (Ia) are found to be active in inhibiting replication of flaviviridae viruses, wherein R1, R2, R3 and R4 are as defined in the claims.
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Page/Page column 20
(2008/06/13)
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- Novel series of 8H-quinazolino[4,3-b]quinazolin-8-ones via two Niementowski condensations
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Efficient microwave-assisted multi-step synthesis of 8H-quinazolino[4,3-b]quinazolin-8-one was investigated. The synthesis involved two Niementowski condensations from anthranilic acids. Homogeneous or heterogeneous conditions were studied with the aim to develop convenient syntheses of the desired compounds.
- Alexandre, Fran?ois-René,Berecibar, Amaya,Wrigglesworth, Roger,Besson, Thierry
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p. 1413 - 1419
(2007/10/03)
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- Discovery of quinazolines as a novel structural class of potent inhibitors of NF-κB activation
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We disclose here a new structural class of low-molecular-weight inhibitors of NF-κB activation that were designed and synthesized by starting from quinazoline derivative 6a. Structure-activity relationship (SAR) studies based on 6a elucidated the structural requirements essential for the inhibitory activity toward NF-κB transcriptional activation, and led to the identification of the 6-amino-4-phenethylaminoquinazoline skeleton as the basic framework. In this series of compounds, 11q, containing the 4-phenoxyphenethyl moiety at the C(4)-position, showed strong inhibitory effects on both NF-κB transcriptional activation and TNF-α production. Furthermore, 11q exhibited an anti-inflammatory effect on carrageenin-induced paw edema in rats.
- Tobe, Masanori,Isobe, Yoshiaki,Tomizawa, Hideyuki,Nagasaki, Takahiro,Takahashi, Hirotada,Fukazawa, Tominaga,Hayashi, Hideya
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p. 383 - 391
(2007/10/03)
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- Structure-activity relationships of quinazoline derivatives: Dual-acting compounds with inhibitory activities toward both TNF-α production and T cell proliferation
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We synthesized 4-chlorophenethylaminoquinazoline derivatives and evaluated their inhibitory activities toward both TNF-α production and T cell proliferation responses. Compound 2f, containing a piperazine ring at the C(7)-position of the quinazoline ring, exhibited more potent inhibitory activities toward both than the lead compound 1a. A smaller N-substituent in the piperazine ring was required for inhibition of TNF-α production.
- Tobe, Masanori,Isobe, Yoshiaki,Tomizawa, Hideyuki,Matsumoto, Mitsuhiro,Obara, Fumihiro,Nagasaki, Takahiro,Hayashi, Hideya
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p. 545 - 548
(2007/10/03)
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