- Synthesis and antiviral activity of novel glycyrrhizic acid conjugates with D-amino acid esters
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Glycyrrhizic acid (GA) conjugates with methyl and ethyl esters of D-amino acids (D-Trp, D-Phe, D-Tyr, D-Val, D-Leu) have been synthesized by the activated esters method using mixtures of N-hydroxybenzotriazole or N-hydroxysuccinimide with N,N′-dicyclohexylcarbodiimide. GA conjugate with D-Trp ethyl ester exhibited antiviral activity against influenza viruses A/H3N2, A/H1N1/pdm09, A/H5N1, B (SI > 10–29), and HRSV (SI > 25). GA conjugate with D-Trp methyl ester inhibited influenza virus A/H1N1/pdm09 (SI > 30).
- Fayrushina,Baltina,Baltina,Konovalova,Petrova,Eropkin, M. Yu.
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- RETRACTED ARTICLE: Synthesis, kinetic studies and pharmacological evaluation of mutual azo prodrug of 5-aminosalicylic acid with d-phenylalanine for colon specific drug delivery in inflammatory bowel disease
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Mutual azo prodrug of 5-aminosalicylic acid with d-phenylalanine was synthesized by coupling d-phenylalanine with salicylic acid, for targeted drug delivery to the inflamed gut tissue in inflammatory bowel disease. The structure of synthesized prodrug was
- Dhaneshwar, Suneela S.,Gairola, Neha,Kandpal, Mini,Bhatt, Lokesh,Vadnerkar, Gaurav,Kadam
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- Optical Resolution of Amino Acid Esters by N-Protected Aspartylphenylalanine Esters
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A new method was studied for optical resolution of racemic amino acids esters by using, as resolving agents, N-protected L-α-aspartyl-L-phenylalanine alkyl esters, typically, N-benzyloxycarbonyl-L-α-aspartyl-L-phenylalanine methyl ester, the precursor to the synthetic sweetener aspartame.Thus, when the dipeptide and racemic amino acid ester were mixed in solvents, precipitation took place by formation of salt preferentially with D-amino acid ester to effect the optical resolution.
- Oyama, Kiyotaka,Itoh, Mikio,Nonaka, Yuji
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- Catalysts and temperature driven melt polycondensation reaction for helical poly(ester-urethane)s based on natural L-amino acids
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Catalyst and temperature driven melt polycondensation reaction was developed for natural L-amino acid monomers to produce new classes of poly(ester-urethane)s. Wide ranges of catalysts from alkali, alkali earth metal, transition metal and lanthanides were developed for the condensation of amino acid monomers with diols to yield poly(ester-urethane)s. A-B Diblock and A-B-A triblock species were obtained by carefully choosing mono- or diols in model reactions. More than two dozens of transition metal and lanthanide catalysts were identified for the polycondensation to yield high molecular weight poly(ester-urethane)s. Theoretical studies revealed that the carbonyl carbon in ester possessed low electron density compared to the carbonyl carbon in urethane which driven the thermo-selective polymerization process. Optical purity of the L-amino acid residues in the melt polycondensation process was investigated using D- and L-isomers and the resultant products were analyzed by chiral-HPLC and CD spectroscopy. CD analysis revealed that the amino acid based polymers were self-assembled as β-sheet and polyproline type II secondary structures. Electron and atomic force microscopic analysis confirmed the formation of helical nano-fibrous morphology in poly(ester-urethane)s. The newly developed melt polycondensation process is very efficient and optimized for wide range of catalysts to produce diverse polymer structures from natural L-amino acids.
- Anantharaj, Santhanaraj,Jayakannan, Manickam
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- Modular Fragment Synthesis and Bioinformatic Analysis Propose a Revised Vancoresmycin Stereoconfiguration
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Elaborate fragments of the proposed stereostructure of the complex polyketide antibiotic vancoresmycin have been synthesized in a stereoselective fashion based on a modular and convergent approach. Significant nuclear magnetic resonance differences in one of these subunits compared with the natural product question the proposed stereoconfiguration. Consequently, an extensive bioinformatics analysis of the biosynthetic gene cluster was carried out, leading to a revised stereoconfigurational proposal for this highly potent antibiotic.
- Adamek, Martina,Essig, Sebastian,Kurz, Michael,Menche, Dirk,Sch?nenbroicher, Max,Seul, Maximilian,Spindler, Stefanie,Wingen, Lukas M.,Ziemert, Nadine
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supporting information
p. 1175 - 1180
(2021/01/13)
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- Convenient method for the synthesis of some novel chiral methyl 2-(2-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)propanoate derivatives and biological evaluation of their antioxidant, cytotoxic, and molecular docking properties
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Ten chiral methyl 2-(2-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)propanoate derivatives 6a-6j have been synthesized from optically pure amino methyl phenol 5 and 4-nitrophenyl chloroformate. These derivatives 6a-6j are characterized by 1H NMR, 13C NMR, FT-IR, and HRMS spectral techniques. Optical purity of these derivatives was confirmed by chiral HPLC method. Ten synthesized ester derivatives 6a-6j were screened for their in vitro antioxidant activity. Among the compounds 6b-d and 6h-j have exhibited comparable antioxidant activity with ascorbic acid as a standard. Compounds 6a and 6e-g have shown moderate antioxidant activity. Further, the in vitro cytotoxicity of these compounds were studied through MTT cell proliferation assay in addition the effect on LDH leakage and NO release. Among the derivatives, 6j showed extremely best activity and the IC50 value (12.54 ± 0.71 μM) is very close to doxorubicin (7.2 ± 0.58 μM) as a standard. Compounds 6b, 6h, and 6i showed better inhibition next to compound 6j on the viability of HepG2 cells with an IC50 value (μM) of 56.02 ± 1.4, 41.76 ± 0.58, and 38.17 ± 0.34, respectively. Also, molecular docking studies have been carried out with STAT-3 (PDB ID: 1BG1) and BCL-2 (PDB ID: 4AQ3) proteins against the four active compounds 6b, 6h, 6i, and 6j. The binding energies of the tested compounds were in the range of ?7.76 to ?8.41 kcal/mol, which is very close to doxorubicin (?8.53 kcal/mol) as a standard. These molecular docking results are in good agreement with the in vitro studies.
- Matam, Sivakumar,Kaliyan, Prabakaran,Selvaraj, Loganathan,Muthu, Seenivasa Perumal,Lohanathan, Bharathi Priya,Viswanadhan, Vijaya Padma,Makala, Himesh,Venkatasubramanian, Ulaganathan
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supporting information
p. 569 - 579
(2020/12/11)
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- Mechanoresponsive, proteolytically stable and biocompatible supergelators from ultra short enantiomeric peptides with sustained drug release propensity
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Stimuli-responsive low molecular weight hydrogelators attract immense interest from diverse segments of biomedicine and biotechnology. Distinctly, herein we report newly synthesized enantiomeric ultrashort peptides of general formula Me-(CH2)8-CO-NH-CH(X)-COOH, where X = CH2Ph in hydrogelators I (l-Phe) and II (d-Phe) respectively, which display excellent self-assembling propensity in physiological buffer at room temperature. Interestingly these biomolecules were endowed with mechanoresponsiveness, injectability and high mechanical integrity as confirmed by rheological measurements. Importantly they revealed resistance towards proteolytic degradation. Indeed dose dependent cell viability studies using MTT assay in four different cell lines, namely PANC-1, S1, HCT-116 and MDAMB-231, further confirmed the biocompatibility of the hydrogelators in vitro. The structural aspect of β-sheets of the hydrogelators was concluded on the basis of temperature dependent NMR, IR, PXRD and computational studies. We developed a user friendly delivery system, hydrogel nanoparticles (HNPs), with our mechanoresponsive and biocompatible hydrogelators, as these particles exhibited promising influence due to their enhanced surface area. Also the HNPs revealed excellent drug release kinetics for the model drugs 5FU/doxorubicin under physiological conditions in a sustained manner depending on the physicochemical parameters of the drugs. Taking these results together we envision that our designed hydrogelators and the delivery vehicle generated therefrom might represent a promising tool for administration of significant drug concentrations at lesion sites for a prolonged period, thus providing a better strategy for quick pain relief, rapid recovery and reduced systemic side effects.
- Basu, Anindya,Christman, Ryann M.,Duttkonar, Anita,Harjit, Jeena,Mehra, Radha Rani,Mishra, Anil K.,Tiwari, Amit K.
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p. 6346 - 6354
(2020/05/13)
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- In search of bioinspired hydrogels from amphiphilic peptides: A template for nanoparticle stabilization for the sustained release of anticancer drugs
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The development of potent stimuli-responsive hydrogels has rapidly expanded in the last decades due to their diversified applications in the field of biomedicines. In accordance with this drift, herein, we aimed at modulating a series of amphiphilic peptide analogues with the general formula Me-(CH2)14-CO-NH-CH(X)-COOH, where X = CH2Ph in hydrogelators I (l-Phe) and II (d-Phe) and X = CH2Ph(OH) in hydrogelator III (l-Tyr), which displayed an excellent propensity to immobilize water at room temperature with a minimum gelation concentration of 0.04%/0.05%/0.02% w/v for hydrogelators I-III, respectively, regardless of their configuration at the C-terminal centre. To validate this threshold concentration difference, we performed computational analysis that demonstrated the ability of the side-chains of hydrogelators I and III to remain highly planar with the methylene units of the amphiphile and aromatic rings, promoting favourable correspondence through van der Waals forces and pi-pi stacking. Consequently hydrogelators I and III self-assembled in an ordered organisation superior to hydrogelator II. Furthermore, the spectroscopic and microscopic experiments revealed that the hydrogelators manifested a β-sheet conformation and nanofibrous morphology at the supramolecular level. As observed visually and additionally confirmed by differential scanning calorimetry (DSC) and rheological measurements, the hydrogels exhibited thermo-reversibility, injectability and high mechanical strength. Importantly, these biomaterials were also found to be resistant towards proteolytic degradation and non-cytotoxic in the cell line HEK 293 using a dose-dependant cell viability assay. To date, the development of a structured approach for the release of drugs in a predictable manner from an optimised formulation, using peptide-based hydrogel nanoparticles as a delivery system remains in its infancy. Hence, we developed hydrogel nanoparticles (HNPs) with our fabricated amphiphilic peptides that exploited the weak noncovalent interactions for their fabrication, unlike other cross-linked polymers that require strong covalent or ionic bonds for their formation. Interestingly, the as-synthesized nanoparticles showed an unprecedented ability to release the anticancer drugs 5-fluoro uracil/doxorubicin at physiological conditions depending on the physico-chemical parameters of the drugs. We believe that the reported injectable, biocompatible, amphiphilic peptide-based hydrogels hold future promise as a potential tool to transport drugs to a targeted site at a greater concentration, thus relieving the patient from surgical injury and simultaneously aiding in a faster recovery.
- Mehra, Radha Rani,Tiwari, Priyanka,Basu, Anindya,Duttkonar, Anita
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p. 11666 - 11678
(2019/07/31)
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- Rhodium-Catalyzed Enantioselective Synthesis of Oxazinones via an Asymmetric Ring Opening-Lactonization Cascade of Oxabicyclic Alkenes
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The rhodium-catalyzed asymmetric ring opening reaction of oxabicyclic alkenes is shown to be an efficient method for synthesizing chiral heterocycles. We demonstrate that the pairwise combination of chiral catalyst with chiral amino-acid-derived pronucleophiles results in a stereodivergent synthesis of diastereomeric hydroxyesters. A favorable conformational preference induces the subsequent lactonization of one diastereomer leading to the highly enantioselective synthesis of oxazinones.
- Yen, Andy,Pham, Anh Hoang,Larin, Egor M.,Lautens, Mark
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supporting information
p. 7549 - 7553
(2019/10/02)
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- ((S)-3-Mercapto-2-methylpropanamido)acetic acid derivatives as metallo-β-lactamase inhibitors: Synthesis, kinetic and crystallographic studies
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The emergence and global spread of metallo-β-lactamase (MBL) mediated resistance to almost all β-lactam antibacterials poses a serious threat to public health. Since no clinically useful MBL inhibitors have been reported, there is an urgent need to develop new potent broad-spectrum MBL inhibitors effective against antibacterial resistance. Herein, we synthesized a set of 2-substituted ((S)-3-mercapto-2-methylpropanamido) acetic acid derivatives, some of which displayed potent inhibition with high ligand efficiency to the clinically relevant MBL subtypes, Verona Integron-encoded MBL (VIM)-2 and New Delhi MBL (NDM)-1. Kinetic studies revealed that the inhibitors are not strong zinc chelators in solution, and they bind reversibly to VIM-2 but dissociate very slowly. Crystallographic analyses revealed that they inhibit VIM-2 via chelating the active site zinc ions and interacting with catalytically important residues. Further cell- and zebrafish-based assays revealed that the inhibitors slightly increase susceptibility of E. coli cells expressing VIM-2 to meropenem, and they have no apparent toxicity to the viability of HEK293T cells and the zebrafish embryogenesis.
- Liu, Sha,Jing, Li,Yu, Zhu-Jun,Wu, Chengyong,Zheng, Yongxiang,Zhang, En,Chen, Qiang,Yu, Yamei,Guo, Li,Wu, Yong,Li, Guo-Bo
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p. 649 - 660
(2018/02/10)
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- Design, synthesis, SAR and biological investigation of 3-(carboxymethyl)rhodanine and aminothiazole inhibitors of Mycobacterium tuberculosis Zmp1
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Sixteen 3-(carboxymethyl)rhodanines, and twelve aminothiazoles as rhodanine-mimetics were designed, synthesized and tested as inhibitors of the Zmp1 enzyme from Mycobacterium tuberculosis (Mtb). Almost all rhodanines (5a–d, 5f–n, and 7a–b) exhibited Zmp1 inhibition with IC50 values in the range 1.3–43.9 μM, whereas only aminothiazoles 12b and 12d proved active with IC50 values of 41.3 and 35.7 μM, respectively. Structure-activity relationships (SAR) were coupled with molecular modeling studies to highlight structural determinants for Zmp1 inhibition. Moreover, rhodanines 5a and 5c induced 23.4 and 53.8% of Mtb growth inhibition in THP-1 infected cells, respectively, at the non-toxic concentration of 10 μg/ml. This work represents a step forward in targeting Zmp1 by small molecules.
- Mori, Mattia,Deodato, Davide,Kasula, Mohan,Ferraris, Davide M.,Sanna, Adriana,De Logu, Alessandro,Rizzi, Menico,Botta, Maurizio
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supporting information
p. 637 - 641
(2018/02/06)
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- Chiral-pool synthesis of 1,2,4-trisubstituted 1,4-diazepanes as novel σ1 receptor ligands
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Starting from enantiomerically pure amino acids, 1,4-diazepanes with various substituents in 1, 2, and 4-position were synthesized following the late stage diversification strategy. The key step in the formation of the seven-membered ring was the intramolecular EDC coupling of amino acids 15, 26, and 39. The configuration in 2-position does not influence the σ1 affinity and selectivity over related receptors. A cyclohexylmethyl or a butyl group are the preferred substituents in 4-position, whereas a methyl moiety in 2-position and a (substituted) benzyl moiety in 1-position result in the highest σ1 affinity. These results fit nicely to the reported σ1 pharmacophore models. The compounds did not inhibit the structurally related fungal enzyme sterol Δ8,7-isomerase, but showed inhibition of diverse enzymes in late cholesterol biosynthesis at high concentrations. In a screening against more than 50 target proteins, (2S)-1-benzyl-4-(4-methoxybenzyl)-2-methyl-1,4-diazepane ((S)-28b, Ki(σ1) = 0.86 nM) showed a clean receptor profile. The dose dependent potentiation of electrically stimulated contractions of guinea pig vas deferens indicates σ1 agonistic activity of (S)-28b. Even at a dose of 100 mg/kg (S)-28b did not induce severe toxic or behavioral effects in the Irwin screen. Clear cognition enhancing effects were observed for (S)-28b after inducing amnesia by scopolamine.
- Fanter, Lena,Müller, Christoph,Schepmann, Dirk,Bracher, Franz,Wünsch, Bernhard
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p. 4778 - 4799
(2017/10/05)
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- A novel aggregation-induced emission enhancement triggered by the assembly of a chiral gelator: from non-emissive nanofibers to emissive micro-loops
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In this study, a novel aggregation-induced emission (AIE) enhancement triggered by the self-assembly of chiral gelator is described. Tuning of molecular chirality in situ triggers different assemblies of superstructures exhibiting fluorescence. This novel AIE material can constitute an emerging library of chiral supramolecules for turn-on fluorescent sensors. It will also help in better understanding the effects of chiral factors on the photophysical process.
- Chen, Wenrui,Qing, Guangyan,Sun, Taolei
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supporting information
p. 447 - 450
(2017/01/03)
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- Mechanochemical Encapsulation of Fullerenes in Peptidic Containers Prepared by Dynamic Chiral Self-Sorting and Self-Assembly
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Molecular capsules composed of amino acid or peptide derivatives connected to resorcin[4]arene scaffolds through acylhydrazone linkers have been synthesized using dynamic covalent chemistry (DCC) and hydrogen-bond-based self-assembly. The dynamic character of the linkers and the preference of the peptides towards self-assembly into β-barrel-type motifs lead to the spontaneous amplification of formation of homochiral capsules from mixtures of different substrates. The capsules have cavities of around 800 ?3 and exhibit good kinetic stability. Although they retain their dynamic character, which allows processes such as chiral self-sorting and chiral self-assembly to operate with high fidelity, guest complexation is hindered in solution. However, the quantitative complexation of even very large guests, such as fullerene C60 or C70, is possible through the utilization of reversible covalent bonds or the application of mechanochemical methods. The NMR spectra show the influence of the chiral environment on the symmetry of the fullerene molecules, which results in the differentiation of diastereotopic carbon atoms for C70, and the X-ray structures provide unique information on the modes of peptide-fullerene interactions.
- Szymański, Marek,Wierzbicki, Micha?,Gilski, Miros?aw,J?drzejewska, Hanna,Sztylko, Marcin,Cmoch, Piotr,Shkurenko, Aleksander,Jaskólski, Mariusz,Szumna, Agnieszka
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supporting information
p. 3148 - 3155
(2016/03/23)
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- γ-Glutamyl-dipeptides: Easy tools to rapidly probe the stereoelectronic properties of the ionotropic glutamate receptor binding pocket
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γ-Glutamyl-dipeptides, built by condensing the distal carboxylate of L-Glu (or D-Glu) onto a series of differently functionalized amino acids, were prepared and used as tools for rapidly probing the stereo-electronic properties of iGluRs, searching for subtype-selective ligands.
- Tamborini, Lucia,Nicosia, Veronica,Conti, Paola,Dall'Oglio, Federica,De Micheli, Carlo,Nielsen, Birgitte,Jensen, Anders A.,Pickering, Darryl S.,Pinto, Andrea
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p. 8486 - 8492
(2016/11/28)
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- Isolation, Structure Elucidation, Biosynthesis, and Synthesis of Antalid, a Secondary Metabolite from Polyangium species
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The isolation, structure elucidation, and synthesis of antalid (1), a novel secondary metabolite from Polyangium sp., is described herein. The structure elucidation of 1 was performed with the aid of mass spectrometry, high field NMR experiments, and crystal structure analysis. The absolute configuration of antalid was confirmed through the Mosher ester method and ultimately by total synthesis. In addition, the biosynthetic origin of this hybrid PKS-NRPS natural product was unraveled by the in silico analysis of its biosynthetic gene cluster.
- Tautz, Thomas,Hoffmann, Judith,Hoffmann, Thomas,Steinmetz, Heinrich,Washausen, Peter,Kunze, Brigitte,Huch, Volker,Kitsche, Andreas,Reichenbach, Hans,H?fle, Gerhard,Müller, Rolf,Kalesse, Markus
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supporting information
p. 2560 - 2563
(2016/06/15)
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- BRD4 Structure-Activity Relationships of Dual PLK1 Kinase/BRD4 Bromodomain Inhibitor BI-2536
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A focused library of analogues of the dual PLK1 kinase/BRD4 bromodomain inhibitor BI-2536 was prepared and then analyzed for BRD4 and PLK1 inhibitory activities. Particularly, replacement of the cyclopentyl group with a 3-bromobenzyl moiety afforded the most potent BRD4 inhibitor of the series (39j) with a Ki = 8.7 nM, which was equipotent against PLK1. The superior affinity of 39j over the parental compound to BRD4 possibly derives from improved interactions with the WPF shelf. Meanwhile, substitution of the pyrimidine NH with an oxygen atom reversed the PLK1/BRD4 selectivity to convert BI-2536 into a BRD4-selective inhibitor, likely owing to the loss of a critical hydrogen bond in PLK1. We believe further fine-tuning will furnish a BRD4 "magic bullet" or an even more potent PLK1/BRD4 dual inhibitor toward the expansion and improved efficacy of the chemotherapy arsenal.
- Chen, Lijia,Yap, Jeremy L.,Yoshioka, Makoto,Lanning, Maryanna E.,Fountain, Rachel N.,Raje, Mithun,Scheenstra, Jacob A.,Strovel, Jeffrey W.,Fletcher, Steven
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supporting information
p. 764 - 769
(2015/08/06)
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- Solvent-induced helical assembly and reversible chiroptical switching of chiral cyclic-dipeptide-functionalized naphthalenediimides
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Understanding the roles of various parameters in orchestrating the preferential chiral molecular organization in supramolecular self-assembly processes is of great significance in designing novel molecular functional systems. Cyclic dipeptide (CDP) chiral auxiliary-functionalized naphthalenediimides (NCDPs 1-6) have been prepared and their chiral self-assembly properties have been investigated. Detailed photophysical and circular dichroism (CD) studies have unveiled the crucial role of the solvent in the chiral aggregation of these NCDPs. NCDPs 1-3 form supramolecular helical assemblies and exhibit remarkable chiroptical switching behaviour (M- to P-type) depending on the solvent composition of HFIP and DMSO. The strong influence of solvent composition on the supramolecular chirality of NCDPs has been further corroborated by concentration and solid-state thin-film CD studies. The chiroptical switching between supramolecular aggregates of opposite helicity (M and P) has been found to be reversible, and can be achieved through cycles of solvent removal and redissolution in solvent mixtures of specific composition. The control molecular systems (NCDPs 4-6), with an achiral or D-isomer second amino acid in the CDP auxiliary, did not show chiral aggregation properties. The substantial roles of hydrogen bonding and π-π interactions in the assembly of the NCDPs have been validated through nuclear magnetic resonance (NMR), photophysical, and computational studies. Quantum chemical calculations at the ab initio, semiempirical, and density functional theory levels have been performed on model systems to understand the stabilities of the right (P-) and left (M-) handed helical supramolecular assemblies and the nature of the intermolecular interactions. This study emphasizes the role of CDP chiral auxiliaries on the solvent-induced helical assembly and reversible chiroptical switching of naphthalenediimides.
- Manchineella, Shivaprasad,Prathyusha,Priyakumar, U. Deva,Govindaraju
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supporting information
p. 16615 - 16624
(2014/01/06)
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- Molecular architectonics of stereochemically constrained π-complementary functional modules
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The elucidation of the complex factors that govern recognition events at the molecular level represents a daunting challenge in our quest to master the art of pre-programmed molecular assemblies. In this context, we present the molecular architectonics of thoughtfully designed amino acid appended functional molecules 1-5. Naphthalenediimide (NDI and pyrene were employed as functional modules due to their unusual topological shape similarity as well as complementary π-acidic and π-basic character, respectively. In addition, we show that dyads of such unusual functional modules energetically favour alternate assembly in contrast to the predominant self-sorted assembly observed for single-component systems. Moreover, by incorporating minute structural mutations into the amino acid side-chains of 1-5, we successfully tailored their assemblies into well-defined supramolecular architectures, namely supercoiled helices, twisted nanoribbons, nanobelts, comb-edged nanoflakes and nanosheets. A detailed analysis with the aid of experimental and theoretical studies has generated interesting insights into the factors that govern the recognition events at the molecular level. In a quest to master pre-programmed molecular assemblies, we show that alternate stacking over self-sorting of functional aromatic modules can be energetically controlled by smarter molecular design. Furthermore, by introducing structural mutations into the side-chain of amino acid auxiliaries, the molecular assemblies form tailored well-defined 1D and 2D supramolecular nanoarchitectures. Copyright
- Avinash,Samanta, Pralok K.,Sandeepa,Pati, Swapan K.,Govindaraju
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p. 5838 - 5847
(2013/09/23)
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- Substituted 2-hydroxy-N-(arylalkyl)benzamides induce apoptosis in cancer cell lines
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Variously substituted 2-hydroxy-N-(arylalkyl)benzamides were prepared and screened for antiproliferative and cytotoxic activity in cancer cell lines in vitro. Five compounds, out of 33 showed single-digit micromolar IC50 values against several human cancer cell lines. One of the most potent compounds N-((R)-1-(4-chlorophenylcarbamoyl)-2-phenylethyl)-5-chloro-2-hydroxybenzamide (6k) reduced proliferation and induced apoptosis in the melanoma cell line G361 in a dose-dependent manner, as shown by decrease in 5-bromo-2′- deoxyuridine incorporation and increase in several apoptotic markers, including subdiploid population increase, activation of caspases and site-specific poly-(ADP-ribose)polymerase (PARP) cleavage.
- Imramovsky, Ale?,Jorda, Radek,Pauk, Karel,?ezní?ková, Eva,Du?ek, Jan,Hanusek, Ji?í,Kry?tof, Vladimír
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supporting information
p. 253 - 259
(2013/10/01)
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- Chiral transcription and retentive helical memory: Probing peptide auxiliaries appended with naphthalenediimides for their one-dimensional molecular organization
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Right or left paradox: Homochiral, heterochiral and achiral peptide auxiliaries appended with naphthalenediimide (NDI, see figure) were employed to demonstrate chiral transcription. We report an interesting phenomenon coined as retentive helical memory. R
- Pandeeswar,Avinash,Govindaraju
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supporting information; experimental part
p. 4818 - 4822
(2012/06/04)
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- Antimicrobial toxicity studies of ionic liquids leading to a 'hit' MRSA selective antibacterial imidazolium salt
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Imidazolium salts can be classed as surfactants, detergents, ionic liquids, reagents, catalysts or solvents. A study of the toxicity and ecotoxicity of these salts yields valuable information for their use as pharmaceuticals as well as impact on the environment. Our approach to screen a series of chiral imidazolium salts for toxicity to bacteria and fungi, including clinical pathogen strains, has led to the identification of a 'hit' MRSA selective antimicrobial compound. Preliminary structure-activity-relationship (SAR) information (required position of l-phenylalanine and l-valine group) is also elucidated within this first generation of compounds. Conversely, most of the imidazolium salts were nontoxic (IC95 > 2 mM) to the 12 fungi strains and 8 bacteria strains screened, and we propose that they are suitable candidates for 'green chemistry' applications. Ecotoxicity studies (Biodegradation ISO 14593 'CO2 Headspace Test') of two bromide ionic liquids containing l-phenylalanine residues indicate that these ionic liquids passed the test (>60% in 28 days) and classed as readily biodegradable.
- Coleman, Deborah,Spulak, Marcel,Garcia, M. Teresa,Gathergood, Nicholas
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body text
p. 1350 - 1356
(2012/06/16)
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- Enzymatic synthesis of chiral phenylalanine derivatives by a dynamic kinetic resolution of corresponding amide and nitrile substrates with a multi-enzyme system
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Mutant α-amino-ε-caprolactam (ACL) racemase (L19V/L78T) from Achromobacter obae with improved substrate specificity toward phenylalaninamide was obtained by directed evolution. The mutant ACL racemase and thermostable mutant D-amino acid amidase (DaaA) from Ochrobactrum anthropi SV3 co-expressed in Escherichia coli (pACLmut/pDBFB40) were utilized for synthesis of (R)-phenylalanine and non-natural (R)-phenylalanine derivatives (4-OH, 4-F, 3-F, and 2-F-Phe) by dynamic kinetic resolution (DKR). Recombinant E. coli with DaaA and mutant ACL racemase genes catalyzed the synthesis of (R)-phenylalanine with 84% yield and 99% ee from (RS)-phenylalaninamide (400 mM) in 22 h. (R)-Tyrosine and 4-fluoro-(R)-phenylalanine were also efficiently synthesized from the corresponding amide compounds. We also co-expresed two genes encoding mutant ACL racemase and L-amino acid amidase from Brevundimonas diminuta in E. coli and performed the efficient production of various (S)-phenylalanine derivatives. Moreover, 2-aminophenylpropionitrile was converted to (R)-phenylalanine by DKR using a combination of the non-stereoselective nitrile hydratase from recombinamt E. coli and mutant ACL racemase and DaaA from E. coli encoding mutant ACL racemase and DaaA genes. Copyright
- Yasukawa, Kazuyuki,Asano, Yasuhisa
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supporting information
p. 3327 - 3332
(2013/01/15)
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- Synthesis, characterization and pharmacological evaluation of amino acid conjugates of ketoprofen
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Ketoprofen is used for its antipyretic, analgesic and antiinflammatory properties by inhibiting cyclooxygenase-1 and cyclooxygenase-2 enzymes reversibly, which decreases production of proinflammatory prostaglandin precursors. Ketoprofen suffers from the general side effects of nonsteroidal antiinflammatory drugs, owing to presence of free carboxylic acid group. The study aimed to retard the adverse effects of gastrointestinal origin. Different conjugates of ketoprofen have been synthesized by amidation with methyl esters of amino acids namely, phenylalanine, lysine, arginine, glycine, cysteine, valine, glutamine, serine, proline and alanine. Synthesized conjugates were characterized and evaluated for analgesic and antiinflammatory activities.
- Dubey,Jain,Bhadoria,Sinha
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experimental part
p. 1170 - 1174
(2012/08/28)
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- SELF ASSEMBLY OF NAPHTHALENE DIIMIDE DERIVATIVES AND PROCESS THEREOF
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The present disclosure is in relation to nanotechnology/nanobiotechnology, in particular to nano, meso and micro structures of Naphthalene diimide derivatives. The disclosure provides a method for supramolecular self-assembling of Naphthalene diimide deri
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Page/Page column 17
(2012/08/07)
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- A PROCESS FOR THE PREPARATION OF NATEGLINIDE
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The present invention relates to a process for the preparation of substantially pure nateglinide of formula (I), substantially free from the cis-isomer and L-enantiomer and preparation of enantiomerically pure nateglinide form B, directly from the hydrolysis of a (-)-N-(trans-4-isopropylcyclohexyl-1-carbonyl)-D-phenylalanine alkyl ester in a ketonic solvent or water or mixture thereof.
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Page/Page column 17-18
(2012/01/06)
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- Chiral phosphanylferrocenecarboxamides with amino acid pendant groups as ligands for Cu-mediated asymmetric conjugate additions of diethylzinc to chalcones - Structural characterisation of precursors to the Cu catalyst
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A series of chiral phosphanylferrocenecarboxamides was prepared by treatment of either l'-(diphenylphosphanyl)ferrocene-1-carboxylic acid (Hdpf) or its planar-chiral 1,2isomers with amino acid methyl esters in the presence of peptide coupling agents. The compounds were characterised by spectroscopic methods, and the crystal structure of one representative was determined by X-ray diffraction. Catalytic testing of these donors in Cu-catalysed asymmetric conjugate additions of diethylzinc to chalcones revealed that the reaction outcomes were highly sensitive to the ligand structure and the reaction conditions (copper source and solvent), whereas the chalcone substituents (Me, MeO, or Cl in positions 4 or 4') had a less pronounced influence. Compounds based on Hdpf proved to be better ligands than their planarchiral analogues. Under optimised conditions, the reaction with L-valine-Hdpf conjugate, (S)-Ph2PfcCONHCH(CHMe2)CO2Me (fc = ferrocene-1,1'-diyl) and unsubstituted chalcone gave the alkylation product with complete conversion (20 °C/ 4 h) and in 87 % ee. The catalytic behaviour of the amidophosphane ligands was correlated to the results of a model coordination study and the crystal structure of [Cu(Ph2PfcCONHCH 2CO2Me)2](CF3SO3) ·2CHCl3.
- Tauchman, Jiri,Cisarova, Ivana,Stepnicka, Petr
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supporting information; experimental part
p. 4276 - 4287
(2010/10/21)
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- A PROCESS FOR THE PREPARATION OF N-[[TRANS-4-(1-METHYLETHYL)CYCLOHEXYL]CARBONYL]-D-PHENYLALANINE
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The present invention is directed to an novel, industrially viable and cost effective process for preparation of substantially pure N-[[trans-4-(l-methylethyl) cyclohexyl] carbonyl]-D- phenylalanine commonly known as Nateglinide.
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Page/Page column 17
(2010/10/03)
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- COMPOSITIONS AND METHODS FOR CYCLOFRUCTANS AS SEPARATION AGENTS
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The present invention relates to derivatized cyclofructan compounds, compositions comprising derivatized cyclofructan compounds, and methods of using compositions comprising derivatized cyclofructan compounds for chromatographic separations of chemical species, including enantiomers. Said compositions may comprise a solid support and/or polymers comprising derivatized cyclofructan compounds.
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Page/Page column 45-49; 59
(2010/12/31)
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- Homotyrosine-containing cyanopeptolins 880 and 960 and anabaenopeptins 908 and 915 from Planktothrix agardhii CYA 126/8
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Two homotyrosine-bearing cyanopeptolins are described from Planktothrix agardhii CYA 126/8. The compounds feature a common homotyrosine-containing cyclohexadepsipeptide and differ by sulfation of an exocyclically located 2-O-methyl-D-glyceric acid residue. In addition we describe two anabaenopeptins, which contain two homotyrosine residues, one of which is N-methylated. The anabaenopeptins have a common cyclopentapeptide portion and differ in the amino acid linked to it via an ureido bond, arginine and tyrosine, respectively.
- Okumura, Hilary S.,Philmus, Benjamin,Portmann, Cyril,Hemscheidt, Thomas K.
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supporting information; experimental part
p. 172 - 176
(2009/06/27)
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- Synthesis, kinetic studies and pharmacological evaluation of mutual azo prodrugs of 5-aminosalicylic acid for colon-specific drug delivery in inflammatory bowel disease
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Colon-specific mutual azo prodrugs of 5-aminosalicylic acid with essential amino acids were synthesized for the management of inflammatory bowel disease. The structures were confirmed by elemental and spectral analyses. 85-88% release of 5-aminosalicylic acid was achieved in rat fecal matter with half-lives ranging from 140 to 160 min, following first order kinetics. The prodrugs exhibited comparable ameliorating effect as that of sulfasalazine on trinitrobenzenesulfonic acid-induced experimental colitis in rats with a better safety profile.
- Dhaneshwar, Suneela S.,Gairola, Neha,Kandpal, Mini,Vadnerkar, Gaurav,Bhatt, Lokesh,Rathi, Badal,Kadam
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experimental part
p. 3922 - 3929
(2009/12/04)
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- Synthesis of novel C2-symmetric chiral crown ethers and investigation of their enantiomeric recognition properties
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A series of new C2-symmetric chiral aza crown ether macrocycles 1-4 have been synthesized from (S)-3-aryloxy-1,2-propanediol and (S)-1,2-propanediol for the enantiomeric recognition of amino acid ester derivatives. These new macrocycles have be
- Turgut, Yilmaz,Aral, Tarik,Hosgoren, Halil
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experimental part
p. 2293 - 2298
(2010/03/24)
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- Colon-specific mutual amide prodrugs of 4-aminosalicylic acid for their mitigating effect on experimental colitis in rats
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Mutual amide prodrugs of 4-aminosalicylic acid with d-phenylalanine and l-tryptophan were synthesized for targeted drug delivery to the inflamed gut tissue in inflammatory bowel disease. Stability studies in aqueous buffers (pH 1.2 and 7.4) showed that the synthesized prodrugs were stable in both the buffers over a period of 10 h. In rat fecal matter the release of 4-aminosalicylic acid from the prodrugs was in the range of 86-91% over a period of 20 h, with half-lives ranging between 343 and 412 min following first order kinetics. Targeting potential of the carrier system and the ameliorating effect of the amide conjugates were evaluated in trinitrobenzenesulfonic acid-induced experimental colitis model in rats. The prodrugs were assessed for their probable damaging effects on pancreas and liver with the help of histopathological analysis and for their ulcerogenic potential by Rainsford's cold stress method. They were found to have improved safety profile than sulfasalazine, oral 4- and 5-aminosalicylic acid with similar pharmacological spectrum and advantages of sulfasalazine.
- Dhaneshwar, Suneela S.,Chail, Mukta,Patil, Mahavir,Naqvi, Salma,Vadnerkar, Gaurav
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experimental part
p. 131 - 142
(2009/04/07)
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- Novel glycine like amino acids from glyco-α-aminonitriles as building blocks for peptide synthesis
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Our interest in the glycoaminocyanation reaction led us to apply this methodology to introduce amino acids on a monosaccharide using the N-terminal position. The GAAs described in this paper are characterized by having the amino and carboxylic acid functionalities on a disubstituted position of the saccharide backbone leading to α,α-disubstituted glycines. These new sugar amino acids showed a restricted conformation involving a spontaneous intramolecular cyclization between the C- and N-terminal positions during hydrolysis or hydrogenolysis to give the corresponding oxopiperazine. Tripeptide mimics were obtained by the introduction of an additional amino acid using one-pot conditions starting from these cyclic by-products under basic media. We demonstrated that these pseudo tripeptides are good candidates for extension of the peptidic scaffold and cyclization.
- Ducatel, Helene,Van Nhien, Albert Nguyen,Postel, Denis
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-
- Process for the preparation of nateglinide, preferably in B-form
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The present invention relates to a process for the preparation of nateglinide, preferably in B-form, substantially free from the H-form, comprising three steps starting from D-phenylalanine methyl ester or a salt thereof.
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Page/Page column 4
(2008/06/13)
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- Preparation of optically active (2RS,3SR)-2-amino-3-hydroxy-3- phenylpropanoic acid (threo-β-phenylserine) via optical resolutions by replacing and preferential crystallization
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To obtain optically active threo-2-amino-3-hydroxy-3-phenylpropanoic acid (1) via optical resolutions by replacing and preferential crystallization, the racemic structure of (2RS,3SR)-1 hydrochloride [(2RS,3SR)-1·HCl] was examined based on the melting poi
- Shiraiwa, Tadashi,Kawashima, Yuka,Ikaritani, Atsushi,Suganuma, Yumiko,Saijoh, Reiichi
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p. 1170 - 1174
(2007/10/03)
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- Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives
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We report the application of phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes affect antiviral activity and metabolic stability. Separate and distinct SARs were noted for HIV and HBV. Additionally, ProTides were prepared from the D-nucleoside D-Cd4A and the dideoxy analogues L-CddA and D-CddA. These compounds showed more modest potency improvements over the parent drug. In conclusion, the ProTide approach is highly successful when applied to L-Cd4A with potency improvements in vitro as high as 9000-fold against HIV. With a view to preclinical candidate selection we carried out metabolic stability studies using cynomolgus monkey liver and intestinal S9 fractions.
- McGuigan, Christopher,Hassan-Abdallah, Alshaimaa,Srinivasan, Sheila,Wang, Yikang,Siddiqui, Adam,Daluge, Susan M.,Gudmundsson, Kristjan S.,Zhou, Huiqiang,McLean, Ed W.,Peckham, Jennifer P.,Burnette, Thimysta C.,Marr, Harry,Hazen, Richard,Condreay, Lynn D.,Johnson, Lance,Balzarini, Jan
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p. 7215 - 7226
(2007/10/03)
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- SULFONAMIDE COMPOUNDS
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Certain sulfonamide compounds are dual CCK1/CCK2 inhibitors useful in the treatment of CCK1/CCK2 mediated diseases.
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Page/Page column 27
(2010/10/20)
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- Process for the preparation of nateglinide, preferably in b-form
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The present invention relates to a process for the preparation of nateglinide, preferably in B-form, substantially free from the H-form, comprising three steps starting from D-phenylalanine methyl ester or a salt thereof.
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Page/Page column 6
(2010/02/11)
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- PROCESS FOR THE PREPARATION OF NATEGLINIDE
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One-pot process for the preparation of nateglinide, which process comprises reacting an alkyl ester of D-phenylalanine of formula (II) where R represents C1-4alkyl, typically methyl, either as the free base or in salt form (typically the hydrochloride), with trans-4-isopropylcyclohexanecarboxylic acid of formula (III) where X represents hydroxy or halo, typically chloro, to obtain a C1-4 alkyl ester of nateglinide of formula (IV), preferably the methyl ester of nateglinide followed by hydrolysis to yield nateglinide of formula (I).
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Page/Page column 14-16
(2010/02/15)
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- Highly Diastereoselective Synthesis of trans-2,5-Disubstituted Tetrahydrofurans
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trans-2,5-Disubstituted tetrahydrofurans were obtained as major diastereomers (trans / cis ratio 90:10-100: 0) when acetylated y-lactols derived from (S)-glutamic acid were treated with titanium enolates of N-acetyl (R)-oxazolidin-2-thiones. A simple tran
- Jalce, Gael,Seck, Matar,Franck, Xavier,Hocquemiller, Reynald,Figadere, Bruno
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p. 3240 - 3241
(2007/10/03)
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- Substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl-phenylalanine analogues as potent VLA-4 antagonists
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A series of substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl- and α-methyl-L-prolyl-phenylalanine derivatives was prepared as VLA-4/VCAM antagonists. The compounds showed excellent potency with a wide variety of neutral, polar, electron withdrawing or donating groups on the phenylalanine ring (IC50~1 nM). Heteroaryl ring substitution for phenylalanine was also well tolerated. Pharmacokinetic studies in rat were performed on a representative set of compounds in both series.
- Kopka, Ihor E,Young, David N,Lin, Linus S,Mumford, Richard A,Magriotis, Plato A,MacCoss, Malcolm,Mills, Sander G,Riper, Gail Van,McCauley, Ermengilda,Egger, Linda E,Kidambi, Usha,Schmidt, John A,Lyons, Kathryn,Stearns, Ralph,Vincent, Stella,Colletti, Adria,Wang, Zhen,Tong, Sharon,Wang, Junying,Zheng, Song,Owens, Karen,Levorse, Dorothy,Hagmann, William K
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p. 637 - 640
(2007/10/03)
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- Heterocyclic derivatives and their use as antithrombotic agents
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The present invention relates to antithrombotic compounds comprising the group Q, Q having formula (I), wherein the substructure (i) is a structure selected from (a, b and c), wherein X is O or S; X′ being independently CH or N; and m is 0, 1, 2 or 3; wherein the group Q is bound through an oxygen atom or an optionally substituted nitrogen or carbon atom, or a pharmaceutically acceptable salt thereof or a prodrug thereof. The compounds of the invention are therapeutically active and in particular are antithrombotic agents.
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- Synthesis and characterization of various benzyl diethylenetriaminepentaacetic acids (dtpa) and their paramagnetic complexes, potential contrast agents for magnetic resonance imaging
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Four derivatives of diethylenetriaminepentaacetic acid (=3,6,9- tris(carboxymethyl)-3,6,9-triazaundecanedioic acid (H5dtpa)), potential contrast agents for magnetic resonance imaging (MRI), carrying benzyl groups at various positions of the par
- Laurent, Sophie,Elst, Luce Vander,Houze, Sylvain,Guerit, Nathalie,Muller, Robert N.
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p. 394 - 406
(2007/10/03)
-
- Method for producing optically active amino acid of derivative thereof having high optical purity
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A method for producing an optically active amino acid or derivative thereof having a high optical purity from an optically active amino acid comprising optical isomers or derivative thereof, which comprises any one of processes (A), (B), and (C), wherein the process (A) comprises the steps: (1) previously preparing an optically active amino acid or derivative thereof having an optical purity higher than a convergent value of a mutual solubility of the optical isomers and (2) crystallizing the optically active amino acid or the derivative thereof that exists in excess, said convergent value being a ratio of the desired optical isomer in the optical isomers dissolved in a mother liquor in which crystals of a racemate and an optically active compound coexist at equilibrium (the optical purity in a mother liquor). The processes (B) and (C) are described in the specification.
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- Deracemization process of α-aminoesters via pyridoxal. I.- Synthesis and activity of polymerizable forms of pyridoxal
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In order to immobilize pyridoxal, which is a racemization agent of α-aminoesters and could be used in an α-aminoacid deracemization process, two polymerizable analogues of this coenzyme have been synthesized.They were obtained by functionalization in the 2' or 5' position of the pyridinic ring, by a chain containing an acryloyl end group.Their catalytic activity in the homogeneous phase were evaluated in biomimetic conditions (water, pH 7, 25 deg C), was the same as in the case of pyridoxal.Keywords: racemization / α-aminoester / pyridoxal analogue / multistep synthesis / homogeneous catalysis
- Honnoraty, Anne-Marie,Mion, Louis,Collet, Helene,Teissedre, Robert,Commeyras, Auguste
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p. 709 - 720
(2007/10/02)
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- Unusual amino acids V. Asymmetric hydrogenation of (Z)-N-acylaminocinnamic acid derivatives bearing different protective groups.
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The rhodium-catalyzed asymmetric hydrogenation of acylaminocinnamic acid esters, bearing different protective groups, has been investigated in the presence of PROPRAPHOS, BPPM, DIOP, and Ph-β-GLUP as chiral ligands. The influence of the protective group o
- Kreuzfeld,Dobler,Krause,Facklam
-
p. 2047 - 2051
(2007/10/02)
-
- A Practical Synthesis of threo-3-Amino-2-hydroxycarboxylic Acids
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An expeditious synthesis of (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid (2) and (2S,3R)-3-amino-2-hydroxy-4-phenylbutyric acid (4), the key components of the renin inhibitor (1) and bestatin (3), respectively, have been accomplished by featuring hi
- Matsuda, Fuyuhiko,Mtsumoto, Teruyo,Ohsaki, Masako,Ito, Yoshio,Terashima, Shiro
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p. 360 - 365
(2007/10/02)
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