- Photo-Triggered Self-Induced Homolytic Dechlorinative Sulfonylation/Cyclization of Unactivated Alkenes: Synthesis of Quinazolinones Containing a Sulfonyl Group
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A self-photocatalyzed sulfonylation/cyclization of quinazolinones containing unactivated alkenes with various sulfonyl chlorides was developed. The protocol provides access to sulfonyl radicals via energy transfer from the quinazolinone skeleton to the sulfonyl chloride. Notably, the transformations proceeded without any external photocatalysts, additives, or oxidants, providing an alternative method for fabricating sulfonylated compounds.
- Sun, Bin,Ding, Hao,Tian, Hai-Xia,Huang, Pan-Yi,Jin, Can,Wu, Chun-Lei,Shen, Run-Pu
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supporting information
p. 766 - 772
(2021/12/22)
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- Design, synthesis, and evaluation of novel (E)-N'-(3-allyl-2-hydroxy)benzylidene-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides as antitumor agents
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In our continuing search for novel small-molecule anticancer agents, we designed and synthesized a series of novel (E)-N'-(3-allyl-2-hydroxy)benzylidene-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides (5), focusing on the modification of substitution in the quinazolin-4(3H)-one moiety. The biological evaluation showed that all 13 designed and synthesized compounds displayed significant cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). The most potent compound 5l displayed cytotoxicity up to 213-fold more potent than 5-fluorouracil and 87-fold more potent than PAC-1, the first procaspase-activating compound. Structure–activity relationship analysis revealed that substitution of either electron-withdrawing or electron-releasing groups at positions 6 or 7 on the quinazolin-4(3H)-4-one moiety increased the cytotoxicity of the compounds, but substitution at position 6 seemed to be more favorable. In the caspase activation assay, compound 5l was found to activate the caspase activity by 291% in comparison to PAC-1, which was used as a control. Further docking simulation also revealed that this compound may be a potent allosteric inhibitor of procaspase-3 through chelation of the inhibitory zinc ion. Physicochemical and ADMET calculations for 5l provided useful information of its suitable absorption profile and some toxicological effects that need further optimization to be developed as a promising anticancer agent.
- Dung, Do T. M.,Park, Eun J.,Anh, Duong T.,Hai, Pham-The,Huy, Le D.,Jun, Hye W.,Kwon, Joo-Hee,Young Ji,Kang, Jong S.,Tung, Truong T.,Dung, Phan T. P.,Han, Sang-Bae,Nam, Nguyen-Hai
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- Visible-Light Photosynthesis of CHF2/CClF2/CBrF2-Substituted Ring-fused Quinazolinones in Dimethyl Carbonate
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With eco-friendly and sustainable CO2-derived dimethyl carbonate as the sole solvent, the visible-light-induced cascade radical reactions have been established as a green and efficient tool for constructing various CHF2/CClF2/CBrF2-substituted ring-fused quinazolinones.
- Gui, Qing-Wen,He, Wei-Min,Huang, Wen-Jie,Lu, Zi-Qin,Ouyang, Wen-Tao,Teng, Fan,Xun, Changping,Yang, Hao,Zhu, Meng-Xue
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- Self-catalyzed phototandem perfluoroalkylation/cyclization of unactivated alkenes: Synthesis of perfluoroalkyl-substituted quinazolinones
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A novel visible-light-induced radical tandem trifluoromethylation/cyclization of unactivated alkenes with sodium perfluoroalkanesulfinates (Rf = CF3, C3F7, C4F9, C6F13, C8F17) under air atmosphere has been developed. A range of quinazolinones containing unactivated alkene moiety and sodium perfluoroalkanesulfinates were compatible with this transformation, leading to a variety of perfluoroalkyl-substituted quinazoline alkaloids. Remarkably, the experiment can be carried out without any metal catalyst, strong oxidant, or external photosensitizer.
- Sun, Bin,Huang, Panyi,Yan, Zhiyang,Shi, Xiayue,Tang, Xiaoli,Yang, Jin,Jin, Can
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supporting information
p. 1026 - 1031
(2021/02/06)
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- Photoinduced homolytic decarboxylative acylation/cyclization of unactivated alkenes with α-keto acid under external oxidant and photocatalyst free conditions: access to quinazolinone derivatives
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A novel and green strategy for the synthesis of acylated quinazolinone derivativesviaphoto-induced decarboxylative cascade radical acylation/cyclization of quinazolinone bearing unactivated alkenes has been developed. The protocol provides a novel route to access acyl radicals from α-keto acids through a self-catalyzed energy transfer process. Most importantly, the reaction proceeded smoothly without any external photocatalyst, additive or oxidant, and could be easily scaled-up in flow conditions with sunlight irradiation.
- Sun, Bin,Shi, Rongcheng,Zhang, Kesheng,Tang, Xiaoli,Shi, Xiayue,Xu, Jiayun,Yang, Jin,Jin, Can
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supporting information
p. 6050 - 6053
(2021/06/21)
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- Photo-triggered self-catalyzed fluoroalkylation/cyclization of unactivated alkenes: Synthesis of quinazolinones containing the CF2R group
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A novel photo-triggered self-catalyzed fluoroalkylation/cyclization of quinazolinones containing unactivated alkenes with various fluoroalkyl bromides has been developed. This transformation exhibits excellent substrate generality with respect to both the coupling partners. Of note is that this is the first example describing the Csp3-Br bond homolysis of alkyl bromides via a substrate (quinazolinones) induced energy transfer process. Additionally, the mild conditions, tolerance to a wide range of functional groups and operational simplicity make this protocol practical for the synthesis of fluorine-containing ring-fused quinazolinones. This journal is
- Yang, Jin,Sun, Bin,Ding, Hao,Huang, Pan-Yi,Tang, Xiao-Li,Shi, Rong-Cheng,Yan, Zhi-Yang,Yu, Chuan-Ming,Jin, Can
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supporting information
p. 575 - 581
(2021/01/28)
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- Visible-Light-Induced Radical Difluoromethylation/Cyclization of Unactivated Alkenes: Access to CF2H-Substituted Quinazolinones
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A mild and efficient visible-light-induced radical difluoromethylation/cyclization of unactivated alkenes toward the synthesis of substituted quinazolinones with easily accessible difluoromethyltriphenylphosphonium bromide has been developed. The transformation has the advantages of wide functional group compatibility, a broad substrate scope, and operational simplicity. The benign protocol offers a facile access to pharmaceutically valuable difluoromethylated polycyclic quinazolinones.
- Chen, Xiaoyu,Liu, Bo,Pei, Congcong,Li, Jingya,Zou, Dapeng,Wu, Yangjie,Wu, Yusheng
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supporting information
p. 7787 - 7791
(2021/10/20)
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- Discovery of BPR1R024, an Orally Active and Selective CSF1R Inhibitor that Exhibits Antitumor and Immunomodulatory Activity in a Murine Colon Tumor Model
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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
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supporting information
p. 14477 - 14497
(2021/10/20)
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- 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
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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
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- Quinazolin-4(3H)-one-Based Hydroxamic Acids: Design, Synthesis and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity
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The present article describes the synthesis and biological activity of various series of novel hydroxamic acids incorporating quinazolin-4(3H)-ones as novel small molecules targeting histone deacetylases. Biological evaluation showed that these hydroxamic acids were potently cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI?H23, lung). Most compounds displayed superior cytotoxicity than SAHA (suberoylanilide hydroxamic acid, Vorinostat) in term of cytotoxicity. Especially, N-hydroxy-7-(7-methyl-4-oxoquinazolin-3(4H)-yl)heptanamide (5b) and N-hydroxy-7-(6-methyl-4-oxoquinazolin-3(4H)-yl)heptanamide (5c) (IC50 values, 0.10–0.16 μm) were found to be approximately 30-fold more cytotoxic than SAHA (IC50 values of 3.29–3.67 μm). N-Hydroxy-7-(4-oxoquinazolin-3(4H)-yl)heptanamide (5a; IC50 values of 0.21–0.38 μm) was approximately 10- to 15-fold more potent than SAHA in cytotoxicity assay. These compounds also showed comparable HDAC inhibition potency with IC50 values in sub-micromolar ranges. Molecular docking experiments indicated that most compounds, as represented by 5b and 5c, strictly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA.
- Hieu, Doan Thanh,Anh, Duong Tien,Hai, Pham-The,Thuan, Nguyen Thi,Huong, Le-Thi-Thu,Park, Eun Jae,Young Ji,Soon Kang, Jong,Phuong Dung, Phan Thi,Han, Sang-Bae,Nam, Nguyen-Hai
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- IDENTIFICATION AND USE OF ERK5 INHIBITORS
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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.
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Page/Page column 51; 75-76
(2019/10/01)
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- A in the aqueous phase under microwave conditions using halogenated benzamide fast synthesis of quinazoline compounds of the method
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The invention discloses a in the aqueous phase under microwave conditions using halogenated benzamide fast synthesis of quinazoline compounds of the method, the use of palladium chloride to serve as the catalyst, in water under microwave heating conditions, neighbouring halogen benzamide with an isocyanate reaction to produce the quinazoline compounds of the method, the invention an environment-friendly, the operation is simple, cheap and safe, efficient process for producing quinazoline compounds of the method. Compared with the prior art, this method not only can be applied to a large number of functional groups, the productive rate is high, few by-products, and the operation is simple, safe, low cost, environmental protection.
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Paragraph 0015; 0035
(2019/02/13)
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- A in ammonia water condition of microwave halo benzoic acid synthesis method of the quinazoline compounds
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The invention discloses a in ammonia water condition of microwave halo benzoic acid synthetic quinazoline compounds of the method, the use of palladium chloride to serve as the catalyst, in ammonia water under the microwave heating condition, neighbouring halogen benzoic acid generated by the reaction with the isocyanate of the quinazoline compounds of the method, the invention an environment-friendly, the operation is simple, cheap and safe, efficient process for producing quinazoline compounds of the method. Compared with the prior art, this method not only can be applied to a large number of functional groups, the productive rate is high, few by-products, and the operation is simple, safe, low cost, environmental protection.
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Paragraph 0017; 0037
(2019/02/13)
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- Novel N-Hydroxybenzamides or N-Hydroxypropenamides Incorporating Quinazolin-4(3H)-ones as Histone Deacetylase Inhibitors and Anticancer Composition Comprising the Same
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The present invention relates to novel N-hydroxy benzamides or N-hydroxy propenamides based on quinazoline-4(3H)-ones as histone deacetylase (HDAC) inhibitors and a use thereof. More specifically, a compound according to the present invention has a strong HDAC inhibitory activity, thereby being able to be used as proliferation inhibitors for various cancer cells. Therefore, the compound according to the invention is expected to be able to be developed as an active component of strong anti-cancer drugs.COPYRIGHT KIPO 2019
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Paragraph 0135; 0136
(2019/05/15)
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- Novel Hydroxamic Acid Incorporating Quinazolin-4(3H)-ones as Histone Deacetylase Inhibitors and Anticancer Composition Comprising the Same
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The compound according HDAC(histone deacetylase) to the present -4(3H)- won invention can, be used as an active. ingredient of, a potent anticancer agent, HDAC since the compound according, to the present invention can be used. as, an active ingredient of a potent anticancer agent, since the compound. according to the present invention can be used as an active ingredient of a potent anticancer agent. (by machine translation)
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Paragraph 0105-0106
(2020/03/03)
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- Quinazoline-Based Hydroxamic Acids: Design, Synthesis, and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity
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In our search for novel histone deacetylases inhibitors, we have designed and synthesized a series of novel hydroxamic acids and N-hydroxybenzamides incorporating quinazoline heterocycles (4a?–?4i, 6a?–?6i). Bioevaluation showed that these quinazoline-based hydroxamic acids and N-hydroxybenzamides were potently cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung). In term of cytotoxicity, several compounds, e.g., 4g, 4c, 4g?–?4i, 6c, and 6h, displayed from 5- up to 10-fold higher potency than SAHA (suberoylanilidehydroxamic acid, vorinostat). The compounds were also generally comparable to SAHA in inhibiting HDACs with IC50 values in sub-micromolar range. Some compounds, e.g., 4g, 6c, 6e, and 6h, were even more potent HDAC inhibitors compared to SAHA in HeLa extract assay. Docking studies demonstrated that the compounds tightly bound to HDAC2 at the active binding site with binding affinities higher than that of SAHA. Detailed investigation on the estimation of absorption, distribution, metabolism, excretion, and toxicity (ADMET) suggested that compounds 4g, 6c, and 6g, while showing potent HDAC2 inhibitory activity and cytotoxicity, also potentially displayed ADMET characteristics desirable to be expected as promising anticancer drug candidates.
- Hieu, Doan Thanh,Anh, Duong Tien,Hai, Pham-The,Huong, Le-Thi-Thu,Park, Eun Jae,Choi, Jeong Eun,Kang, Jong Soon,Dung, Phan Thi Phuong,Han, Sang-Bae,Nam, Nguyen-Hai
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- Hepatitis C virus inhibitors
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Hepatitis C virus inhibitors having the general formula (I) are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 612
(2017/01/23)
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- Molecular targeting anticancer photosensitizer AKT - phthalocyanine conjugates
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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.
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Paragraph 0056-0057
(2017/05/18)
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- A microwave catalysis in the aqueous phase a method of preparing Quinazolinone compounds
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The invention discloses a method for preparing quinazolinone in water phase through microwave catalysis. The method comprises the step: by utilizing a water-soluble coordination compound (such as 8-hydroxyquinoline) as a catalyst, carrying out high-efficiency microwave catalysis on the reaction of 2-halogenated benzaldehyde and amidine salts in pure water phase. The invention relates to a method for preparing a quinazolinone compound, which is environment-friendly, simple and convenient to operate, safe and low-cost, and high-efficiency. Compared with the prior art, the method not only can be applicable to a great deal of functional groups, high in yield, fewer in side products, but also is simple and safe to operate, low in cost, and environment-friendly.
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Paragraph 0057
(2017/02/09)
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- Small-molecule phosphodiesterase probes: Discovery of potent and selective CNS-penetrable quinazoline inhibitors of PDE1
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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.
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p. 1290 - 1296
(2014/10/15)
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- Hepatitis C Virus Inhibitors
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Hepatitis C virus inhibitors having the general formula (I) are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column
(2013/05/21)
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- Design, synthesis and analgesic properties of novel conformationally-restricted N-acylhydrazones (NAH)
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A set of six azaheterocycles were designed as conformationnaly-constrained N-acylhydrazones and tested as analgesics.
- Kuemmerle, Arthur E.,Vieira, Marina M.,Schmitt, Martine,Miranda, Ana L.P.,Fraga, Carlos A.M.,Bourguignon, Jean-Jacques,Barreiro, Eliezer J.
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scheme or table
p. 4963 - 4966
(2010/03/24)
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- CHEMICAL COMPOUNDS
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The invention relates to chemical compounds of the formula (I) or pharmaceutically acceptable salts thereof, which possess B Raf inhibitory activity and are accordingly useful for their anti cancer activity and thus in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti-cancer effect in a warm blooded animal such as man.
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Page/Page column 52
(2008/06/13)
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