- Discovery of phthalazino[1,2-b]-quinazolinone derivatives as multi-target HDAC inhibitors for the treatment of hepatocellular carcinoma via activating the p53 signal pathway
-
In view of histone deacetylases (HDACs) as a promising target for cancer therapy, a series of phthalazino[1,2-b]-quinazolinone units were hybrided with ortho-aminoanilide or hydroxamic acid to serve as multi-target HDAC inhibitors for the treatment of solid tumors. Among the target compounds, 8h possessed nano-molar IC50 values toward the tested cancer cells and HDAC subtypes, which was more potent than the HDAC inhibitor SAHA (vorinostat). Mechanism study revealed that compound 8h could suppress the HepG2 cell proliferation via prompting the acetylation of histone 3 (H3) and α-tubulin, and activating the p53 signal pathway as designed. In addition, compound 8h exhibited much stronger in vivo antitumor efficacy than SAHA in the HepG2 xenograft tumor model with negligible toxicity. As a novel multi-target HDAC inhibitor, compound 8h deserves further development as a potential anticancer agent.
- Liu, Qingqing,Zhang, Bin,Wang, Yuanjiang,Wang, Xinyi,Gou, Shaohua
-
-
- Multi-target anti-tumor small molecules and their derivatives, preparation methods, pharmaceutical compositions and applications
-
The present invention discloses a class of multi-target anti-tumor small molecules and derivatives thereof, preparation methods, pharmaceutical compositions and applications. The chemical structure of such small molecules as shown in formula I, the derivative of which relates to a pharmaceutically acceptable salt of the small molecule. This class of small molecules and their derivatives has a highly efficient tumor suppressor effect in vivo and abroad, low toxicity to cells and organisms, no genotoxicity; anti-tumor activity is achieved through multi-target action, with pan-HDAC inhibitory activity, and can also effectively activate the p53 pathway, inhibit topoisomerase activity, can be used to prepare anti-tumor drugs; the preparation method is simple and easy to operate.
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Paragraph 0039-0043
(2022/01/05)
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- Total synthesis of acronycine and noracronycine: An aryne amination approach
-
Acronycine and noracronycine are chromene-containing alkaloids with significant biological activity. We have accomplished a concise total synthesis of acronycine and noracronycine. The key step, regioselective nucleophilic addition of anthranilate to chromene-type arynes under mild and transition-metal-free conditions was achieved. In addition, further modifications of nucleophilic addition products, such as hydrogenation, O-functionalization and palladium-catalyzed coupling reactions have also been developed, providing a concise procedure for these alkaloids and their derivatives.
- Xu, Yuan-Ze,Wen, Qi-Ling,Sha, Feng,Li, Qiong,Wu, Xin-Yan
-
-
- Benzimidazoquinazolines as new potent anti-TB chemotypes: Design, synthesis, and biological evaluation
-
In search for new molecular entities as anti-TB agents, the benzimidazoquinazoline polyheterocyclic scaffold has been designed adopting the scaffold hopping strategy. Thirty-two compounds have been synthesized through an improved tandem decarboxylative nucleophilic addition cyclocondensation reaction of o-phenylenediamine with isatoic anhydride followed by further cyclocondensation of the intermediately formed 2-(o-aminoaryl)benzimidazole with trialkyl orthoformate/acetate. The resultant benzimidazoquinazolines were evaluated in vitro for anti-TB activity against M. tuberculosis H37Rv (ATCC27294 strain). Fourteen compounds exhibiting MIC values in the range of 0.4–6.25 μg/mL were subjected to cell viability test against RAW 264.7 cell lines and were found to be non-toxic (30% inhibition at 50 μg/mL). The active compounds were further evaluated against INH resistant Mtb strains. The most active compound 6x [MIC (H37Rv) of 0.4 μg/mL] and the compound 6d [MIC (H37Rv) of 0.78 μg/mL] were also found to be active against INH resistant Mtb strain with MIC values of 12.5 and 0.78 μg/mL, respectively.
- Chakraborti, Asit K.,Dhameliya, Tejas M.,Jadhavar, Pradeep S.,Krishna, Vagolu Siva,Patel, Kshitij I.,Saha, Nirjhar,Sriram, Dharmarajan,Vaja, Maulikkumar D.
-
-
- Synthesis of novel tryptanthrin derivatives as dual inhibitors of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase
-
Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are promising drug development targets due to their implications in pathologies such as cancer and neurodegenerative diseases. The search for IDO1 inhibitor has been intensely pursued but there is a paucity of potent TDO and IDO1/TDO dual inhibitors. Natural product tryptanthrin has been confirmed to bear IDO1 and/or TDO inhibitory activities. Herein, twelve novel tryptanthrin derivatives were synthesized and evaluated for the IDO1 and TDO inhibitory potency. All of the compounds were found to be IDO1/TDO dual inhibitors, in particular, compound 9a and 9b bore IDO1 inhibitory activity similar to that of INCB024360, and compound 5a and 9b had remarkable TDO inhibitory activity superior to that of the well-known TDO inhibitor LM10. This work enriches the collection of IDO1/TDO dual inhibitors and provides chemical molecules for potential development into drugs.
- Cui, Menghan,Kuang, Chunxiang,Li, Yuanyuan,Liu, Wei,Wang, Rong,Yang, Qing,Zhang, Shengnan
-
supporting information
(2020/04/10)
-
- APPLICATION OF N-BENZYL TRYPTANTHRIN DERIVATIVE AS TRYPTOPHAN DIOXYGENASE (TDO) INHIBITOR
-
The present invention provides an application of N-benzyl tryptanthrin derivative as tryptophan dioxygenase (TDO) inhibitor, and more specifically an application of N-benzyl tryptanthrin derivative or a pharmaceutically acceptable salt thereof. Said derivative has a structural general formula as represented by formula 1, wherein each group is defined as in the specification. The derivative of the present invention has a good TDO inhibiting activity and can be used to prepare a treatment for diseases associated with TDO activity and expression.
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Paragraph 0102; 0104
(2020/04/24)
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- Target protein degradation inducing compound, preparation method thereof and pharmaceutical composition for preventing or treating targeted protein related diseases containing the same as an active ingredient
-
The present invention relates to a degraducer for inducing the decomposition of target protein, a producing method thereof, and a pharmaceutical composition for preventing or treating target protein-related diseases by containing the degraducer as an active ingredient. A novel compound represented by chemical formula 1, ULB-L-PTM, by the present invention, as a degraducer compound inducing the decomposition of target protein using cereblon E3 ubiquitin ligase, is able to significantly achieve a target protein degradation-inducing activity with an excellent binding activity of a cereblon E3 ubiquitin ligase binder thereby, being able to achieve an excellent protein degradation activity by targeting protein or polypeptide related to various diseases. The bromodomain-containing pharmaceutical composition for preventing or treating protein-related diseases or conditions contains the novel compound represented by chemical formula 1 as an active ingredient and has a useful effect of providing a health functional food composition for prevention or improvement.(AA) Example 22 (nM, 24h)COPYRIGHT KIPO 2020
- -
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Paragraph 0609; 0611-0613
(2020/05/01)
-
- NOVEL PIPERIDINE-2,6-DIONE DERIVATIVE AND USE THEREOF
-
The present disclosure relates to a novel piperidine-2,6-dione derivative and a use thereof and, more specifically, to a piperidine-2,6-dione derivative compound having a structure of a thalidomide analog. A compound of chemical formula 1 according to the present disclosure specifically binds with CRBN protein, and is involved in functions thereof. Therefore, the compound of the present disclosure can be favorably used in the prevention or treatment of leprosy, chronic graft versus host disease, an inflammatory disease, or cancer, which are caused by actions of CRBN protein.
- -
-
Paragraph 0146-0148
(2020/03/09)
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- Protein arginine methyltransferase 5 (PRMT5) inhibitor, pharmaceutical products thereof, and methods thereof
-
The present invention provides a PRMT5 inhibitor of formula (I); R1 is a non-hydrogen monovalent group; W is a direct bond or-NH-; T, U and V are independently from each other selected from C and N; R2 is H or halogen; m is 1 or 2; X is carbon, nitrogen or oxygen; Y is C or N; Z is a direct bond or carbon; R3 is H, a non-hydrogen monovalent group, an oxo group, a divalent spiro-forming group or adivalent bridge-forming group; and n is 1 or 2, and represents a single or double bond. The present invention also provides pharmaceutical products comprising the PRMT5 inhibitor and use thereof in the treatment of proliferative disorders such as cancer, metabolic disorders, hematological disorders, autoimmune diseases and inflammatory diseases.
- -
-
Paragraph 0334-0338
(2020/11/05)
-
- Carbene-Catalyzed Enantioselective Decarboxylative Annulations to Access Dihydrobenzoxazinones and Quinolones
-
A direct decarboxylative strategy for the generation of aza-o-quinone methides (aza-o-QMs) by N-heterocyclic carbene (NHC) catalysis has been discovered and explored. This process requires no stoichiometric additives in contrast with current approaches. Aza-o-QMs react with trifluoromethyl ketones through a formal [4+2] manifold to access highly enantioenriched dihydrobenzoxazin-4-one products, which can be converted to dihydroquinolones through an interesting stereoretentive aza-Petasis–Ferrier rearrangement sequence. Complementary dispersion-corrected density functional theory (DFT) studies provided an accurate prediction of the reaction enantioselectivity and lend further insight to the origins of stereocontrol. Additionally, a computed potential energy surface around the major transition structure suggests a concerted asynchronous mechanism for the formal annulation.
- Lee, Ansoo,Zhu, Joshua L.,Feoktistova, Taisiia,Brueckner, Alexander C.,Cheong, Paul H.-Y.,Scheidt, Karl A.
-
supporting information
p. 5941 - 5945
(2019/04/03)
-
- Preparation method and application of tryptanthrin (TRYP) derivative containing boric acid
-
The invention relates to preparation method and application of a tryptanthrin (TRYP) derivative. The preparation method is characterized in that 5-bromoisatin can be used as a raw material to be oxidized into 5-bromoisatoic anhydride; 5-bromoisatoic anhydride is subjected to a reflux reaction with 5-fluoroisatin to obtain 2-bromo-8-fluorotryptanthrin by taking acetonitrile as solvent under the alkalescent condition of triethylamine; then the 2-bromo-8-fluorotryptanthrin and bis(pinacolato)diboron are catalyzed by 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium to obtain 2-pinacol borate-8-fluorotryptanthrin in the presence of potassium acetate by taking N,N-dimethylformamide as solvent; the 2-pinacol borate-8-fluorotryptanthrin is added with sodium periodate to obtain an orange product, that is, 2-borono-8-fluorotryptanthrin by taking tetrahydrofuran and water as solvent. The method provided by the invention has the advantages that the operation is simple, the conditions are mild and industrial production is convenient. The tryptanthrin derivative containing boric acid can obviously inhibit the activity of indoleamine-2,3-dioxygenase (IDO), has broad application prospects and value, and can be applied to the prevention and treatment of IDO-mediated diseases such as cancer, Alzheimer disease, depression, and cataract.
- -
-
Paragraph 0033-0035; 0045-0047; 0055-0057; 0065-0067
(2019/10/10)
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- N-Benzyl/Aryl Substituted Tryptanthrin as Dual Inhibitors of Indoleamine 2,3-Dioxygenase and Tryptophan 2,3-Dioxygenase
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Indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes the initial and rate-limiting step of the kynurenine pathway of tryptophan catabolism, has emerged as a key target in cancer immunotherapy because of its role in enabling cancers to evade the immune system. Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase 2 (IDO2) catalyze the same reaction and play a potential role in cancer immunotherapy. Starting from our previously discovered tryptanthrin IDO1 inhibitor scaffold, we synthesized novel N-benzyl/aryl substituted tryptanthrin derivatives and evaluated their inhibitory efficacy on IDO1, TDO, and IDO2. Most compounds showed similar high inhibitory activities on both IDO1 and TDO, which were significantly superior over that of IDO2 with magnitude difference. We showed that N-benzyl/aryl substituted tryptanthrin directly interacted with IDO1, TDO, and IDO2, significantly augmented the proliferation of T cells in vitro, blocked the kynurenine pathway, and suppressed tumor growth when administered to LLC and H22 tumor-bearing mice.
- Yang, Dan,Zhang, Shengnan,Fang, Xin,Guo, Leilei,Hu, Nan,Guo, Zhanling,Li, Xishuai,Yang, Shuangshuang,He, Jin Chao,Kuang, Chunxiang,Yang, Qing
-
p. 9161 - 9174
(2019/10/16)
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- Tryptanthrin derivative containing olefine acid, and preparation method and application thereof
-
The invention discloses a tryptanthrin derivative, and a preparation method and application thereof. The preparation method comprises the following steps: with 5-methylisatin as a raw material, oxidizing 5-methylisatin into 5-methylisatoic anhydride; under the weak alkaline condition of triethylamine, subjecting 5-methylisatoic anhydride and 5-fluoroisatin to reflux with acetonitrile as a solvent,and carrying out filtration and washing to obtain 2-methyl-8-fluorotryptanthrin; subjecting 2-methyl-8-fluorotryptanthrin and N-bromosuccinimide to reflux in a carbon tetrachloride solvent; and reacting a concentrated product with malonic acid in pyridine, and carrying out acidification, washing and filtering to obtain the desired tryptanthrin derivative. The tryptanthrin derivative of the invention has excellent inhibitory activity against indoleamine-2,3-dioxygenase (IDO), increases the water solubility of tryptanthrin, has broad application prospects and can be used for treating diseases with pathological features of the IDO-mediated tryptanthrin metabolism pathway, e.g., cancer, Alzheimer's disease, depression and cataract. The preparation method of the invention has the advantages ofsimple operation, mild conditions and the like, and is easy to be industrialized.
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Page/Page column 22-29
(2019/11/20)
-
- INHIBITORS OF PROTEIN ARGININE METHYLTRANSFERASE 5 (PRMT5), PHARMACEUTICAL PRODUCTS THEREOF, AND METHODS THEREOF
-
The present invention provides PRMT5 inhibitors of Formula (I), wherein R1 is a non-hydrogen monovalent group; W is a direct bond or -NH-; T, U, and V are independently of each other selected from C and N; R2 is H or a halo; m is 1 or 2; X is a carbon, a nitrogen, or an oxygen; Y is C or N; Z is a direct bond or a carbon; R3 is H, a non-hydrogen monovalent group, an oxo group, a bivalent spiro ring-forming group, or a bivalent bridge-forming group; n is 1 or 2; and Formula (II) stands for a single bond or a double bond. Pharmaceutical products comprising the PRMT5 inhibitors and use thereof in treating proliferative disorders such as cancer, metabolic disorders, blood disorders, autoimmune diseases, and inflammatory diseases are also provided.
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-
Paragraph 0193; 0194
(2019/10/01)
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- Quinolines from the cyclocondensation of isatoic anhydride with ethyl acetoacetate: Preparation of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate and derivatives
-
A convenient two-step synthesis of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate derivatives has been developed starting from commercially available 2-aminobenzoic acids. In step 1, the anthranilic acids are smoothly converted to isatoic anhydrides using solid triphosgene in THF. In step 2, the anhydride electrophiles are reacted with the sodium enolate of ethyl acetoacetate, generated from sodium hydroxide, in warm N,N-dimethylacetamide resulting in the formation of substituted quinolines. A degradation–buildup strategy of the ethyl ester at the 3-position allowed for the construction of the α-hydroxyacetic acid residue required for the synthesis of key arylquinolines involved in an HIV integrase project.
- Jentsch, Nicholas G.,Hume, Jared D.,Crull, Emily B.,Beauti, Samer M.,Pham, Amy H.,Pigza, Julie A.,Kessl, Jacques J.,Donahue, Matthew G.
-
supporting information
p. 2529 - 2536
(2018/10/21)
-
- Gold-Catalyzed Selective 6-exo-dig and 7-endo-dig Cyclizations of Alkyn-Tethered Indoles to Prepare Rutaecarpine Derivatives
-
An efficient method to synthesize rutaecarpine derivatives via the gold-catalyzed selective cyclization of alkyn-tethered indoles under mild conditions is described. The alkyn-tethered indole can undergo 6-exo-dig cyclization by oxidation and sequential gold catalysis, while it goes through 7-endo-dig cyclization by gold catalysis and sequential oxidation. Substrate scope studies reveal that the selectivity of cyclization was controlled by the substrates with sp3 and sp2 hybridization of carbon at the 2 position in quinazolinone. Furthermore, the rutaecarpine scaffold was prepared in 67% yield at gram scale easily in four steps from isatoic anhydride.
- Kong, Xiang-Fei,Zhan, Feng,He, Guo-Xue,Pan, Cheng-Xue,Gu, Chen-Xi,Lu, Ke,Mo, Dong-Liang,Su, Gui-Fa
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p. 2006 - 2017
(2018/02/23)
-
- Preparation method of medicine for treating breast cancers
-
The invention provides a preparation method of a medicine for treating breast cancers, in particular to a novel method for preparing N-{3-chloro-4-[(3-fluorobenzyl)methoxyl]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)furan-2-yl]-4-quinazoline ami
- -
-
Paragraph 0112; 0113; 0114
(2017/08/28)
-
- Palladium-Catalyzed Cyclization Reaction of o-Iodoanilines, CO2, and CO: Access to Isatoic Anhydrides
-
Isatoic anhydrides, a class of valuable synthetic intermediates and RNA structure probing reagents, are usually prepared with highly toxic phosgene or stoichiometric oxidants. Herein we report a highly selective palladium-catalyzed cyclization reaction for the efficient synthesis of isatoic anhydrides from readily available o-iodoanilines, CO2, and CO. The reaction proceeds under mild conditions and is redox-neutral. Both CO2 and CO are indispensable C1 building blocks for this catalytic reaction.
- Zhang, Wen-Zhen,Zhang, Ning,Sun, Yu-Qian,Ding, Yu-Wei,Lu, Xiao-Bing
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p. 8072 - 8076
(2017/12/08)
-
- Design, Synthesis, and Potency of Pyruvate Dehydrogenase Complex E1 Inhibitors against Cyanobacteria
-
Safe and effective algaecides are needed to control agriculturally and environmentally significant algal species. Four series (6, 10, 17, and 21) of 29 novel 4-aminopyrimidine derivatives were rationally designed and synthesized. A part of 10, 17, and 21 displayed potent inhibition of Escherichia coli pyruvate dehydrogenase complex E1 (E. coli PDHc-E1) (IC50 = 2.12-18.06 μM) and good inhibition of Synechocystis sp. PCC 6803 (EC50 = 0.7-7.1 μM) and Microcystis sp. FACH 905 (EC50 = 3.7-7.6 μM). The algaecidal activity of these compounds positively correlated with their inhibition of E. coli PDHc-E1. In particular, 21l and 10b exhibited potent algaecidal activity against PCC 6803 (EC50 = 0.7 and 0.8 μM, respectively), values that were 2-fold increased compared to that of copper sulfate (EC50 = 1.8 μM), and showed the best inhibition of cyanobacterium PDHc-E1 (IC50 = 5.10 and 6.06 μM, respectively). 17h and 21e, the best inhibitors of E. coli PDHc-E1, were studied by molecular docking, site-directed mutagenesis, and enzymatic assays. These results revealed that the improved inhibition of novel inhibitors compared with that of the lead compound I was due to the formation of a new hydrogen bond with Leu264 at the active site of E. coli PDHc-E1. The results proved the great potential to obtain effective algaecides via the rational design of PDHc-E1 inhibitors. [Figure Presented]
- Zhou, Yuan,Feng, Jiangtao,He, Hongwu,Hou, Leifeng,Jiang, Wen,Xie, Dan,Feng, Lingling,Cai, Meng,Peng, Hao
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p. 6491 - 6502
(2017/12/26)
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- N- alkane primary coloramine alkone derivative and its preparation method and application
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An N-alkyl tryptanthrin derivative, a preparation method for same, and an application thereof are provided. The structure of the derivative is as represented by formula I. The N-alkyl tryptanthrin derivative can serve as a highly active IDO inhibitor, for use in preparing a medicament for prevention and/or treatment of a disease having a pathological characteristic of an IDO-mediated tryptophan metabolic pathway.
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-
Paragraph 0085; 0086; 0087
(2016/10/09)
-
- Quinolinone compound and application thereof in drugs
-
The invention relates to a quinolinone compound and application thereof in drugs, particularly relates to a novel quinolinone compound, a pharmaceutical composition thereof and use of the compound or the pharmaceutical composition in preparing drugs. The drug is used for protecting, disposing, treating or alleviating HIF-related and/or EPO-related diseases of patients, wherein the HIF-related and/or EPO-related diseases comprise anemia, vascular diseases, regional myocardial ischaemia, metabolic disturbance, wound healing and the like.
- -
-
Paragraph 0302; 0303; 0304; 0305; 0306; 0307
(2016/10/07)
-
- Design and synthesis of DNA-encoded libraries based on a benzodiazepine and a pyrazolopyrimidine scaffold
-
Selection-based screening of large DNA-encoded libraries of drug-like small molecules is a validated method to identify bioactive compounds. Among the chemical space of bioactive compounds certain scaffold structures are well represented. These are commonly called "privileged scaffolds". We have synthesized DNA-encoded libraries based on two representatives of these scaffolds, a benzodiazepine and a pyrazolopyrimidine, and additionally a third library based on propargyl glycine. All three core structures possess a carboxylic acid to couple them to aminolinker-modified DNA. For subsequent library synthesis they contained an amino function to which a set of carboxylic acid building blocks were coupled, and a terminal alkyne that was reacted with a set of azides to furnish triazoles. The two sets of building blocks, 114 carboxylic acids and 104 azides, were selected with the help of chemoinformatic methods in order to control the physicochemical properties of the final libraries, remove unwanted substructures, and maximize diversity. The set of building blocks contained desthiobiotin allowing for validation of library synthesis. The DNA-encoded libraries were synthesized by split-and-pool combinatorial chemistry yielding three libraries that contain 28.254 compounds together. For DNA barcoding, 5′-phosphorylated double-stranded coding DNA sequences with four base overhangs were ligated with T4 ligase. The resulting DNA-encoded libraries were compared to bioactivity databases and, though being based on core structures well-established in medicinal chemistry, showed novelty with respect to the known bioactive chemical space.
- ?kopi?, M. Klika,Bugain,Jung,Onstein,Brandherm,Kalliokoski,Brunschweiger
-
supporting information
p. 1957 - 1965
(2016/10/22)
-
- Recyclable (PhSe)2-catalyzed selective oxidation of isatin by H2O2: a practical and waste-free access to isatoic anhydride under mild and neutral conditions
-
After a series of careful conditional optimizations and catalyst screenings, a methodology to prepare isatoic anhydrides through organoselenium-catalyzed selective oxidation of isatins by H2O2 under mild and neutral conditions was developed. The reactions were very practical because of the recyclability of the catalyst and solvent and the convenient isolation procedures of the products. This work reports the organoselenium-catalyzed oxidation of heterocycles that greatly expands the application scopes of organoselenium catalysis. It also indicates that the organoselenium catalysts are robust enough to be recycled in industrial production if suitable isolation procedures are developed.
- Yu, Lei,Ye, Jianqing,Zhang, Xu,Ding, Yuanhua,Xu, Qing
-
p. 4830 - 4838
(2015/10/05)
-
- Synthesis and biological evaluation of some amino- and sulfanyl-3H-quinazolin-4-one derivatives as potential anticancer agents
-
A series of 6-substituted quinazolinone derivatives were prepared by the reaction of 6-bromoquinazolinones with aryl or alkyl amines and thiols, in the presence of a Pd(OAc)2/Xantphos system, under Buchwald-Hartwig-type reaction conditions. The 6-bromoquinazolinones were obtained in the three-components reaction of 5-bromoisatoic anhydride, triethyl orthoformate and an appropriate amine. Biological screening of the potential cytotoxicity of synthesized compounds on HT29 and HCT116 cell lines, as well as on the lymphocytes, showed that some derivatives of quinazolinone have significant anticancer activities. The detailed synthesis, spectroscopic data, and biological assays were reported.
- Malinowski, Zbigniew,Fornal, Emilia,Nowak, Monika,Kontek, Renata,Gajek, Gabriela,Borek, Bartlomiej
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p. 1723 - 1731
(2015/09/15)
-
- Palladium-catalyzed carbonylation of o-iodoanilines for synthesis of isatoic anhydrides
-
A novel palladium-catalyzed oxidative double carbonylation of o-iodoanilines for the synthesis of isatoic anhydrides has been developed. The reaction employs readily available o-iodoanilines as the starting materials and proceeds under mild conditions. For extension, palladium-catalyzed oxidative carbonylation of anthranilic acids was developed for the synthesis of substituted isatoic anhydrides in high to excellent yields.
- Gao, Sha,Chen, Ming,Zhao, Mi-Na,Du, Wei,Ren, Zhi-Hui,Wang, Yao-Yu,Guan, Zheng-Hui
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p. 4196 - 4200
(2014/05/20)
-
- Indoxylic acid esters as convenient intermediates towards indoxyl glycosides
-
Indoxylic acid methyl and allyl esters with varied halide-substitution patterns were obtained in excellent yields using a scalable route. Phase-transfer glycosylation of these key intermediates was carried out with various glycosyl halides. Subsequent mild silver-mediated decarboxylation followed by Zemplen deacetylation led to indoxyl glycosides in good overall yields. Indoxyl glycosides are well-established and widely used tools for enzyme screening and enzyme-activity monitoring. In the past, their synthesis has been difficult, so this new approach has led to a variety of useful structures. Indoxyl glycosides with varied halide-substitution patterns were synthesized using indoxylic acid esters as key intermediates. Glycosylation under phase-transfer conditions, ester cleavage, and mild decarboxylation led to the indoxyl glycosides in good yields. This approach enables access to a number of different indoxyl compounds. Copyright
- Boettcher, Stephan,Thiem, Joachim
-
p. 564 - 574
(2014/02/14)
-
- Is the 2,3-carbon-carbon bond of indole really inert to oxidative cleavage by Oxone?-Synthesis of isatoic anhydrides from indoles
-
A recent report has indicated that the oxidizing agent Oxone does not possess the ability to cleave the 2,3-carbon-carbon bond of indole. Work in our laboratory shows that this is not the case. Indole and a variety of aryl ring substituted derivatives readily react to form synthetically important isatoic anhydrides.
- Nelson, Amber C.,Kalinowski, Emily S.,Czerniecki, Nikolas J.,Jacobson, Taylor L.,Grundt, Peter
-
supporting information
p. 7455 - 7457
(2013/11/06)
-
- Discovery of a 3-pyridylacetic acid derivative (TAK-100as a potent, selective and orally active dipeptidyl peptidase IV (DPP-4) inhibitor
-
Inhibition of dipeptidyl peptidase IV (DPP-4is an exciting new approach for the treatment of diabetes. To date there has been no DPP-4 chemotype possessing a carboxy group that has progressed into clinical trials. Originating from the discovery of the str
- Miyamoto, Yasufumi,Banno, Yoshihiro,Yamashita, Tohru,Fujimoto, Tatsuhiko,Oi, Satoru,Moritoh, Yusuke,Asakawa, Tomoko,Kataoka, Osamu,Yashiro, Hiroaki,Takeuchi, Koji,Suzuki, Nobuhiro,Ikedo, Koji,Kosaka, Takuo,Tsubotani, Shigetoshi,Tani, Akiyoshi,Sasaki, Masako,Funami, Miyuki,Amano, Michiko,Yamamoto, Yoshio,Aertgeerts, Kathleen,Yano, Jason,Maezaki, Hironobu
-
experimental part
p. 831 - 850
(2011/04/12)
-
- Discovery of potent, selective, and orally bioavailable quinoline-based dipeptidyl peptidase IV inhibitors targeting Lys554
-
Dipeptidyl peptidase IV (DPP-4) inhibition is a validated therapeutic option for type 2 diabetes, exhibiting multiple antidiabetic effects with little or no risk of hypoglycemia. In our studies involving non-covalent DPP-4 inhibitors, a novel series of quinoline-based inhibitors were designed based on the co-crystal structure of isoquinolone 2 in complex with DPP-4 to target the side chain of Lys554. Synthesis and evaluation of designed compounds revealed 1-[3-(aminomethyl)-4-(4-methylphenyl)-2-(2-methylpropyl)quinolin-6-yl] piperazine-2,5-dione (1) as a potent, selective, and orally active DPP-4 inhibitor (IC50 = 1.3 nM) with long-lasting ex vivo activity in dogs and excellent antihyperglycemic effects in rats. A docking study of compound 1 revealed a hydrogen-bonding interaction with the side chain of Lys554, suggesting this residue as a potential target site useful for enhancing DPP-4 inhibition.
- Maezaki, Hironobu,Banno, Yoshihiro,Miyamoto, Yasufumi,Moritou, Yuusuke,Asakawa, Tomoko,Kataoka, Osamu,Takeuchi, Koji,Suzuki, Nobuhiro,Ikedo, Koji,Kosaka, Takuo,Sasaki, Masako,Tsubotani, Shigetoshi,Tani, Akiyoshi,Funami, Miyuki,Yamamoto, Yoshio,Tawada, Michiko,Aertgeerts, Kathleen,Yano, Jason,Oi, Satoru
-
experimental part
p. 4482 - 4498
(2011/09/19)
-
- The use of biochemical and biophysical tools for triage of high-throughput screening hits - aa case study with escherichia coli phosphopantetheine adenylyltransferase
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High-throughput screening is utilized by pharmaceutical researchers and, increasingly, academic investigators to identify agents that act upon enzymes, receptors, and cellular processes. Screening hits include molecules that specifically bind the target and a greater number of non-specific compounds. It is necessary to 'triage' these hits to identify the subset worthy of further exploration. As part of our antibacterial drug discovery effort, we applied a suite of biochemical and biophysical tools to accelerate the triage process. We describe application of these tools to a series of 9-oxo-4,9-dihydropyrazolo[5, 1-b]quinazoline-2-carboxylic acids (PQ) hits from a screen of Escherichia coli phosphopantetheine adenylyltransferase (PPAT). Initial confirmation of specific binding to phosphopantetheine adenylyltransferase was obtained using biochemical and biophysical tools, including a novel orthogonal assay, isothermal titration calorimetry, and saturation transfer difference NMR. To identify the phosphopantetheine adenylyltransferase sub-site bound by these inhibitors, two techniques were utilized: steady-state enzyme kinetics and a novel 19F NMR method in which fluorine-containing fragments that bind the ATP and/or phosphopantetheine sites serve as competitive reporter probes. These data are consistent with PQs binding the ATP sub-site. In addition to identification of a series of PPAT inhibitors, the described hit triage process is broadly applicable to other enzyme targets in which milligram quantities of purified target protein are available.
- Miller, J. Richard,Thanabal, Venkataraman,Melnick, Michael M.,Lall, Manjinder,Donovan, Charles,Sarver, Ronald W.,Lee, Doh-Yeel,Ohren, Jeff,Emerson, Don
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scheme or table
p. 444 - 454
(2011/02/21)
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- QUINAZOLINES USEFUL AS MODULATORS OF ION CHANNELS
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The present invention relates to compounds useful as inhibitors of voltage-gated sodium channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.
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Page/Page column 169
(2008/06/13)
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- Thiazolinone 2-substituted quinolines
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Thiazolinone substituted quinoline derivatives where the quinoline ring is substituted at the 2 position which derivatives demonstrates CDK1 antiproliferative activity and are useful as anti-cancer agents.
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Page/Page column 11
(2010/10/20)
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- Quinazoline thiazolinones
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Quinazoline thiazolinone derivatives which demonstrate CDK1 antiproliferative activity and are useful as anti-cancer agents.
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Page/Page column 12
(2008/06/13)
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- ANTIBACTERIAL AGENTS
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The present invention relates to antibacterial agents that are useful for sterilization, sanitation, antisepsis, and disinfection.
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- Non-imidazole benzodiazepine inhibitors of farnesyl protein transferase
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Inhibition of farnesyl transferase, which is an enzyme involved in ras oncogene expression, is effected by compounds of the formulas their enantiomers, diastereomers, and pharmaceutically acceptable salts, prodrugs and solvates thereof.
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- Synthesis of 2-aminoquinazoline-4(3H)-one derivatives as potential potassium channel openers
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Starting from 2-thioxoquinazolin-4-one, the synthesis of 2-amino-4(3H)- one derivatives, structurally related to potassium channels openers pinacidil and diazoxide, is described.
- Erb, Benedicte,Akue, Rufine,Rigo, Benoit,Pirotte, Bernard,Couturier, Daniel
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p. 253 - 260
(2007/10/03)
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- Evidence for the Conservation of Conformational Topography at Five Major GABAA/Benzodiazepine Receptor Subsites. Potent Affinities of the (S)-Enantiomers of Framework-Constrained 4,5-Substituted Pyrroloimidazobenzodiazepines
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The synthesis and in vitro affinities of a series of optically active pyrrolo or azetidinylimidiazobenzodiazepines at five recombinant GABAA/BzR subtypes expressed from human cell lines are described. Examination of the in vitro binding data indicates that the (S)-enantiomers of these ligands are much more potent in vitro than their corresponding (R)-isomers. The binding affinities of these framework constrained (rigid) ligands provide evidence for the first time which indicates the conformational preference for BzR ligands is highly conserved at these five recombinant receptor subsites. The configurational preference for the (S)-enantiomers in both series suggests that pharmacophoric descriptors H1, H2 and L1 are the same in these five binding subsites in agreement with previous modeling studies.1 In addition, substituents at both the 3- and 8-positions of these framework constrained imidazobenzodiazepines are important in regard to subtype selectivity. For example, the (S)-pyrroloimidazobenzodiazepines 4a, 5a, 6a and azetidinyl analog 13 were 45 to 57 times more selective for α5β3γ2 subsites in comparison to the α1β3γ2 isoform. Modification of the 4- and 5-positions of the (S)-enantiomers of these imidazobenzodiazepines did not alter subsite selectivity. Even the oxadiazole 7c in the (S)-pyrroloimidazo series was found to be 36 times more selective for recombinant α5 isoforms. Data from the present study should be useful for understanding the conformational requirements of GABAA/BzR subtypes as well as providing some insight into the conservation of binding site topography across a series of BzR binding subsites.
- Liu, Ruiyan,Zhang, Puwen,Gan, Tong,McKernan, Ruth M.,Cook, James M.
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- Synthesis of quinazoline-2,4-dione and naphthalimide derivatives as new 5-HT3 receptor antagonists
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New potent 5-HT3 receptor antagonists have been designed from the naphthalimide moiety and a quinuclidine heterocycle and the structure-activity relationships are discussed here on the basis of the nature of the substituent on the aromatic system. The biological activity of the compounds was evaluated in binding assays with [3H]BRL-43694 and by inhibition of the Bezold-Jarisch reflex. Compound 22 with a 4-amino substituent was equipotent to the reference compounds. In contrast to the benzamide derivatives, the activity resides essentially in the (R) enantiomer (K(i) = 0.15 ± 0.05 nM, ID50 = 1.6 μg/kg/iv) and it is demonstrated that the additional carbonyl group is involved in the inversion of the enantioselectivity of the receptor. Conformational studies of (R)-22 demonstrated the presence of a locked structure with 4 minimal energy conformers which were compared to those of (S)-zacopride. The superimposition of the putative active conformers emphasized the presence of a second polar group in the binding site. The fluorescent properties of the compounds were studied and indicate that (R)-22 and its derivatives may be promising tools for the direct visualization of 5-HT3 receptors.
- Langlois,Soulier,Rampillon,Gallais,Bremont,Shen,Yang,Giudice,Sureau
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p. 925 - 940
(2007/10/02)
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- Intramolecular 1,3-Dipolar Cycloadditions. Part 1. A Facile Synthesis of Benzimidazo- and Quinazolinotriazolobenzodiazepines
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The synthesis of hitherto unknown 9H-benzimidazotriazolobenzodiazepines (4, 11a-e and 12a-c) and 9H-quinazolinotriazolobenzodiazepin-11-ones (5 and 18a-g) is reported. 2-(2-Azidoaryl)benzimidazoles (6 and 10a-h) and 2-(2-azidoaryl)quinazolin-4(3H)-ones (7 and 17a-g) react with propargyl bromide to give non-isolable intermediates which undergo an intramolecular 1,3-dipolar cycloaddition to the title compounds.
- Mohiuddin, Ghulam,Reddy, Padala Satyanarayana,Ahmed, Khalil,Ratnam, Chengalvala Venkata
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p. 1839 - 1868
(2007/10/02)
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