- Discovery of AdipoRon analogues as novel AMPK activators without inhibiting mitochondrial complex I
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Activation of AMPK emerges as a potential therapeutic approach to metabolic diseases. AdipoRon is claimed to be an adiponectin receptor agonist that activates AMPK through adiponectin receptor 1 (AdipoR1). However, AdipoRon also exhibits moderate inhibition of mitochondrial complex I, leading to increased risk of lactic acidosis. In order to find novel AdipoRon analogues that activate AMPK without inhibition of complex I, 27 analogues of AdipoRon were designed, synthesized and biologically evaluated. As results, benzyloxy arylamide B10 was identified as a potent AMPK activator without inhibition of complex I. B10 dose-dependently improved glucose tolerance in normal mice, and significantly lowered fasting blood glucose level and ameliorated insulin resistance in db/db diabetic mice. More importantly, unlike the pan-AMPK activator MK-8722, B10 did not cause cardiac hypertrophy, probably owing to its selective activation of AMPK in the muscle tissue but not in the heart tissue. Together, B10 represents a novel class of AMPK activators with promising therapeutic potential against metabolic disease.
- Chen, Caiping,Cheng, Keguang,Cheng, Yalong,Dai, Liang,Li, Haobin,Qian, Ming,Sun, Geng,Wang, Pengfei,Wen, Xiaoan,Xu, Qing-Long,You, Yanping,Yuan, Haoliang,Zhou, Xinyu
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supporting information
(2020/06/08)
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- Design, synthesis, and biological evaluation of sorafenib derivatives containing indole (ketone) semicarbazide analogs as antitumor agents
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A series of new sorafenib derivatives was designed and synthesized. The antiproliferative activity of the synthesized compounds against human lung cancer cell (A549), human pancreatic cancer cell (PC-3), human leukemia cell (K562), and human hepatoma cell (SMMC-7721) was evaluated by MTT assay. The results revealed that several compounds displayed more significant antitumor activities than commercial anticancer agent sorafenib against SMMC-7721. In addition, compounds 7a, 7g, 7l, 7m, and 7p represented obvious growth inhibition with IC50 values of 1-9 μM against four cancer cell lines, demonstrating more predominant activities against cancer cells as compared to sorafenib. Furthermore, some structure-activity relationships have also been established. Compounds containing indole and benzene ring substituted by halogen showed better activity than sorafenib. Wound healing assay suggested that cells would be targeted on their migratory capacity by 7g, potentially affecting the migration activity of these tumors. The effects of A549 and PC-3 cell apoptosis induced by compound 7g were significantly increased compared with sorafenib. Importantly, the result of western blot assay showed that 7g inhibited cell growth by suppressing the activity of EGFR, especially the expression of p-EGFR (Tyr1068).
- Li, Wen,Qi, Ya-Yun,Wang, Yuan-Yuan,Gan, Yi-Yuan,Shao, Li-Hui,Zhang, Li-Qiong,Tang, Zhen-Hua,Zhu, Mei,Tang, Si-Yu,Wang, Zhen-Chao,Ouyang, Gui-Ping
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p. 2548 - 2560
(2020/04/02)
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- Synthesis, cytotoxicity, and in vivo antitumor activity study of parthenolide semicarbazones and thiosemicarbazones
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Parthenolide is an important sesquiterpene lactone with potent anticancer activities. In order to further improve its biological activity, a series of parthenolide semicarbazone or thiosemicarbazone derivatives was synthesized and evaluated for their anti
- Du, Guohua,Jia, Xinxin,Li, Yan,Liu, Qi,Wang, Shiyi,Zeng, Binglin,Zhang, Chen
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- Discovery of 4-piperazinyl-2-aminopyrimidine derivatives as dual inhibitors of JAK2 and FLT3
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Hybridization strategy is an effective strategy to obtain multi-target inhibitors in drug design. In this study, we assembled the pharmacophores of momelotinib and tandutinib to get a series of 4-piperazinyl-2-aminopyrimidine derivatives. All compounds were tested for the inhibition of JAK2 and FLT3 enzymes, of which, compounds with potent enzyme activities were assayed for antiproliferative activities against three cancer cell lines (HEL, MV4-11, and HL60). The structure-activity relationship studies were conducted through variations in two regions, the “A” phenyl ring and “B” phenyl ring. Compound 14j showed the most balanced in vitro inhibitory activity against JAK2 and FLT3 (JAK2 IC50 = 27 nM, FLT3 IC50 = 30 nM), and it also showed potent inhibition against the above tested cell lines. In the cellular context, 14j strongly induced apoptosis by arresting cell cycle in the G1/S phase, and was selected as a promising JAK2/FLT3 dual inhibitor.
- Li, Yingxiu,Ye, Tianyu,Xu, Le,Dong, Yuhong,Luo, Yong,Wang, Chu,Han, Yufei,Chen, Ke,Qin, Mingze,Liu, Yajing,Zhao, Yanfang
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- 2 - Amino pyrimidine compounds and their use (by machine translation)
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The invention belongs to the technical field of pharmaceutical chemical synthesis, relates to the general formula (I) indicated by the 2 - amino pyrimidine compounds and their pharmaceutically acceptable salt, solvate or prodrug, their method of preparation and containing pharmaceutical composition of said compound, wherein substituent R1 , R2 , R6 With the meanings given in the specification. The invention also relates to the compounds of the formula I or its pharmaceutical composition for treating and/or preventing malignant blood diseases or other proliferative diseases in the use of the medicament. (by machine translation)
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Paragraph 0099; 0110; 0111
(2019/10/22)
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- Spontaneous and direct transformation of N,O-diaryl carbamates into N,N′-diarylureas
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We have discovered a spontaneous reaction of N,O-diaryl carbamates to afford symmetrical N,N′-diarylureas. Optimization of the conditions indicated that N,N-dimethylformamide (DMF) was the best solvent and triethylamine (Et3N) was the best additive for this transformation. The reaction requires the presence of aryl groups on the nitrogen and oxygen atoms of carbamates. Substrates bearing an electron-donating methoxy group on either of the aryl groups reacted slowly under these conditions.
- Yamasaki, Ryu,Honjo, Yutaka,Ito, Ai,Fukuda, Kazuo,Okamoto, Iwao
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p. 880 - 884
(2018/09/10)
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- N-(3,5-dimethyladamantane-1-yl)-N'-substituted phenylurea compound as well as preparation method and application thereof
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The invention belongs to the technical field of medicinal chemistry, in particular to N-(3,5-dimethyladamantane-1-yl)-N'-substituted phenylurea compounds as well as preparation methods and application thereof. The compounds have the structure shown in the formula I. The compounds are proved that the compounds can improve the image recognition memory, the working and learning memory, the spatial learning and memory ability of model rats and has good anti-alzheimer effects by the new object discrimination experiments, Y-maze experiments, positioning navigation and space exploration experiments in mats. The formula I is shown in the description.
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Paragraph 0072; 0073; 0088; 0089
(2017/12/28)
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- Silver-mediated radical coupling reaction of isocyanides and alcohols/phenols in the presence of water: unprecedented hydration and radical coupling reaction sequence
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The radical coupling of isocyanides and alcohols/phenols promoted by silver in the presence of water is reported for the first time, which led to the formation of diverse carbamates. In contrast to the well-known 1,1-addition to form imidoyl radicals, a novel reaction mechanism, involving sequential hydration of isocyanides and coupling with alkoxyl/phenoxyl radicals, is disclosed by combining experimental and theoretical studies.
- Zhang, Lin,Xiao, Pin,Guan, Xiaoxue,Huang, Zhouliang,Zhang, Jingping,Bi, Xihe
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supporting information
p. 1580 - 1583
(2017/02/23)
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- Highly Regioselective Carbamoylation of Electron-Deficient Nitrogen Heteroarenes with Hydrazinecarboxamides
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The use of hydrazinecarboxamides as a new class of carbamoylating agents has been established through the dehydrazinative Minisci reaction of electron-deficient nitrogen heteroarenes. A wide range of electron-deficient nitrogen heteroarenes, including isoquinoline, quinoline, pyridine, phenanthridine, quinoxaline, and phthalazine, underwent copper/acid-catalyzed oxidative carbamoylation with hydrazinecarboxamide hydrochlorides to afford structurally diverse nitrogen-heteroaryl carboxamides as single regioisomers in moderate to excellent yields. The functional group tolerance was substantially demonstrated in the direct carbamoylation of quinine obviating multistep sequences involving protecting groups and prefunctionalization of the heterocycle.
- He, Zeng-Yang,Huang, Chao-Fan,Tian, Shi-Kai
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supporting information
p. 4850 - 4853
(2017/09/23)
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- Preparation of substituted semicarbazides from corresponding amines and hydrazines via phenyl carbamates
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A simple synthetic procedure for the conversion of amines and hydrazines into substituted semicarbazides was developed. The initial condensation between the desired amine and phenyl chloroformate into phenyl carbamate is followed by the addition of hydrazine under basic conditions. The reaction is tolerable to a variety of functional groups, with mild conditions and high percent yields.
- Hron, Rebecca,Jursic, Branko S.
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supporting information
p. 1540 - 1543
(2014/03/21)
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- Synthesis, characterization and biological screening of various O-phenyl-N-aryl carbamates
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A series of O-phenyl-N-aryl carbamates (3a-i) were synthesized by the reaction of phenyl chloroformate (1) with different aromatic amines (2a-i). The compounds were characterized by IR and 1H-NMR and screened against acetylcholinesterase, butrylcholinesterase and lipoxygenase enzymes. The results revealed that O-phenyl-N-phenyl carbamate (3a) and O-phenyl-N-(3-hydroxyphenyl) carbamate (3e) were active against acetylcholinesterase while O-phenyl-N-benzyl carbamate (3b), O-phenyl-N-(4-hydroxyphenyl) carbamate (3f) and O-phenyl-N-(3-methoxyphenyl) carbamate (3h) exhibited potential inhibitory activity against 5-lipoxygenase. All these carbamates were also assayed for their antimicrobial and hemolytic activities. O-phenyl-N-(2-hydroxyphenyl) carbamate (3d), O-phenyl-N-(4-hydroxyphenyl) carbamate (3f) and O-phenyl-N-(3-methoxyphenyl) carbamate (3h) showed good antimicrobial and hemolytic activity among all the carbamates.
- Abbasi, Muhammad Athar,Sonia, Ayesha,Aziz-Ur-Rehman,Khan, Khalid Mohammed,Ashraf, Muhammad,Afzal, Iftikhar,Ambreen, Nida,Shahid, Muhammd,Abbas, Mazhar
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p. 385 - 390
(2013/07/27)
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- Synthesis and evaluation in vitro of 1-[2-(10-dihydroartemisininoxy) ethyl]-3-phenylurea derivatives as potential agents against cancer
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In order to develop potent and selective anticancer agents, a series of novel artemisinin derivatives bearing urea moiety 1a-n were facilely synthesized herein and screened for their activities in vitro against ten human tumor cell lines (HeLa, MCF-7, U937, K562, HL60, HCT116, HepG2, A549, A375-S2, and HT1080). The pharmacological results indicated that some compounds showed excellent activity against cancer cell lines and good selectivity, especially the compound 1c which proved to be the most active against the cancer cells as well as distinctive patterns of selectivity.
- Luo, Wei,Xia, Ming-Yu,Ikejima, Takashi,Li, Li-Hua,Guo, Chun
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p. 3170 - 3176
(2013/07/19)
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- Concerted aminolysis of diaryl carbonates: Kinetic sensitivity on the basicity of the nucleophile, nonleaving group, and nucleofuge
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The kinetics of the reactions of 4-methylphenyl, phenyl, and 4-chlorophenyl 2,4,6-trinitrophenyl carbonates (1, 2, and 3, respectively) with a series of anilines and secondary alicyclic (SA) amines has been carried out spectrophotometrically in 44 wt% ethanol-water, at 25.0°C, ionic strength 0.2 M. The BrAnsted plots (statistically corrected) for the reactions of carbonates 1-3 with anilines and SA amines were linear with slopes (βN) in the range of 0.69-0.78 and 0.45-0.48, respectively, attributed to a concerted mechanism. The negative values found for the sensitivity of log kN to the basicity of the nonleaving (βnlg) and leaving (βlg) groups are discussed. Anilines are more reactive than isobasic SA amines, probably because of the greater steric hindrance offered by the latter.
- Castro, Enrique A.,Cubillos, Maria,Iglesias, Rocio,Santos, Jose G.
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experimental part
p. 604 - 611
(2012/09/08)
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- Identification of oxazolidinediones and thiazolidinediones as potent 17β-hydroxysteroid dehydrogenase type 3 inhibitors
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Novel and potent inhibitors of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) were identified based on oxazolidinedione and thiazolidinedione derivatives, starting from a high-throughput screening hit, 5-(3-bromo-4-hydroxybenzyl)-3-(4-methoxyphenyl)-1
- Harada, Koichiro,Kubo, Hideki,Tanaka, Akio,Nishioka, Kazuhiko
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scheme or table
p. 504 - 507
(2012/03/11)
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- Synthesis and biological activities of novel artemisinin derivatives as cysteine protease falcipain-2 inhibitors
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A series of novel artemisinin derivatives were synthesized from artemisinin and different anilines. All compounds were obtained as β-isomers. The target compounds were evaluated for inhibition activity against Plasmodium falciparum falcipain-2 in vitro, and most of them exhibited potent inhibition in the low micromolar range and proved to be new types of falcipain-2 inhibitors.
- Liu, Yang,Lu, Wei-Qiang,Cui, Kun-Qiang,Luo, Wei,Wang, Jian,Guo, Chun
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p. 1525 - 1531
(2013/03/14)
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- Anilinolysis of reactive aryl 2,4-dinitrophenyl carbonates: Kinetics and mechanism
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The reactions of a series of anilines with phenyl 2,4-dinitrophenyl (1), 4-nitrophenyl 2,4-dinitrophenyl (2), and bis(2,4-dinitrophenyl) (3) carbonates are subjected to a kinetic investigation in 44 wt% ethanol-water, at 25.0 ± 0.1°C and an ionic strength of 0.2 M. Under amine excess pseudo-first-order rate coefficients (kobs) are obtained. Plots of kobs against free amine concentration at constant pH are linear, with slopes kN. The BrAnsted plots (log kN vs. anilinium pKa) for the anilinolysis of 1-3 are linear, with slope (β) values of 0.52, 0.61, and 0.63, respectively. The values of these slopes and other considerations suggest that these reactions are ruled by a concerted mechanism. For these reactions, the kN values follow the reactivity sequence: 3 > 2 > 1. Namely, the reactivity increases as the number of nitro groups attached to the nonleaving group increases. Comparison of the reactions of this work with the stepwise pyridinolysis of carbonates 1-3 indicates that the zwitterionic tetrahedral intermediate (T±) formed in the pyridinolysis reactions is destabilized by the change of its pyridino moiety by an isobasic anilino group. This is attributed to the superior leaving ability from the T± intermediate of anilines, relative to isobasic pyridines, which destabilize kinetically this intermediate. The kN values for the anilinolysis of carbonates 1-3 are similar to those found in the reactions of these carbonates with secondary alicyclic amines. With the kinetic data for the anilinolysis of the title substrates and 4-methylphenyl and 4-chlorophenyl 2,4-dinitrophenyl carbonates, a multiparametric equation is derived for log kN as a function of the pKa of the conjugate acids of anilines and nonleaving groups.
- Castro, Enrique A.,Domecq, Claudia,Santos, Jose G.
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supporting information; experimental part
p. 191 - 197
(2011/10/04)
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- Convenient synthesis of sorafenib and its derivatives
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This article describes a convenient synthesis of sorafinib and its derivatives from phenyl carbamates in good yields. This procedure, avoiding toxic phosgene, is especially suitable for large-scale preparation. Copyright
- Zhang, Lijuan,Xia, Wenpin,Wang, Bo,Luo, Yu,Lu, Wei
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experimental part
p. 3140 - 3146
(2011/09/20)
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- Phenyl 4,5-dichloro-6-oxopyridazine-1(6H)-carboxylate as carbonyl source: Facile and selective synthesis of carbamates and ureas under mild conditions
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The selective syntheses of carbamates, symmetric -ureas, and unsymmetrical ureas have been accomplished by the -reaction of amines with phenyl 4,5-dichloro-6-oxopyridazine-1(6H)-carboxylate as a carbonyl source under mild conditions. It is noteworthy that this process is mild, economic, and convenient.
- Lee, Hyung-Geun,Kim, Min-Jung,Park, Song-Eun,Kim, Jeum-Jong,Kim, Bo Ram,Lee, Sang-Gyeong,Yoon, Yong-Jin
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experimental part
p. 2809 - 2814
(2010/03/03)
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- Preparation of N-substituted aryl and alkyl carbamates and their inhibitory effect on oat seed germination.
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A series of N-substituted aryl and alkyl carbamates (RNHCOOR'; R: aryl, alkyl; R': aryl, alkyl) was prepared and screened for inhibitory activity toward the germination of oat seeds. The activity of each compound was compared with that of chlorpropham (isopropyl 3-chlorocarbanilate). Some of the synthetic carbamates possessing the N-(phenylthio)methyl group, PhSCH2NHCOOR', showed inhibitory activity close or comparable to that of chlorpropham.
- Alizadeh, Babak Heidary,Sugiyama, Takeyoshi,Oritani, Takayuki,Kuwahara, Shigefumi
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p. 422 - 425
(2007/10/03)
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- A practical synthesis of ureas from phenyl carbamates
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Using DMSO as solvent, a mild and efficient procedure for the synthesis of unsymmetrical N,N'-disubstituted ureas from phenyl carbamates is described. The carbamates are treated with a stoichiometric amount of amine at ambient temperature, generating the
- Thavonekham, Bounkham
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p. 1189 - 1194
(2007/10/03)
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- α-Haloalkyl Haloformates and Related Compounds 1. A Convenient Synthesis of Carbamates via Chloromethyl Carbamates
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The preparation of carbamates under mild conditions utilizing a new class of activated carbonates (containing chloromethyl function) is described.
- Patonay, Tamas,Patonay-Peli, Erzsebet,Mogyorodi, Ferenc
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p. 2865 - 2885
(2007/10/02)
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