- Development of anti-breast cancer PI3K inhibitors based on 7-azaindole derivatives through scaffold hopping: Design, synthesis and in vitro biological evaluation
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Breast cancer is the cancer with the highest incidence all over the world. Phosphatidylinositol 3-kinase is an important regulator of intracellular signaling pathways, which is frequently mutated and overexpressed in majority of human breast cancers, and the inhibition of PI3K has been considered as a promising approach for the treatment of the cancer. Here, we report our design and synthesis of new 7-azaindole derivatives as PI3K inhibitors through the scaffold hopping strategy. By varying the groups at the 3-position of 7-azaindole, we identified a series of potent PI3K inhibitors, whose antiproliferative activities against two human breast cancer MCF-7 and MDA-MB-231 cell lines were evaluated. Representative derivatives FD2054 and FD2078 showed better activity than BKM120 in antiproliferation, reduced the levels of phospho-AKT and induced cell apoptosis. All these results suggested that FD2054 and FD2078 are potent PI3K inhibitors that could be considered as potential candidates for the development of anticancer agents.
- Chen, Yi,Deng, Mingli,Jia, Yu,Ling, Yun,Liu, Xiaofeng,Lu, Mingzhu,Qiu, Tianze,Xiang, Ruiqing,Yang, Chengbin,Yang, Yongtai,Zhou, Yaming
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supporting information
(2021/10/19)
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- Micro-reactor tandem synthesis method of indole anticancer drug molecules
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The invention relates to a micro-reactor tandem synthesis method of indole anticancer drug molecules. The method comprises the following steps: a reaction liquid 1 and a reaction liquid 2 are mixed, then are introduced into a first micro-reactor, and are reacted to obtain a first effluent, the first effluent and a reaction liquid 3 are mixed, then are introduced into a second micro-reactor, and are reacted to obtain a second effluent, the second effluent and a reaction liquid 4 are mixed, then are introduced into a third micro-reactor, and are reacted to obtain a final effluent, and the finaleffluent is concentrated and separated to obtain the indole anticancer drug molecules, wherein the reaction liquid 1 is a mixed solution containing 5-bromine-3-amino-2-substituted (R1)-pyridine, the reaction liquid 2 is substituted (R2)-benzenesulfonyl chloride, the reaction liquid 3 is a mixed solution containing bis(pinacolato)diboron, the reaction liquid 4 is a mixed solution containing a 5-bromo-7-azaindole derivative, and the indole anticancer drug molecules are benzenesulfonamidopyridylazaindole compounds. Compared with the prior art, the method of the invention has the advantages of high reaction efficiency, few side reactions and simple production process.
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Paragraph 0104; 0107
(2019/12/08)
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- Discovery of new thienopyrimidine derivatives as potent and orally efficacious phosphoinositide 3-kinase inhibitors
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A series of new thienopyrimidine derivatives has been discovered as potent PI3K inhibitors. The systematic SAR studies for these analogues are described. Among them, 8a and 9a exhibit nanomolar enzymatic potencies and sub-micromolar cellular anti-prolifer
- Lin, Songwen,Wang, Chunyang,Ji, Ming,Wu, Deyu,Lv, Yuanhao,Sheng, Li,Han, Fangbin,Dong, Yi,Zhang, Kehui,Yang, Yakun,Li, Yan,Chen, Xiaoguang,Xu, Heng
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p. 637 - 646
(2018/01/05)
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- Discovery of a Novel Series of 7-Azaindole Scaffold Derivatives as PI3K Inhibitors with Potent Activity
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The phosphoinositide 3-kinase (PI3K) inhibitors potently inhibit the signaling pathway of PI3K/AKT/mTOR, which provides a promising new approach for the molecularly targeted cancer therapy. In this work, a novel series of 7-azaindole scaffold derivatives was discovered by the fragment-based growing strategy. The structure-activity relationship profiles identified that the 7-azaindole scaffold derivatives exhibit potent activity against PI3K at molecular and cellular levels as well as cell proliferation in a panel of human tumor cells.
- Yang, Chengbin,Zhang, Xi,Wang, Yi,Yang, Yongtai,Liu, Xiaofeng,Deng, Mingli,Jia, Yu,Ling, Yun,Meng, Ling-Hua,Zhou, Yaming
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supporting information
p. 875 - 880
(2017/08/16)
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- Compound containing L-prolinamide fragment, and preparation method and application thereof
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The invention discloses a compound containing an L-prolinamide fragment, and a preparation method and an application thereof and belongs to the technical field of antitumor drugs. The compound containing the L-prolinamide fragment comprises a 5-aryl pyrid
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Paragraph 0048; 0049
(2017/07/12)
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- PI3K inhibitor, preparation method and application thereof in pharmacy
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The invention belongs to the technical field of pharmaceuticals and particularly relates to a PI3K inhibitor, a preparation method and application thereof in the pharmacy. The PI3K inhibitor is a compound of the structure shown by the general formula I or medically acceptable salt of the inhibitor. After the PI3K inhibitor is tested with a PI3K biochemical activity test method, the compound has excellent inhibitory activity to PI3K alpha and PI3K gamma, wherein the IC50 values of a plurality of compounds to the PI3K alpha and PI3K gamma reach nanomole grades (smaller than 100 nM). The result shows that the compounds can provide the inhibitor with better effectiveness and selectivity for curing PI3K-acted proliferative disease, and further a targeted drug for curing No. I type diabetes mellitus, lung disease, breast cancer, prostatic cancer, solid tumor, lymphoma, cardiovascular disease, rheumatoid arthritis, leukemia and the like can be hopefully developed. (Please see the general formula I in the description.).
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Paragraph 0173; 0174; 0175
(2016/12/26)
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- PI3 kinase modulators and methods of use thereof, and use thereof
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The invention belongs to the field of medicines, concretely relates to a compound for treating cancer, a composition and an application of the composition and particularly relates to a PI3 kinase regulator as well as a use method and application of the PI3 kinase regulator. The invention provides a compound as shown in the formula (I), a pharmaceutically accepted salt of the compound and a pharmaceutical preparation of the compound, wherein the compound is used for regulating the activity of protein kinase and intercellular or intracellular signal response. The invention also relates to a pharmaceutical composition containing the compound and a method for treating high-proliferative diseases of mammals and particularly human beings by using the pharmaceutical composition as shown in the formula (I).
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Paragraph 0313; 0555; 0556
(2016/10/07)
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- Synthesis and anticancer effects evaluation of 1-alkyl-3-(6-(2-methoxy-3-sulfonylaminopyridin-5-yl)benzo[d]thiazol-2-yl)urea as anticancer agents with low toxicity
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As a PI3K and mTOR dual inhibitor, N-(2-chloro-5-(2-acetylaminobenzo[d]thiazol-6-yl)pyridin-3-yl)-4-fluorophenylsulfonamide displays toxicity when orally administrated. In the present study, alkylurea moiety replaced the acetamide group in the compound an
- Xie, Xiao-Xiao,Li, Huan,Wang, Juan,Mao, Shuai,Xin, Min-Hang,Lu, She-Min,Mei, Qi-Bing,Zhang, San-Qi
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p. 6477 - 6485
(2015/10/05)
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- PI3 KINASE MODULATORS AND METHODS OF USE
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This invention relates to the field of lipid kinases and modulators thereof. In particular, the invention relates to modulators of phosphatidylinositol 3-kinases (PI3 kinases or PBKs) signaling pathways, and methods of their use. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in modulating of PI3K signaling pathways and their related disorders in mammals, especially humans.
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Paragraph 0152; 0209
(2014/02/16)
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- Synthesis and anticancer activity evaluation of a series of [1,2,4] triazolo[1,5-a]pyridinylpyridines in vitro and in vivo
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A series of [1,2,4]triazolo[1,5-a]pyridinylpyridines were synthesized and characterized. Their anti-proliferative activities in vitro were evaluated by MTT against three human cancer cell lines including HCT-116, U-87 MG and MCF-7 cell lines. The SAR of target compounds was preliminarily discussed. The compounds 1c and 2d with potent antiproliferative activities were tested for their effects on the AKT and p-AKT473. The anticancer effect of 1c was evaluated in mice bearing sarcoma S-180 model. The results suggest that the title compounds are potent anticancer agents.
- Wang, Xiao-Meng,Xu, Jing,Li, Yi-Ping,Li, Huan,Jiang, Cong-Shan,Yang, Guang-De,Lu, She-Min,Zhang, San-Qi
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p. 243 - 251
(2013/10/01)
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- Structure-activity relationships of phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors: Investigations of various 6,5-heterocycles to improve metabolic stability
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N-(6-(6-Chloro-5-(4-fluorophenylsulfonamido)pyridin-3-yl)benzo[d] thiazol-2-yl)acetamide (1) is a potent and efficacious inhibitor of PI3Kα and mTOR in vitro and in vivo. However, in hepatocyte and in vivo metabolism studies, 1 was found to undergo deacet
- Stec, Markian M.,Andrews, Kristin L.,Booker, Shon K.,Caenepeel, Sean,Freeman, Daniel J.,Jiang, Jian,Liao, Hongyu,McCarter, John,Mullady, Erin L.,San Miguel, Tisha,Subramanian, Raju,Tamayo, Nuria,Wang, Ling,Yang, Kevin,Zalameda, Leeanne P.,Zhang, Nancy,Hughes, Paul E.,Norman, Mark H.
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experimental part
p. 5174 - 5184
(2011/09/16)
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- Phospshoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors: Discovery and structure-activity relationships of a series of quinoline and quinoxaline derivatives
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The phosphoinositide 3-kinase (PI3K) family catalyzes the ATP-dependent phosphorylation of the 3′-hydroxyl group of phosphatidylinositols and plays an important role in cell growth and survival. There is abundant evidence demonstrating that PI3K signaling is dysregulated in many human cancers, suggesting that therapeutics targeting the PI3K pathway may have utility for the treatment of cancer. Our efforts to identify potent, efficacious, and orally available PI3K/mammalian target of rapamycin (mTOR) dual inhibitors resulted in the discovery of a series of substituted quinolines and quinoxalines derivatives. In this report, we describe the structure-activity relationships, selectivity, and pharmacokinetic data of this series and illustrate the in vivo pharmacodynamic and efficacy data for a representative compound.
- Nishimura, Nobuko,Siegmund, Aaron,Liu, Longbin,Yang, Kevin,Bryan, Marian C.,Andrews, Kristin L.,Bo, Yunxin,Booker, Shon K.,Caenepeel, Sean,Freeman, Daniel,Liao, Hongyu,McCarter, John,Mullady, Erin L.,San Miguel, Tisha,Subramanian, Raju,Tamayo, Nuria,Wang, Ling,Whittington, Douglas A.,Zalameda, Leeanne,Zhang, Nancy,Hughes, Paul E.,Norman, Mark H.
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experimental part
p. 4735 - 4751
(2011/09/20)
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- INHIBITORS OF PI3 KINASE
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The present invention relates to compounds of Formula I, II or III or a pharmaceutically acceptable salt thereof; methods of treating diseases or conditions, such as cancer, using the compounds; and pharmaceutical compositions containing the compounds, wherein the variables are as defined herein
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Page/Page column 43-45
(2010/10/03)
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- Inhibitors of PI3 kinase
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The present invention relates to compounds of Formula I, or a pharmaceutically acceptable salt thereof, that inhibit phosphoinositide 3-kinase; methods of treating diseases or conditions, such as cancer, using the compounds; and pharmaceutical compositions containing the compounds.
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Page/Page column 24
(2009/07/10)
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- INHIBITORS OF PI3 KINASE
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The present invention relates to compounds of Formula (I), or a pharmaceutically acceptable salt thereof; methods of treating diseases or conditions, such as cancer, using the compounds; and pharmaceutical compositions containing the compounds, wherein Q, X1, X2, R1 and Z are as defined herein.
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Page/Page column 84-85
(2010/01/12)
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