- Spin-labeled derivatives of cardiotonic steroids as tools for characterization of the extracellular entrance to the binding site on Na+,K+-ATPase
-
The information obtained from crystallized complexes of the Na+,K+-ATPase with cardiotonic steroids (CTS) is not sufficient to explain differences in the inhibitory properties of CTS such as stereoselectivity of CTS binding or effect of glycosylation on the preference to enzyme isoforms. The uncertainty is related to the spatial organization of the hydrophilic cavity at the entrance of the CTS-binding site. Therefore, there is a need to supplement the crystallographic description with data obtained in aqueous solution, where molecules have significant degree of flexibility. This work addresses the applicability of the electron paramagnetic resonance (EPR) method for the purpose. We have designed and synthesized spin-labeled compounds based on the cinobufagin steroid core. The length of the spacer arms between the steroid core and the nitroxide group determines the position of the reporting group (N-O) confined to the binding site. High affinity to Na+,K+-ATPase is inferred from their ability to inhibit enzymatic activity. The differences between the EPR spectra in the absence and presence of high ouabain concentrations identify the signature peaks originating from the fraction of the spin labels bound within the ouabain site. The degree of perturbations of the EPR spectra depends on the length of the spacer arm. Docking of the compounds into the CTS site suggests which elements of the protein structure might be responsible for interference with the spin label (e.g., steric clashes or immobilization). Thus, the method is suitable for gathering information on the cavity leading to the CTS-binding site in Na+,K+-ATPase in all conformations with high affinity to CTS.
- Guo, Jin-Hua,Jiang, Ren-Wang,Andersen, Jacob Lauwring,Esmann, Mikael,Fedosova, Natalya U.
-
-
Read Online
- Multitarget CFTR Modulators Endowed with Multiple Beneficial Side Effects for Cystic Fibrosis Patients: Toward a Simplified Therapeutic Approach ?
-
Cystic fibrosis (CF) is a multiorgan disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR). In addition to respiratory impairment due to mucus accumulation, viruses and bacteria trigger acute pulmonary exacerbations, accelerating disease progression and mortality rate. Treatment complexity increases with patients' age, and simplifying the therapeutic regimen represents one of the key priorities in CF. We have recently reported the discovery of multitarget compounds able to "kill two birds with one stone" by targeting F508del-CFTR and PI4KIIIβ and thus acting simultaneously as CFTR correctors and broad-spectrum enterovirus (EV) inhibitors. Starting from these preliminary results, we report herein a hit-to-lead optimization and multidimensional structure-activity relationship (SAR) study that led to compound 23a. This compound showed good antiviral and F508del-CFTR correction potency, additivity/synergy with lumacaftor, and a promising in vitro absorption, distribution, metabolism, and excretion (ADME) profile. It was well tolerated in vivo with no sign of acute toxicity and histological alterations in key biodistribution organs.
- Tassini, Sabrina,Langron, Emily,Delang, Leen,Mirabelli, Carmen,Lanko, Kristina,Crespan, Emmanuele,Kissova, Miroslava,Tagliavini, Giulia,Fontò, Greta,Bertoni, Simona,Palese, Simone,Giorgio, Carmine,Ravanetti, Francesca,Ragionieri, Luisa,Zamperini, Claudio,Mancini, Arianna,Dreassi, Elena,Maga, Giovanni,Vergani, Paola,Neyts, Johan,Radi, Marco
-
-
Read Online
- Carbonylative lactonization via carbonyl oxygen attack: A short and selective total synthesis of uncinine and its analogues
-
A novel cytotoxic butenolide alkaloid, uncinine, has been synthesized for the first time in 8 steps from propargyl alcohol. The sequence features a mild and efficient tandem carbonylative lactonization of a β-iodoenone precursor using an inorganic base at 1 atm CO, and an indirect attachment of the pyrrolidinone ring via nucleophilic substitution with methyl γ-aminobutyrate.
- Fáková, Helena,Pour, Milan,Kune?, Ji?í,?enel, Petr
-
-
Read Online
- Structural modification of histone deacetylase inhibitors with a phenylglycine scaffold
-
During the discovery of histone deacetylase inhibitors (HDACIs) as antitumor drugs, a series of potent phenylglycine-based HDACIs were developed. However, further development is restricted by the poor solubility. Therefore, structural modifications were performed in the present study in the development of potent HDACIs with improved pharmacokinetic properties. The synthesized molecules were designed by the substitution of fatty linkers for aromatic linkers, and showed good solubility profiles. Among the compounds derived, molecule HD9 showed a potent enzyme-inhibitory effect (IC50 values of 76 nmol/l) and in-vitro antiproliferative activities (IC50 values of 0.51, 0.83, and 0.76 μmol/l against U937, K562, and HL60 cells, respectively). Molecule HD9 showed selectivity of HDAC3 over HDAC6 in the isoform selectivity assays. Molecular docking studies showed good binding patterns of molecule HD9 to the active site of HDAC3. Results from the present work indicated that molecule HD9 is a promising lead compound for the tumor therapy.
- Zhang, Lei,Zhang, Li,Bian, Jiang,Jiang, Qixiao,Gao, Jianjun,Song, Weiguo
-
-
Read Online
- Gossypol with Hydrophobic Linear Esters Exhibits Enhanced Antitumor Activity as an Inhibitor of Antiapoptotic Proteins
-
A series of gossypol Schiff bases that were derived from unnatural linear amino acid methyl esters were identified and found to be much more potent than gossypol and ABT-199 in terms of anticancer activity. This is the first example of gossypol Schiff bases with increased activity. The investigation of the Schiff base side chain of gossypol revealed that the unique anticancer effect was achieved by the introduction of hydrophobic ester groups. The optimized products showed low micromolar pan antitumor activities against NCI-60 tumor cell lines, which is promising for further drug development. Studies on the preliminary mechanism of action for their cellular activities was also carried out with antiapoptotic protein (Bcl-2 and Mcl-1) inhibition FP assays. The molecular modeling analysis demonstrated a possible binding mode for these compounds with Bcl-2, which could explain the binding affinity of the novel gossypol Schiff bases with these proteins.
- Lu, Yuzhi,Wu, Shuangchan,Yue, Yuan,He, Si,Li, Jun,Tang, Jun,Wang, Wei,Zhou, Hai-Bing
-
-
Read Online
- Design, synthesis, and biological characterization of tamibarotene analogs as anticancer agents
-
In our efforts of developing novel compounds as potential anticancer agents, a series of tamibarotene analogs containing Zn2+-binding moieties were designed and developed. Biological characterization identified compound 7b as the most potent one with improved antiproliferative activities against multiple cancer cell lines, compared to parent compound tamibarotene. Further characterization also demonstrated that compound 7b exhibited moderate activities as a histone deacetylase inhibitor with IC50 of 1.8?±?0.1?μm, thus suggesting that this could contribute to the improved antiproliferative activities of 7b. Pharmacokinetic studies revealed that compound 7b could release tamibarotene after administration and prolong the circulation time of tamibarotene, and this may also potentially contribute to the improved antiproliferative activities. Collectively, the results demonstrated that compound 7b could serve as a new lead for further development of more potent analogs as potential anticancer agents.
- Jiang, Yuqi,Li, Xiaoyang,Wang, Xue,Wang, Zhonglan,Zhang, Jian,Wu, Jingde,Xu, Wenfang
-
-
Read Online
- Acetyl chloride-methanol as a convenient reagent for: A) quantitative formation of amine hydrochlorides; B) carboxylate ester formation; C) mild removal of N-t-Boc-protective group
-
Hydrogen chloride quatitativaly generated in situ by the addition of acetyl chloride to alcoholic solutions is a useful reagent for carboxylic acid esterification, N-t-Boc deprotection and phosphoramide solvolysis reactions.
- Nudelman, Ayelet,Bechor, Yosi,Falb, Eliezer,Fischer, Bilha,Wexler, Barry A.,Nudelman, Abraham
-
-
Read Online
- New amino-acid conjugates of glycyrrhizic acid
-
New conjugates of glycyrrhizic acid (GA) containing two amino-acid methyl esters (4-aminobutanoic, 6-aminohexanoic, 11-aminoundecanoic) were synthesized by the activated-ester method using N-hydroxysuccinimide (HOSu)-N,N″- dicyclohexylcarbodiimide (DCC). The conjugate of GA with 6-aminohexanoic acid possessed pronounced antiviral activity against influenza virus AH1N1/pdm09 with EC50 = 12.7 μM and SI = 32.
- Stolyarova,Baltina,Kondratenko,Fedorova,Orshanskaya,Zarubaev,Baltina
-
-
Read Online
- Transition Metal-Free N-Arylation of Amino Acid Esters with Diaryliodonium Salts
-
A transition metal-free approach for the N-arylation of amino acid derivatives has been developed. Key to this method is the use of unsymmetric diaryliodonium salts with anisyl ligands, which proved important to obtain high chemoselectivity and yields. The scope includes the transfer of both electron deficient, electron rich and sterically hindered aryl groups with a variety of different functional groups. Furthermore, a cyclic diaryliodonium salt was successfully employed in the arylation. The N-arylated products were obtained with retained enantiomeric excess.
- Kervefors, Gabriella,Kersting, Leonard,Olofsson, Berit
-
supporting information
p. 5790 - 5795
(2021/03/08)
-
- Plasma induced acceleration and selectivity in strain-promoted azide-alkyne cycloadditions
-
Strain-promoted azide-alkyne cycloaddition (SPAAC) is an important member of the bioorthogonal reaction family. Over the past decade, much work has been dedicated to the generation of new strained alkynes with improved reactivity. While kinetics studies of SPAAC are often conducted in organic solvents, buffered solutions or mixtures, these media do not reflect the complexity ofin vivosystems. In this work, we show that performing SPAAC in human plasma leads to intriguing kinetics and selectivity effects. In particular, we observed that reactions in plasma could be accelerated up to 70-fold compared to those in methanol, and that selective couplings between a pair of reagents could be possible in competition experiments. These findings highlight the value of evaluating bioorthogonal reactions in such a complex medium, especially whenin vivoapplications are planned, as unsuspected behaviour can be observed, disrupting the usual rules governing the reactivity in simple solvent systems.
- Warther, David,Dursun, Enes,Recher, Marion,Ursuegui, Sylvain,Mosser, Michel,Sobska, Joanna,Krezel, Wojciech,Chaubet, Guilhem,Wagner, Alain
-
supporting information
p. 5063 - 5067
(2021/06/21)
-
- Structure-activity relationship and molecular modelling studies of quinazolinedione derivatives MMV665916 as potential antimalarial agent
-
A series of new quinazolinedione derivatives have been readily synthesized and evaluated for their in vitro antiplasmodial growth inhibition activity. Most of the compounds inhibited P. falciparum FcB1 strain in the low to medium micromolar concentration. The 2-ethoxy 8ag’, 2-trifluoromethoxy 8ai’ and 4-fluoro-2-methoxy 8ak’ showed the best inhibitory activity with EC50 values around 5 μM and were non-toxic to the primary human fibroblast cell line AB943. However, these compounds were less potent than the original hit MMV665916, which showed remarkable growth inhibition with EC50 value of 0.4 μM and presented the highest selectivity index (SI > 250). In addition, a novel approach for determining the docking poses of these quinazolinedione derivatives with their potential protein target, the P. falciparum farnesyltransferase PfFT, was investigated.
- Albrecht, Sébastien,Florent, Isabelle,Mouray, Elisabeth,Mourot, Laura,Schmitt, Marjorie,Spichty, Martin
-
supporting information
(2021/11/22)
-
- Oxidative damage of proline residues by nitrate radicals (NO3): A kinetic and product study
-
Tertiary amides, such as in N-acylated proline or N-methyl glycine residues, react rapidly with nitrate radicals (NO3) with absolute rate coefficients in the range of 4-7 × 108 M-1 s-1 in acetonitrile. The major pathway proceeds through oxidative electron transfer (ET) at nitrogen, whereas hydrogen abstraction is only a minor contributor under these conditions. However, steric hindrance at the amide, for example by alkyl side chains at the α-carbon, lowers the rate coefficient by up to 75%, indicating that NO3-induced oxidation of amide bonds proceeds through initial formation of a charge transfer complex. Furthermore, the rate of oxidative damage of proline and N-methyl glycine is significantly influenced by its position in a peptide. Thus, neighbouring peptide bonds, particularly in the N-direction, reduce the electron density at the tertiary amide, which slows down the rate of ET by up to one order of magnitude. The results from these model studies suggest that the susceptibility of proline residues in peptides to radical-induced oxidative damage should be considerably reduced, compared with the single amino acid.
- Nathanael, Joses G.,Nuske, Madison R.,Richter, Annika,White, Jonathan M.,Wille, Uta
-
supporting information
p. 6949 - 6957
(2020/10/02)
-
- High-Fidelity End-Functionalization of Poly(ethylene glycol) Using Stable and Potent Carbamate Linkages
-
Commercial PEG-amine is of unreliable quality, and conventional PEG functionalization relies on esterification and etherification steps, suffering from incomplete conversion, harsh reaction conditions, and functional-group incompatibility. To solve these challenges, we propose an efficient strategy for PEG functionalization with carbamate linkages. By fine-tuning terminal amine basicity, stable and high-fidelity PEG-amine with carbamate linkage was obtained, as seen from the clean MALDI-TOF MS pattern. The carbamate strategy was further applied to the synthesis of high-fidelity multi-functionalized PEG with varying reactive groups. Compared to with an ester linkage, amphiphilic PEG-PS block copolymers bearing carbamate junction linkage exhibits preferential self-assembly tendency into vesicles. Moreover, nanoparticles of the latter demonstrate higher drug loading efficiency, encapsulation stability against enzymatic hydrolysis, and improved in vivo retention at the tumor region.
- Cen, Jie,Hu, Jinming,Li, Lei,Liu, Guhuan,Liu, Shiyong,Shi, Shengyu,Yao, Chenzhi
-
supporting information
p. 18172 - 18178
(2020/08/21)
-
- Discovery of a series of selective and cell permeable beta-secretase (BACE1) inhibitors by fragment linking with the assistance of STD-NMR
-
Two β-secreatase (BACE1) inhibitors from natural products (cinnamic acid and flavone) were linked to furnish potent, cell permeable BACE1 inhibitors with noncompetitive mode of inhibition, with the assistance of saturated transfer difference (STD)-NMR technique. Some of these conjugates also exhibited selective BACE1 inhibition over other aspartyl proteases such as BACE-2 and renin, as well as poor cytotoxicity. Taken together, conjugates 4 represent a new series of BACE inhibitors warrants further investigation for their potential in Alzheimier's disease therapy.
- Fang, Wei-Shuo,Sun, De-yang,Yang, Shuang,Cheng, Chen,Moschke, Katrin,Li, Tianqi,Sun, Shanshan,Lichtenthaler, Stefan F.,Huang, Jian,Wang, Yinghong
-
supporting information
(2019/09/30)
-
- From hit to lead: Structure-based discovery of naphthalene-1-sulfonamide derivatives as potent and selective inhibitors of fatty acid binding protein 4
-
Fatty acid binding protein 4 (FABP4) plays a critical role in metabolism and inflammatory processes and therefore is a potential therapeutic target for immunometabolic diseases such as diabetes and atherosclerosis. Herein, we reported the identification of naphthalene-1-sulfonamide derivatives as novel, potent and selective FABP4 inhibitors by applying a structure-based design strategy. The binding affinities of compounds 16dk, 16do and 16du to FABP4, at the molecular level, are equivalent to or even better than that of BMS309403. The X-ray crystallography complemented by the isothermal titration calorimetry studies revealed the binding mode of this series of inhibitors and the pivotal network of ordered water molecules in the binding pocket of FABP4. Moreover, compounds 16dk and 16do showed good metabolic stabilities in liver microsomes. Further extensive in vivo study demonstrated that 16dk and 16do exhibited a dramatic improvement in glucose and lipid metabolism, by decreasing fasting blood glucose and serum lipid levels, enhancing insulin sensitivity, and ameliorating hepatic steatosis in obese diabetic (db/db) mice.
- Gao, Ding-Ding,Dou, Hui-Xia,Su, Hai-Xia,Zhang, Ming-Ming,Wang, Ting,Liu, Qiu-Feng,Cai, Hai-Yan,Ding, Hai-Peng,Yang, Zhuo,Zhu, Wei-Liang,Xu, Ye-Chun,Wang, He-Yao,Li, Ying-Xia
-
-
- A structure-based design approach to advance the allyltyrosine-based series of HIV integrase inhibitors
-
As of mid-2017, only one structure of the human immunodeficiency virus (HIV) integrase core domain co-crystallised with an active site inhibitor was reported. In this structure (1QS4), integrase is complexed with a diketo-acid based strand-transfer inhibitor (INSTI). This structure has been a preferred platform for the structure-based design of INSTIs despite concerns relating to structural irregularities arising from crystallographic packing effects. A survey of the current pool of 297 reported integrase catalytic core structures indicated that the anatomy of the active site in the complex structure 1QS4 exhibits subtle variations relative to all other structures examined. Consequently, the 1QS4 structure was employed for docking studies. From the docking of twenty-seven allyltyrosine analogues, a 3-point inhibitor binding motif required for activity was established and successfully utilised in the development of a tripeptide displaying an EC50 value of 10 ± 5 μM in HIV infected human T-cells. Additional docking of “in-house” compound libraries unearthed a methyl ester based nitrile derivative displaying an IC50 value of 0.5 μM in a combined 3′-processing and strand-transfer assay.
- Gordon, Christopher P.,Dalton, Neal,Vandegraaff, Nicholas,Deadman, John,Rhodes, David I.,Coates, Jonathan A.,Pyne, Stephen G.,Griffith, Renate,Bremner, John B.,Keller, Paul A.
-
p. 1253 - 1268
(2017/12/04)
-
- Fluoroquinolone amino derivatives and use thereof in prevention and control of citrus diseases
-
Citrus canker and brown spot are common diseases of citrus. At present, few drugs are available to prevent and control the two diseases and have certain defects. Amino groups at the 7th positions of fluoroquinolone drugs are linked with an active fragment by means of a connecting structure so as to obtain compounds shown in a formula I or a formula II. Experiments prove that the compounds providedby the invention have effects of preventing and controlling the citrus canker and the brown spot and have very good application prospect.
- -
-
Paragraph 0118; 0119
(2018/07/30)
-
- Discovery of the First Environment-Sensitive Fluorescent Probe for GPR120 (FFA4) Imaging
-
GPR120, which is activated by long-chain free fatty acids (FFAs), has been recognized as a new attractive target for the treatment of type 2 diabetes and metabolic disease. The visualization and location of GPR120 in native cells can provide powerful information for guiding the physiological and pathological studies of GPR120. We report herein the first potent fluorescent probes that sensitively detect GPR120. We designed and synthesized a series of novel environment-sensitive probes with suitable fluorescence property, high biological activity on the GPR120, and acceptable cytotoxicity. These fluorescent probes targeting GPR120 are expected to expand the toolkit for further studies on GPR120.
- Liu, Jiaxiang,Tian, Chengsen,Jiang, Tianyu,Gao, Yuqi,Zhou, Yubin,Li, Minyong,Du, Lupei
-
supporting information
p. 428 - 432
(2017/04/21)
-
- The discovery of allyltyrosine based tripeptides as selective inhibitors of the HIV-1 integrase strand-transfer reaction
-
From library screening of synthetic antimicrobial peptides, an O-allyltyrosine-based tripeptide was identified to possess inhibitory activity against HIV-1 integrase (IN) exhibiting an IC50 value of 17.5 μM in a combination 3′-processing and strand transfer microtitre plate assay. The tripeptide was subjected to structure-activity relationship (SAR) studies with 28 peptides, incorporating an array of natural and non-natural amino acids. Resulting SAR analysis revealed the allyltyrosine residue was a key feature for IN inhibitory activity whilst incorporation of a lysine residue and extended hydrophilic chains bearing a terminal methyl ester was advantageous. Addition of hydrophobic aromatic moieties to the N-terminal of the scaffold afforded compounds with improved inhibitory activity. Consolidation of these functionalities lead to the development of the tripeptide 96 which specifically inhibited the IN strand-transfer reaction with an IC50 value of 2.5 μM.
- Dalton, Neal,Gordon, Christopher P.,Boyle, Timothy P.,Vandegraaf, Nicholas,Deadman, John,Rhodes, David I.,Coates, Jonathan A.,Pyne, Stephen G.,Keller, Paul A.,Bremner, John B.
-
supporting information
p. 6010 - 6023
(2016/07/06)
-
- Rhodium-Catalyzed Intramolecular C-H Bond Activation with Triazoles: Preparation of Stereodefined Pyrrolidines and Other Related Cyclic Compounds
-
On treatment of triazoles having an N-sulfonyl-protected benzylamine moiety with [Rh2(C7H15CO2)4], intramolecular C-H bond insertion takes place at the benzylic position to give cis-N-sulfonyl-2-aryl-3-[(sulfonylimino)methyl]pyrrolidines in good yields and with highly stereoselectivities. Analogously, the similar treatment of triazoles having an ether or even an alkyl moiety affords 2-alkyl- or 2-aryl-3-[(sulfonylimino)methyl]tetrahydrofurans or a 2-alkyl-3-[(sulfonylimino)methyl]cyclopentane in good yields. Three is a magic number: On treatment of triazoles with [Rh2(C7H15CO2)4], the rhodium catalyst plays three roles, denitrogenation, C-H bond activation, and stereoselective cyclization, providing a new method for heterocycle synthesis. Intramolecular C-H bond insertion takes place at the benzylic position to give pyrrolidines and related heterocycles in good yields.
- Senoo, Masato,Furukawa, Ayana,Hata, Takeshi,Urabe, Hirokazu
-
supporting information
p. 890 - 895
(2016/01/16)
-
- One-Pot Conversion of Carbohydrates into Pyrrole-2-carbaldehydes as Sustainable Platform Chemicals
-
A practical conversion method of carbohydrates into N-substituted 5-(hydroxymethyl)pyrrole-2-carbaldehydes (pyrralines) was developed by the reaction with primary amines and oxalic acid in DMSO at 90°C. Further cyclization of the highly functionalized pyrralines afforded the pyrrole-fused poly-heterocyclic compounds as potential intermediates for drugs, food flavors, and functional materials. The mild Maillard variant of carbohydrates and amino esters in heated DMSO with oxalic acid expeditiously produced the pyrrole-2-carbaldehyde skeleton, which can be concisely transformed into the pyrrole alkaloid natural products, 2-benzyl- and 2-methylpyrrolo[1,4]oxazin-3-ones 8 and 9, lobechine 10, and (')-hanishin 11 in 23-32% overall yields from each carbohydrate.
- Adhikary, Nirmal Das,Kwon, Sunjeong,Chung, Wook-Jin,Koo, Sangho
-
p. 7693 - 7701
(2015/08/18)
-
- A Maillard approach to 2-formylpyrroles: Synthesis of magnolamide, lobechine and funebral
-
A convenient synthesis of the traditional medicine constituents magnolamide, lobechine and funebral is described. Construction of the 2-formylpyrrole core of these natural products was achieved by means of a Maillard reaction, involving condensation of the sugar surrogate, dihydropyranone 9, with the requisite primary amines. This approach offers a very direct and general route to the 2-formylpyrrole ring system. The synthesis of the 2-formylpyrrole core found in the traditional medicine constituents, magnolamide, lobechine and funebral, was constructed by a Maillard reaction, involving condensation of the sugar surrogate, dihydropyranone 9, with the requisite primary amines. This approach offers a very direct and general route to the 2-formylpyrrole ring system. Copyright
- Yuen, Tsz-Ying,Eaton, Samantha E.,Woods, Tom M.,Furkert, Daniel P.,Choi, Ka Wai,Brimble, Margaret A.
-
p. 1431 - 1437
(2014/03/21)
-
- A Maillard Approach to 2-Formylpyrroles: Synthesis of Magnolamide, Lobechine and Funebral
-
A convenient synthesis of the traditional medicine constituents magnolamide, lobechine and funebral is described. Construction of the 2-formylpyrrole core of these natural products was achieved by means of a Maillard reaction, involving condensation of the sugar surrogate, dihydropyranone 9, with the requisite primary amines. This approach offers a very direct and general route to the 2-formylpyrrole ring system. The synthesis of the 2-formylpyrrole core found in the traditional medicine constituents, magnolamide, lobechine and funebral, was constructed by a Maillard reaction, involving condensation of the sugar surrogate, dihydropyranone 9, with the requisite primary amines. This approach offers a very direct and general route to the 2-formylpyrrole ring system.
- Yuen, Tsz-Ying,Eaton, Samantha E.,Woods, Tom M.,Furkert, Daniel P.,Choi, Ka Wai,Brimble, Margaret A.
-
p. 1431 - 1437
(2015/10/05)
-
- Design, synthesis, and potent antiepileptic activity with latent nerve rehabilitation of novel γ-aminobutyric acid derivatives
-
We aimed to design and synthesize novel γ-aminobutyric acid (GABA) derivatives with the combination of aspirin (ASA) of nerve rehabilitative pharmacophores so as to develop multifunctional drugs useful in the treatment of neurological disorders. Twenty-four novel esters and amides of 1a were synthesized, biologically evaluated for antiepileptic activity with the model of 4-aminopyridine (4-AP), and tested for their capacity of penetrating the blood-brain barrier (BBB) with HPLC. The distribution of 8a, ASA freed by 8a, 7c, and ASA freed by 7c within 24 h in brain tissue was measured. The structure-activity relationship (SAR) was established and the data of Computer Aided Drug Design (CADD) showed good results. With ED50 values of, 0.3684-0.5199 mmol/kg, LD50 1.1487-1.3944 mmol/kg, and therapeutic index (TI) 2.65-3.15, compounds 8a, 3b, 4b, 6c, and 7c exhibited better antiepileptic activities in multiples of 0.3 to 2.2 against the control sodium valproate (VPA). Most importantly, 8a and 7c exhibited excellent antiepileptic activities with TI values of, 3.15 and 3.12, respectively.
- He, Dian,Ma, Jing,Shi, Xiuxiao,Zhao, Chunyan,Hou, Meng,Guo, Qingxin,Ma, Shangxian,Li, Xiaojun,Zhao, Peicheng,Liu, Wenhu,Yang, Zhuqing,Mou, Jianping,Song, Pengfei,Zhang, Yang,Li, Jing
-
p. 967 - 978
(2015/02/19)
-
- OxymaPure/DIC: An efficient reagent for the synthesis of a novel series of 4-[2-(2-acetylaminophenyl)-2-oxo-acetylamino] benzoyl amino acid ester derivatives
-
OxymaPure (ethyl 2-cyano-2-(hydroxyimino)acetate) was tested as an additive for use in the carbodiimide (DIC) approach for the synthesis of a novel series of α-ketoamide derivatives (4-[2-(2-acetylaminophenyl)-2-oxo-acetylamino] benzoyl amino acid ester derivatives). OxymaPure showed clear superiority to HOBt/DIC or carbodiimide alone in terms of purity and yield. The title compounds were synthesized via the ring opening of N-acylisatin. First, N-acetylisatin was reacted with 4-aminobenzoic acid under conventional heating as well as microwave irradiation to afford 4-(2-(2-acetamidophenyl)-2-oxoacetamido)benzoic acid. This α-ketoamide was coupled to different amino acid esters using OxymaPure/DIC as a coupling reagent to afford 4-[2-(2-acetylaminophenyl)-2- oxoacetylamino] benzoyl amino acid ester derivatives in excellent yield and purity. The synthesized compounds were characterized using FT-IR, NMR, and elemental analysis.
- El-Faham, Ayman,Al Marhoon, Zainab,Abdel-Megeed, Ahmed,Albericio, Fernando
-
p. 14747 - 14759
(2014/01/17)
-
- MCR DENDRIMERS
-
The invention relates to a method for producing peptoidic, peptidic and chimeric peptidic-peptoidic dendrimers by multiple iterative multi-component reactions (MCR), in particular Ugi or Passerini multi-component reactions, to compounds produced in this way and to the use thereof.
- -
-
Page/Page column
(2013/08/15)
-
- Structurally diverse polyamides obtained from monomers derived via the Ugi multicomponent reaction
-
The combination of the Ugi four-component reaction (Ugi-4CR) with acyclic diene metathesis (ADMET) or thiol-ene polymerization led to the formation of poly-1-(alkylcarbamoyl) carboxamides, a new class of substituted polyamides with amide moieties in the polymer backbone, as well as its side chains. 10-Undecenoic acid, obtained by pyrolysis of ricinoleic acid, the main fatty acid of castor oil, was used as the key renewable building block. The use of different primary amines, as well as isonitriles (isocyanides) for the described Ugi reactions provided monomers with high structural diversity. Furthermore, the possibility of versatile post-modification of functional groups in the side chains of the corresponding polymers should be of considerable interest in materials science. The obtained monomers were polymerized by ADMET, as well as thiol-ene, chemistry and all polymers were fully characterized. Finally, ortho-nitrobenzylamide-containing polyamides obtained by this route were shown to be photoresponsive and exhibited a dramatic change of their properties upon irradiation with light.
- Kreye, Oliver,Tueruenc, Oguz,Sehlinger, Ansgar,Rackwitz, Jenny,Meier, Michael A. R.
-
supporting information; experimental part
p. 5767 - 5776
(2012/06/01)
-
- Direct C-H alkylation of naphthoquinones with amino acids through a revisited Kochi-Anderson radical decarboxylation: Trends in reactivity and applications
-
In our ongoing research program into the discovery of new anticancer drugs, we were interested in the preparation of naphthoquinone scaffolds bearing aminoalkyl side-chains. Following this aim, we revisited the Kochi-Anderson radical decarboxylation of amino acids in order to set up a versatile route to the direct functionalization of naphthoquinones. The best reaction conditions were applied to a selected series of compounds in a systematic methodological study which allowed us to establish important trends in reactivity. We found that α-substituted β-amino acids were the most suitable substrates for the radical addition. In contrast, α-amino acids gave modest results. The influence of the amine protecting groups on the reaction outcome has also been studied. This practical procedure allows the introduction of various unsymmetrical moieties, including orthogonally protected linear aminoalkyl chains or chiral dipeptidic chains, and opens the door to a wide scope of easily accessible chemical diversity.
- Naturale, Guillaume,Lamblin, Marc,Commandeur, Claude,Dessolin, Jean,Felpin, Francois-Xavier
-
supporting information
p. 5774 - 5788,15
(2020/09/15)
-
- Structure-activity relationship studies of 1-(4-chloro-2,5-dimethoxyphenyl) -3-(3-propoxypropyl)thiourea, a non-nucleoside reverse transcriptase inhibitor of human immunodeficiency virus type-1
-
The reverse transcriptase (RT) of the human immunodeficiency virus type-1 (HIV-1) is still a prime target for drug development due to the continuing need to block drug-resistant RT mutants by new inhibitors. We have previously identified 1-(4-chloro-2,5-dimethoxyphenyl)-3-(3-propoxypropyl)thiourea, compound 1, as a potent RT inhibitor from an available chemical library. Here, we further modified this compound to study structure-activity relationships when replacing various groups in the molecule. Different functional groups were systematically introduced on the aromatic ring and the aliphatic chain of the compound was modified. The effect of these modifications on viral infectivity was then evaluated. The most potent compound found was propyl 4-(amino-N-(4-chloro-2,5-dimethoxyphenyl)methanethioamino)butanoate, 45c, which inhibited infectivity with a calculated IC50 of about 1.1 μM. Docking studies identified potential important interactions between the top scoring ligands and HIV-1 RT, and the predicted relative affinity of the ligands was found to be in agreement with the experimental results.
- Weitman, Michal,Lerman, Keti,Nudelman, Abraham,Major, Dan Thomas,Hizi, Amnon,Herschhorn, Alon
-
experimental part
p. 447 - 467
(2011/03/20)
-
- Collision-induced dissociative chemical cross-linking reagent for protein structure characterization: Applied Edman chemistry in the gas phase
-
Chemical cross-linking combined with a subsequent enzymatic digestion andmass spectrometric analysis of the created crosslinked products presents an alternative approach to assess low-resolution protein structures and to gain insight into protein interfaces. In this contribution, we report the design of an innovative cross-linker based on Edman degradation chemistry, which leads to the formation of indicative mass shifted fragment ions and constant neutral losses (CNLs) in electrospray ionization (ESI)-tandem-mass spectrometry (MS/MS) product ion mass spectra, allowing an unambiguous identification of cross-linked peptides. Moreover, the characteristic neutral loss reactions facilitate automated analysis by multiple reaction monitoring suited for high throughput studies with good sensitivity and selectivity. The functioning of the novel cross-linker relies on the presence of a highly nucleophilic sulfur in a thiourea moiety, safeguarding for effective intramolecular attack leading to predictive and preferred cleavage of a glycyl-prolyl amide bond. Our innovative analytical concept and the versatile applicability of the collision-induced dissociative chemical cross-linking reagent are exemplified for substance P, luteinizing hormone releasing hormone LHRH and lysozyme. The novel cross-linker is expected to have a broad range of applications for probing protein tertiary structures and for investigating protein-protein interactions. Copyright
- Dreiocker, Frank,Mueller, Mathias Q.,Sinz, Andrea,Schaefer, Mathias
-
experimental part
p. 178 - 189
(2010/08/22)
-
- Supramolecular gelation of alcohol and water by synthetic amphiphilic gallic acid derivatives
-
The supramolecular organogelation of alcohols was observed in relatively hydrophobic amphiphiles with a short oligo(ethylene glycol) unit and three long alkyl chains at room temperature, while the hydrogelation occurred in more hydrophilic gelators with a longer poly(ethylene glycol) unit and two long alkyl chains at various temperatures. When a hot aqueous solution of some of the synthetic hydrogelators was cooled down, the supramolecular hydrogel was formed at room temperature. In some other amphiphiles with less intermolecular interactivity in water at room temperature, a reverse phase transition of sol to gel was observed by elevating the temperature of their aqueous systems, especially below a physiological temperature, 37 °C. The supramolecular hydrogelation at a low or high temperature was dependent on a slight molecular modification of the synthetic amphiphiles.
- Tamiaki, Hitoshi,Ogawa, Keishiro,Enomoto, Keisuke,Taki, Kazutaka,Hotta, Atsushi,Toma, Kazunori
-
supporting information; experimental part
p. 1661 - 1666
(2010/04/24)
-
- Acylurea connected straight chain hydroxamates as novel histone deacetylase inhibitors: Synthesis, SAR, and in vivo antitumor activity
-
Thirty-six novel acylurea connected straight chain hydroxamates were designed and synthesized. Structure-activity relationships (SAR) were established for the length of linear chain linker and substitutions on the benzoylurea group. Compounds 5g, 5i, 5n, and 19 showed 10-20-fold enhanced HDAC1 potency compared to SAHA. In general, the cellular potency pIC50 (COLO205) correlates with enzymatic potency pIC50 (HDAC1). Compound 5b (SB207), a structurally simple and close analogue to SAHA, is more potent against HDAC1 and HDAC6 compared to the latter. As a representative example of this series, good in vitro enzymatic and cellular potency plus an excellent pharmacokinetic profile has translated into better efficacy than SAHA in both prostate cancer (PC3) and colon cancer (HCT116) xenograft models.
- Wang, Haishan,Lim, Ze-Yi,Zhou, Yan,Ng, Melvin,Lu, Ting,Lee, Ken,Sangthongpitag, Kanda,Goh, Kee Chuan,Wang, Xukun,Wu, Xiaofeng,Khng, Hwee Hoon,Goh, Siok Kun,Ong, Wai Chung,Bonday, Zahid,Sun, Eric T.
-
scheme or table
p. 3314 - 3321
(2010/08/06)
-
- SAR studies on azasterols as potential anti-trypanosomal and anti-leishmanial agents
-
There is an urgent need for the development of new drugs for the treatment of neglected tropical diseases such as human African trypanosomiasis, Chagas disease and leishmaniasis. Azasterols, have been shown to have activity against the parasites which cause these diseases. In this paper we report synthesis of new azasterols and subsequent analysis of the SAR. The chemistry focused on variations in the ester at the 3β-position of the sterol and the position of the nitrogen in the side chain. The data allowed us to derive preliminary pharmacophore models for the activity of the azasterols against the parasites which cause these diseases.
- Gigante, Federica,Kaiser, Marcel,Brun, Reto,Gilbert, Ian H.
-
experimental part
p. 5950 - 5961
(2009/12/24)
-
- A convenient synthesis of amino acid methyl esters
-
A series of amino acid methyl ester hydrochlorides were prepared in good to excellent yields by the room temperature reaction of amino acids with methanol in the presence of trimethylchlorosilane. This method is not only compatible with natural amino acids, but also with other aromatic and aliphatic amino acids.
- Li, Jiabo,Sha, Yaowu
-
p. 1111 - 1119
(2008/09/21)
-
- SOLUBLE EPOXIDE HYDROLASE INHIBITORS
-
Disclosed are sulfonamide compounds and compositions that inhibit soluble epoxide hydrolase (sEH), methods for preparing the compounds and compositions, and methods for treating patients with such compounds and compositions. The compounds, compositions, and methods are useful for treating a variety of sEH mediated diseases, including hypertensive, cardiovascular, inflammatory, pulmonary, and diabetes-related diseases.
- -
-
Page/Page column 57
(2008/06/13)
-
- Pd-C-induced catalytic transfer hydrogenation with triethylsilane
-
(Chemical Equation Presented) In situ generation of molecular hydrogen by addition of triethylsilane to palladium-charcoal catalyst results in rapid and efficient reduction of multiple bonds, azides, imines, and nitro groups, as well as benzyl group and allyl group deprotection under mild, neutral conditions.
- Mandal, Pijus K.,McMurray, John S.
-
p. 6599 - 6601
(2008/02/10)
-
- Evaluation of azasterols as anti-parasitics
-
In this article, the design and synthesis of some novel azasterols is described, followed by their evaluation against Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani, and Plasmodium falciparum, the causative agents of human African trypanosomiasis, Chagas disease, leishmaniasis, and malaria, respectively. Some of the compounds showed anti-parasitic activity. In particular, a number of compounds appeared to very potently inhibit the growth of the blood stream form T. b. rhodesiense, with one compound giving an IC 50 value of 12 nM. Clear structure activity relationships could be discerned. These compounds represent important leads for further optimization. Azasterols have previously been shown to inhibit sterol biosynthesis in T. cruzi and L. donovani by the inhibition of the enzyme sterol 24-methyltransferase. However, in this case, none of the compounds showed inhibition of the enzyme. Therefore, these compounds have an unknown mode of action.
- Gros, Ludovic,Lorente, Silvia Orenes,Jimenez, Carmen,Yardley, Vanessa,Rattray, Lauren,Wharton, Hayley,Little, Susan,Croft, Simon L.,Ruiz-Perez, Luis M.,Gonzalez-Pacanowska, Dolores,Gilbert, Ian H.
-
p. 6094 - 6103
(2007/10/03)
-
- Methotrexate derivative
-
Disclosed is a compound represented by the formula: STR1 wherein R1 : CH2, CH2 CH2, CH2 O, CH2 S, CH2 SO; R2 : hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms or a benzyl group; n: an integer of 1 to 4; R3 : COOR4, NHCOR5, CONR6 R7, PO3 H2, SO3 H. The compound shows potent antirheumatic function, psoriasis curing function and carcinostatic function and has low toxicity whereby it is available as a medicine.
- -
-
-
- Lariat-bearing cyclophosphazenes: potential molecular sepulchers for magnetic resonance imaging agents
-
Lariat-bearing cyclophosphazenes were prepared by aminolysis of hexachlorocyclotriphosphazene with amino ester hydrochlorides followed by standard alkaline hydrolysis.These cryptands are actually capable complexing gadolinium cations with stability constants larger than 1E28; this is much larger than the values for classical magnetic resonance imaging agents.Unfortunately, these cryptates are much too insoluble in physiological serum to be used for clinical purposes in a facile way.
- Valerio, Christine,Labarre, Marie-Christine,Labarre, Jean-Francois
-
p. 171 - 176
(2007/10/02)
-
- Antihypertensive dihydropyridines with 1,4,4-trisubstitution
-
Dihydropyridines with 1,4,4-trisubstitution were synthesized and tested for antihypertensive activity in a spontaneously hypertensive rat model. This substitution pattern on the dihydropyridine nucleus differs markedly from that found most active in the structure-activity relationship established for nifedipine-like compounds. However, some were found to significantly lower blood pressure at testing doses (30 mg/kg, ip and 100 mg/kg, po) for up to 24 h. Methyl 1,4-dihydro-4,4-dimethyl-1-pyridinepropanoate (2-1), for example, lowered blood pressure 71 mmHg at 30 mg/kg, ip and the effect endured for greater than 24 h. Unlike prototypical dihydropyridines such as nifedipine, these compounds did not seem to have any effect on calcium channels.
- Kukla,Breslin,Gill
-
p. 223 - 228
(2007/10/02)
-
- Enkephalinase inhibitors
-
Mercaptoalkanoyl and acylmercaptoalkanoyl compounds of the formula STR1 wherein n is an integer from one to fifteen possess enkephalinase inhibition activity and are useful as analgesic agents.
- -
-
-
- Dihydropyridine compounds having 1,4,4-trisubstitution useful as antihypertensive agents
-
Dihydropyridine compounds having 1,4,4-trisubstitution of the following formula (I): STR1 wherein R is one of --COR3, R3 being a group such as phenyl or benzyl; R4 where R4 is a heterocycle; --(CH2)n NR5 R6, with R5 and R6 being alkyl or joined to define a ring; or --(CH2)n COOR7, with R7 being alkyl or benzyl. R1 and R2 are alkyl, phenyl or substituted phenyl. The compounds are useful for the treatment of hypertension in mammals, e.g., in humans.
- -
-
-
- A mechanism for the addition of multiple moles of glutamate by folylpolyglutamate synthetase
-
The role of the α-carboxyl group in methotrexate (MeAPA-Glu) and the γ-glutamate derivative of methotrexate (MeAPA-Glu-Glu) in the reaction catalyzed by folylpolyglutamate synthetase (FPGS) has been investigated. MeAPA-Glu and MeAPA-Glu-Glu were accepted as substrates by the same FPGS species contained in an (NH4)2SO4 precipitate of mouse liver protein, as judged by a lack of additivity of product formation at saturating concentrations of both substrates. MeAPA-Gaba, the MeAPA-Glu analogue lacking an α-carboxyl, was inactive as a substrate for this enzyme as was MeAPA-Glu-Gaba, the analogue of MeAPA-Glu-Glu that lacked the α-carboxyl of the terminal glutamic acid. However, MeAPA-Gaba-Glu, the analogue of MeAPA-Glu-Glu without an α-carboxyl on the first glutamic acid, had activity as a substrate for FPGS that approached that of MeAPA-Glu-Glu. These results suggest that the α-carboxyl is essential for the binding of folyl monoglutamates to FPGS in the correct orientation to allow catalysis. Moreover, the binding of the terminal α-carboxyl of folyl oligoglutamates to the same residue(s) responsible for the binding of the α-carboxyl of folyl monoglutamates would allow correct positioning of the terminal γ-carboxyl of the chain for reaction. This binding mechanism would be compatible with the utilization of a single enzyme species for the addition of glutamate to the monoglutamate or oligoglutamate forms of folates and folate analogues.
- Moran,Colman,Forsch,Rosowsky
-
p. 1263 - 1267
(2007/10/02)
-
- Michael Additions of Hydrazones for Carbon-Carbon Bond Formation
-
The lithium salts of t-butyl- and trityl-hydrazones react with methyl crotonate to form C-trapped azo-esters and similar products were observed from a thermal ene-reaction of aldehyde t-butylhydrazones with methyl acrylate or acrylonitrile, and aldehyde phenylhydrazones with methyl acrylate; these products can be diverted into synthetically useful γ-keto-esters, γ-keto-nitriles, saturated esters, γ-alkyl-2-pyrrrolidones, and γ-amino-esters.
- Baldwin, Jack E.,Adlington, Robert M.,Bottaro, Jeffrey C.,Jain, Ashok U.,Kolhe, Jayant N.,et al.
-
p. 1095 - 1096
(2007/10/02)
-
