13031-60-2Relevant articles and documents
Spin-labeled derivatives of cardiotonic steroids as tools for characterization of the extracellular entrance to the binding site on Na+,K+-ATPase
Guo, Jin-Hua,Jiang, Ren-Wang,Andersen, Jacob Lauwring,Esmann, Mikael,Fedosova, Natalya U.
, p. 2292 - 2305 (2018)
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.
Multitarget CFTR Modulators Endowed with Multiple Beneficial Side Effects for Cystic Fibrosis Patients: Toward a Simplified Therapeutic Approach ?
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
, p. 10833 - 10847 (2019)
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.
Carbonylative lactonization via carbonyl oxygen attack: A short and selective total synthesis of uncinine and its analogues
Fáková, Helena,Pour, Milan,Kune?, Ji?í,?enel, Petr
, p. 8137 - 8140 (2005)
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.
Structural modification of histone deacetylase inhibitors with a phenylglycine scaffold
Zhang, Lei,Zhang, Li,Bian, Jiang,Jiang, Qixiao,Gao, Jianjun,Song, Weiguo
, p. 145 - 156 (2018)
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.
Gossypol with Hydrophobic Linear Esters Exhibits Enhanced Antitumor Activity as an Inhibitor of Antiapoptotic Proteins
Lu, Yuzhi,Wu, Shuangchan,Yue, Yuan,He, Si,Li, Jun,Tang, Jun,Wang, Wei,Zhou, Hai-Bing
, p. 1185 - 1190 (2016)
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.
Design, synthesis, and biological characterization of tamibarotene analogs as anticancer agents
Jiang, Yuqi,Li, Xiaoyang,Wang, Xue,Wang, Zhonglan,Zhang, Jian,Wu, Jingde,Xu, Wenfang
, p. 542 - 555 (2016)
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.
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
Nudelman, Ayelet,Bechor, Yosi,Falb, Eliezer,Fischer, Bilha,Wexler, Barry A.,Nudelman, Abraham
, p. 471 - 474 (1998)
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.
New amino-acid conjugates of glycyrrhizic acid
Stolyarova,Baltina,Kondratenko,Fedorova,Orshanskaya,Zarubaev,Baltina
, p. 317 - 320 (2014)
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.
Transition Metal-Free N-Arylation of Amino Acid Esters with Diaryliodonium Salts
Kervefors, Gabriella,Kersting, Leonard,Olofsson, Berit
supporting information, p. 5790 - 5795 (2021/03/08)
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.
Plasma induced acceleration and selectivity in strain-promoted azide-alkyne cycloadditions
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)
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.
