- Modulation of the binding affinity of naproxen to bovine serum albumin by conversion of the drug into amino acid ester salts
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Naproxen (NAP) is one of the most widely prescribed non-steroidal anti-inflammatory drugs. Novel formulations of NAP aiming at better water-solubility, dosage, and the onset of action or new routes of application in order to minimize or prevent side effects of NAP are in the current interest of the pharmaceutical industry. Here, we report the synthesis, chemical, spectral and physicochemical characterization of a series of salts containing cations amino acid alkyl esters (AAE) and NAP anion, which potentially can be used as novel drug formulation. The [L-AAE][NAP] were obtained in three steps: preparation of the AAE hydrochlorides, neutralization of the hydrochlorides to the corresponding AAE, and formation of the target organic salts. All NAP derivatives, tested at a concentration as high as 100 μM, exhibited no toxicity against murine macrophage cell line (RAW 264.7). The binding parameters and stoichiometry of [AAE][NAP]s to bovine serum albumin (BSA) are in the range of that estimated for the parent NAP. Only L-valine isopropyl ester naproxenate characterizes with about one order of magnitude lower binding affinity for BSA, which suggests a faster diffusion rate in the circulatory system than the parent NAP and other derivatives, and therefore faster reach to the target system. Using molecular modeling seven binding pockets of BSA were probed for their suitability to binds the cation and the anion and results are discussed in correlation with the obtained thermodynamic parameters for the binding of NAP derivatives to BSA.
- ?wiatek, Ewelina,Guncheva, Maya,Janus, Ewa,Kardaleva, Proletina,Klebeko, Joanna,Krachmarova, Elena,Ossowicz, Paula,Rangelov, Miroslav,Taneva, Stefka,Todorova, Nadezhda
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- Characterization and cytotoxicity evaluation of biocompatible amino acid esters used to convert salicylic acid into ionic liquids
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The technological utility of active pharmaceutical ingredients (APIs) is greatly enhanced when they are transformed into ionic liquids (ILs). API-ILs have better solubility, thermal stability, and the efficacy in topical delivery than solid or crystalline drugs. However, toxicological issue of API-ILs is the main challenge for their application in drug delivery. To address this issue, 11 amino acid esters (AAEs) were synthesized and investigated as biocompatible counter cations for the poorly water-soluble drug salicylic acid (Sal) to form Sal-ILs. The AAEs were characterized using 1H and 13C NMR, FTIR, elemental, and thermogravimetric analyses. The cytotoxicities of the AAE cations, Sal-ILs, and free Sal were investigated using mammalian cell lines (L929 and HeLa). The toxicities of the AAE cations greatly increased with inclusion of long alkyl chains, sulfur, and aromatic rings in the side groups of the cations. Ethyl esters of alanine, aspartic acid, and proline were selected as a low cytotoxic AAE. The cytotoxicities of the Sal-ILs drastically increased compared with the AAEs on incorporation of Sal into the cations, and were comparable to that of free Sal. Interestingly, the water miscibilities of the Sal-ILs were higher than that of free Sal, and the Sal-ILs were miscible with water at any ratio. A skin permeation study showed that the Sal-ILs penetrated through skin faster than the Sal sodium salt. These results suggest that AAEs could be used in biomedical applications to eliminate the use of traditional toxic solvents for transdermal delivery of poorly water-soluble drugs.
- Moshikur, Rahman Md.,Chowdhury, Md. Raihan,Wakabayashi, Rie,Tahara, Yoshiro,Moniruzzaman, Muhammad,Goto, Masahiro
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- Synthesis, spectroscopic characterization, and in vitro antibacterial evaluation of novel functionalized sulfamidocarbonyloxyphosphonates
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Several new sulfamidocarbonyloxyphosphonates were prepared in two steps, namely carbamoylation and sulfamoylation, by using chlorosulfonyl isocyanate (CSI), α-hydroxyphosphonates, and various amino derivatives and related (primary or secondary amines, β-amino esters, and oxazolidin-2-ones). All structures were confirmed by 1H, 13C, and 31P NMR spectroscopy, IR spectroscopy, and mass spectroscopy, as well as elemental analysis. Eight compounds were evaluated for their in vitro antibacterial activity against four reference bacteria including Gram-positive Staphylococcus aureus (ATCC 25923), and Gram-negative Escherichia coli (ATCC 25922), Klebsiella pneumonia (ATCC 700603), Pseudomonas aeruginosa (ATCC 27853), in addition to three clinical strains of each studied bacterial species. Compounds 1a–7a and 1b showed significant antibacterial activity compared to sulfamethoxazole/trimethoprim, the reference drug used in this study.
- Bouzina, Abdeslem,Bechlem, Khaoula,Berredjem, Hajira,Belhani, Billel,Becheker, Imène,Lebreton, Jacques,Le Borgne, Marc,Bouaziz, Zouhair,Marminon, Christelle,Berredjem, Malika
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- The reactions of α-amino acids and α-amino acid esters with high valent transition metal halides: synthesis of coordination complexes, activation processes and stabilization of α-ammonium acylchloride cations
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Titanium tetrachloride smoothly reacted with a selection of α-amino acids (aaH) in CH2Cl2 affording yellow to orange solid coordination compounds, 1a-d, in 70-78% yields. The salts [NHEt3][TiCl4(aa)], 2a-b, were obtained from TiCl4/aaH/NEt3 (aa = l-phenylalanine, N,N-dimethylphenylalanine), in 60-65% yields. The complex , 3, was isolated from the reaction of l-proline with NbCl5/NHiPr2, performed in CH2Cl2 at room temperature. The X-ray structure of 3 features a bridging (E)-1,2-bis(3,4-dihydro-2H-pyrrol-5-yl)ethene-1,2-diolate ligand, resulting from the unprecedented C-C coupling between two proline units. Unusually stable α-ammonium acyl chlorides were prepared by the reactions of PCl5/MCln (MCln = NbCl5, WCl6) with l-proline, N,N-dimethylphenylalanine, sarcosine and l-methionine. MX5 (M = Nb, Ta; X = F, Cl) reacted with l-leucine methylester and l-proline ethylester to give ionic coordination compounds, [MX4L2][MX6] (M = Nb, L = Me2CHCH2CH(NH2)CO2Me, X = F, 9; Cl, 11a; M = Nb, X = Cl, , 11c; Ta, 11d), in moderate to good yields. [NbCl5(Me2CHCH2CHNH3CO2Me)][NbCl6], 12, was isolated as a co-product of the reaction of NbCl5 with l-leucine isopropylester, and crystallographically characterized. The reaction of NbCl5 with l-serine isopropylester afforded NbCl3(OCH2CHNHCO2iPr), 13, in 66% yield. The activation of the ester O-R bond was observed in the reactions of l-leucine methyl ester with NbF5 and l-proline ethyl ester with MBr5 (M = Nb, Ta), these reactions proceeding with the release of EtF and EtBr, respectively. All the metal products were characterized by analytical and spectroscopic methods, while DFT calculations were carried out in order to provide insight into the structural and mechanistic aspects.
- Biancalana, Lorenzo,Bortoluzzi, Marco,Ferretti, Eleonora,Hayatifar, Mohammad,Marchetti, Fabio,Pampaloni, Guido,Zacchini, Stefano
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p. 10158 - 10174
(2017/02/15)
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- Enantioselective synthesis of α-secondary and α-tertiary piperazin-2- Ones and piperazines by catalytic asymmetric allylic alkylation
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The asymmetric palladium-catalyzed decarboxylative allylic alkylation of differentially N-protected piperazin-2- ones allows the synthesis of a variety of highly enantioenriched tertiary piperazine-2-ones. Deprotection and reduction affords the corresponding tertiary piperazines, which can be employed for the synthesis of medicinally important analogues. The introduction of these chiral tertiary piperazines resulted in imatinib analogues which exhibited comparable antiproliferative activity to that of their corresponding imatinib counterparts.
- Korch, Katerina M.,Eidamshaus, Christian,Behenna, Douglas C.,Stoltz, Brian M.,Nam, Sangkil,Horne, David
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supporting information
p. 179 - 183
(2015/02/05)
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- Cross aldol condensation of acetaldehyde and formaldehyde in the presence of bifunctional systems
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Liquid-phase cross-aldol condensation of acetaldehyde and formaldehyde in the presence of salts of various saturated and unsaturated linear amines, aromatic amines, diamines, and nitrogen bases, as well as in the presence of substituted piperazines, linear and cyclic amino acids and their derivatives, and nitrogen-containing ionic liquids, was studied. The cross-condensation products were formed in considerable amounts when amine hydrochlorides, N-benzoyl amino acids, and amino acid esters were used as catalyst. The formation of cross-condensation products is favored by increased basicity of the amino nitrogen atom in the salt and of the solvent.
- Dashko, L. V.,Dmitriev, D. V.,Pestov, S. M.,Flid, V. R.
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p. 1732 - 1737
(2015/02/05)
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- Optical activity 1,5-substituted-1,3,5-hexahydrotriazine-2-N-nitroimines: Synthesis and insecticidal activity
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Twelve novel neonicotinoid analogues 1-(2-furfuryl)-5-substituted-1,3,5- hexahydrotriazine-2-N-nitroimines 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3l were synthesized. Their structures were characterized by 1H NMR, IR, and elemental analysis. The preliminary bioassay tests showed that all the title compounds gave ≥90% mortality against Nilaparvata lugen 500 mg/L.
- Xue, Si-Jia,Bu, Hong-Fei,Liu, Li,Xu, Xiao,Ma, Xubo,Zhu, Jun
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p. 1067 - 1070
(2013/10/21)
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- Asymmetric construction of quaternary stereocenters: Synthesis of enantiopure amino acid-based tricyclic α,β-enones through an ipso-Friedel-Crafts/Michael addition cascade
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An efficient reaction of the (2R,1′S)- or (2S,1′S)-N,N-bis(p- methoxybenzyl)-2-(1-aminoalkyl)epoxides, derived from α-amino acids, with boron trifluoride-phosphoric acid complex is described. This process affords highly elaborated enantiopure tricyclic α,β-enones in high yields, through an ipso-Friedel-Crafts/Michael addition cascade. Copyright
- Rodriguez-Solla, Humberto,Concellon, Carmen,Tuya, Paula,Garcia-Granda, Santiago,Diaz, M. Rosario
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experimental part
p. 295 - 300
(2012/04/04)
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- Chiral 1,5-disubstituted 1,3,5-hexahydrotriazine-2-N-nitroimine analogues as novel potent neonicotinoids: Synthesis, insecticidal evaluation and molecular docking studies
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A new series of 1,5-disubstituted 1,3,5-hexahydrotriazine-2-N-nitroimines (4a-4x) were designed and synthesized as novel chiral neonicotinoid analogues. The single-crystal structure of 4n was further determined by X-ray diffraction, and its S configuration was confirmed. Preliminary bioassay showed that compound 4e, 4k, 4u, 4v exhibited excellent insecticidal activities at 100 mg/L, while 4k had >90% mortality at 10 mg/L, which suggested it could be used as a lead for future development. Modeling the inhibitor-nAChR complexes by molecular docking studies explained the structure-activity relationships observed in vitro, and revealed an intriguing molecular binding mode at the active site of nAChR, which raised the possibility that these analogues may arbitrate their insecticidal activity through a mechanism other than imidacloprid.
- Sun, Chuanwen,Zhu, Jun,Wang, Haifeng,Jin, Jia,Xing, Jiahua,Yang, Dingrong
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experimental part
p. 11 - 20
(2011/02/27)
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- Synthesis, crystal structure and insecticidal activity of the optical active neonicotinoid analogues
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Eight novel neonicotinoid analogues 1-(2-tetrahydrofurfuryl)-5-substituted- 1,3,5-hexahydrotriazine-2-N-nitroimines 3a - 3h were synthesized, and their structures were characterized by 1H NMR, IR and elemental analysis. The stereostructure of 3a was determined by the single-crystal X-ray analysis, which exhibits a half-chair conformation and dihedral angle is 49.70° . The preliminary bioassay tests showed that all the title compounds exhibited good insecticide activities against Nilaparvata legen (N. legen).
- Xue, Sijia,Bu, Hongfei,Liu, Li,Xu, Xiao,Ma, Xubo
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scheme or table
p. 1011 - 1016
(2012/01/06)
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- Anthranilic acid based CCK1 receptor antagonists: Blocking the receptor with the same 'words' of the endogenous ligand
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The anthranilic acid diamides represent the more recent class of nonpeptide CCK1 receptor antagonists. This class is characterized by the presence of anthranilic acid, used as a molecular scaffold, and two pharmacophores selected from the C-terminal tetrapeptide of CCK. The lead compound coded VL-0395, endowed with sub-micromolar affinity towards CCK1 receptors, was characterized by the presence of Phe and 2-indole moiety at the C- and N-termini of anthranilic acid, respectively. Herein we describe the first step of the anthranilic acid C-terminal optimization using, instead of Phe, aminoacids belonging to the primary structure of CCK-8 and other not coded residues. Thus we demonstrate that the CCK1 receptor affinity depends on the nature of the aminoacidic side chain as well as that the free carboxy group of the alpha-aminoacids is crucial for the binding. The R enantiomers of the most active compounds represent the eutomers of this class of antagonists confirming thus the stereo preference of the receptor. Moreover this SAR study demonstrates that the receptor binding pocket, that host the aminoacidic side chain, results much more tolerant respect to that accommodating the indole ring. As a result, an appropriate variation of the aminoacidic side chain could provide a better CCK1 receptor affinity diorthosis.
- Lassiani, Lucia,Pavan, Michela V.,Berti, Federico,Kokotos, George,Markidis, Theodoros,Mennuni, Laura,Makovec, Francesco,Varnavas, Antonio
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experimental part
p. 2336 - 2350
(2009/09/05)
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- Cyclic phosphoramidates as prodrugs of 2′-C-methylcytidine
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The currently approved treatment for hepatitis C virus infections is a combination of Ribavirin and pegylated Interferon. It leads to a sustained virologic response in approximately only half of the patients treated. For this reason there is an urgent need of new therapeutic agents. 2′-C-Methylcytidine is the first nucleoside inhibitor of the HCV NS5B polymerase that was efficacious in reducing the viral load in patients infected with HCV. The application of a monophosphate prodrug approach based on unprecedented cyclic phosphoramidates is reported. Our SAR studies led to compounds that are efficiently converted to the active triphosphate in human hepatocytes.
- Meppen, Malte,Pacini, Barbara,Bazzo, Renzo,Koch, Uwe,Leone, Joseph F.,Koeplinger, Kenneth A.,Rowley, Michael,Altamura, Sergio,Di Marco, Annalise,Fiore, Fabrizio,Giuliano, Claudio,Gonzalez-Paz, Odalys,Laufer, Ralph,Pucci, Vincenzo,Narjes, Frank,Gardelli, Cristina
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scheme or table
p. 3765 - 3770
(2009/12/24)
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- Diastereoselective Ugi reaction without chiral amines: the synthesis of chiral pyrroloketopiperazines
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The three-component Ugi reaction with chiral 2-(2-formyl-1H-pyrrol-1-yl)acetic acids prepared from natural l-aminoacids was investigated. The reaction opens a new route to chiral substituted pyrroloketopiperazines. One of the first examples of an asymmetric Ugi reaction without chiral amines is described. The reaction proceeds with moderate diastereoselectivity to give the target compounds in good yields. The scope and limitation of the approach are discussed.
- Nenajdenko, Valentine G.,Reznichenko, Alexander L.,Balenkova, Elizabeth S.
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p. 3031 - 3041
(2007/10/03)
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- Diastereoselective reductive amination of aryl trifluoromethyl ketones and α-amino esters
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(Chemical Equation Presented) Reductionist art: Careful choice of the reducing agent in the reductive amination of trifluoromethyl ketones with α-amino esters allows stereoselective access, from the imine formed, to either the R,S or S,S diastereomers of the resulting amino acids. Whereas NaBH4 affords the R,S diastereomers, Zn(BH4)2 affords the S,S diastereomers (see scheme), which can be easily converted into potent cathepsin K inhibitors.
- Hughes, Greg,Devine, Paul N.,Naber, John R.,O'Shea, Paul D.,Foster, Bruce S.,McKay, Daniel J.,Volante
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p. 1839 - 1842
(2008/02/12)
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- Antiviral phosphoramidates
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The invention provides novel nucleoside compounds of formula I wherein R1, R2a, R2b, R3, R4, R5, R6, R8a, R9 and R10 are as defined herein which are useful for the treatment of Hepatitis C Virus (HCV) mediated diseases. The invention further provides methods for treatment or prophylaxis of HCV mediated diseases with compounds of formula I and pharmaceutical compositions comprising these compounds,
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Page/Page column 18
(2008/06/13)
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- 9. Les β-cetonitriles groupes protecteurs de la fonction amine. Preparation d'amino-alcools
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β-Ketonitrile-Derived Protecting Groups of the Amino Function.Synthesis of Amino Alcohols.The amino group of natural L-amino acid esters is protected by condensation with 2-oxocyclopentanenitrile (1) or 2-formyl-2-phenylacetonitrile (10).Only the ester group of the formed cyanoenamino esters 2 and 11 reacts with nucleophilic reagents such as organometallics (RMgX, RLi), borohydrides, or metal amides, whereas the cyanoenamino group is unchanged (Schemes 1 and 2).Cyanoenamino alcohols obtained by reduction of cyanoenamino esters 2 are hydrolyzed under acidic conditions to amino alcohols with retention of the configuration of the starting amino acid.This sequence of reactions allows to prepare derivatives of L-tyrosinol from (-)-L-tyrosine (see, e.g., Scheme 4).Cyanoenamino esters 11 are readily methylated at the N-atom to give N-methylated cyanoenamino esters (Scheme 3).This property is exploited on the way of multistep procedure to obtain N-methylated amino alcohols homologous to natural (-)-(1R,2S)-ephedrine.
- Abarbri, Mohamed,Guignard, Alain,Lamant, Maurice
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p. 109 - 121
(2007/10/02)
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- CLEAVAGE OF THE N-PChd GROUP FROM PROTECTED AMINO ACIDS AND PEPTIDES BY CATHODIC REDUCTION
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Amino acids and peptide esters protected by the PChd group can be deprotected cathodically under mild conditions.
- Khalifa, M. Hassen,Rieker, Anton
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p. 1027 - 1030
(2007/10/02)
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