cas 5680-79-5, Glycine methyl ester hydrochloride

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Synthesis of N-(imidomethyl)glycine esters from alkyl glycinates, imides of dicarboxylic acids, and formaldehyde
A method for preparing N-(imidomethyl)glycine esters by the reaction of alkyl glycinates with formaldehyde and imides has been developed. - Keywords: alkyl glycinates; formaldehyde; imides; Mannich base.
Zlotin, S. G.,Sharova, I. V.,Luk'yanov, O. A.
p. 1260 - 1261
(1995)
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Optimizing delivery of flurbiprofen to the colon using a targeted prodrug approach
The carboxylic group responsible for the gastric side-effects of the propionic acid derivative, flurbiprofen, was masked temporarily to overcome these side-effects and to accomplish colon-specific delivery of the drug. An amide prodrug (FLU-GLY) was synthesized by coupling flurbiprofen with L-glycine. Confirmation and characterization of the structure of the synthesized prodrug included elemental analysis, Fourier transform (FT)-IR, FT-NMR, mass (FAB) spectroscopy, and determinations of Rf, Rt and R M values, respectively. Aqueous solubility and lipophilicity (log P) value were determined at pH 1.2, 4.0, 6.8 and 7.4. In-vitro reversion of FLU-GLY to flurbiprofen was measured at different pHs and in a simulated colonic environment. Acute toxicity and ulceration potential were evaluated in-vivo in albino rats. Pre-formulation studies showed increased hydrophilicity but a non-significant increase in lipophilicity of the prodrug. In-vitro reversion studies suggested that the prodrug remained intact until colonic pH was attained, when the colonic microfloral enzymes (amidase) hydrolysed the FLU-GLY amide linkage, releasing the free drug. In-vivo evaluation indicated that the prodrug was much less toxic and had less ulcerogenic activity than the parent drug. Selective delivery of drugs to the colon can be useful in terms of reducing the dose administered and reducing undesirable side-effects.
Philip, Anil K.,Dubey, Rajesh K.,Pathak, Kamla
p. 607 - 613
(2008)
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Glycine modified graphene oxide as a novel sorbent for preconcentration of chromium, copper, and zinc ions from water samples prior to energy dispersive X-ray fluorescence spectrometric determination
A novel and selective sorbent for micro-solid phase extraction was synthesized by chemical functionalization of graphene oxide with glycine. The structure of this nanomaterial, referred to as GO-Gly, was confirmed by Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and scanning electron microscopy. GO-Gly was used for preconcentration of chromium, zinc, and copper ions from water samples prior to their determination by energy dispersive X-ray fluorescence spectrometry (EDXRF). The proposed procedure is based on dispersion of micro amounts of GO-Gly in aqueous samples. After adsorption of metal ions on its surface, samples were filtered under vacuum and then membrane filters were directly submitted to energy dispersive X-ray fluorescence spectrometric measurements. In order to obtain optimal preconcentration conditions, some parameters affecting sorption process, such as pH, amount of GO-Gly, sorption times, and sample volume, were examined. Under optimal conditions the calibration curves were linear in a 1-150 ng mL-1 range with recoveries higher than 97%. The obtained detection limits for Cr(iii), Zn(ii), and Cu(ii) determinations are 0.15, 0.07, and 0.08 ng mL-1, respectively. A relative standard deviation of the proposed procedure (at a 10 ng mL-1 level for n = 10) is lower than 2.3%. The proposed method was successfully applied for determination of Cr(iii), Zn(ii), and Cu(ii) ions in water samples.
Pytlakowska, Katarzyna,Kozik, Violetta,Matussek, Marek,Pilch, Micha?,Hachu?a, Barbara,Kocot, Karina
p. 42836 - 42844
(2016)
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Microwave-Assisted Ruthenium- and Rhodium-Catalyzed Couplings of α-Amino Acid Ester-Derived Phosphinamides with Alkynes
Two different types of new phosphinamide α-amino ester derivatives have been prepared in moderate to high yields via ruthenium(II) and rhodium(III)-catalyzed ortho-C?H functionalization under microwave irradiation. Specifically, the ortho-alkenylated phosphinamides were produced through coupling of phosphinamides containing an α-substituted or α,α-disubstituted α-amino ester with internal alkynes under ruthenium catalysis. In contrast, Ru and the more effective Rh-catalyzed coupling of the α-unsubstituted glycine ester phosphinamide with alkynes resulted in formation of oxidative annulation products, phosphaisoquinolin-1-ones. The developed methods feature the use of easily accessible starting materials, short reaction time, exclusive E-stereoselectivity (for ortho-alkenylation) and good functional group tolerance. The alkenylation reaction was readily scaled up to gram scale. Furthermore, the obtained alkenylated phosphinamide could be transformed into P-containing dipeptides through hydrolysis of the ester group in the catalysis product and subsequent condensation with an α-amino ester.
Gong, Jun-Fang,Li, Xue-Hong,Song, Mao-Ping
supporting information

(2021/12/23)

Translation of Mycobacterium Survival Strategy to Develop a Lipo-peptide based Fusion Inhibitor**
The entry of enveloped virus requires the fusion of viral and host cell membranes. An effective fusion inhibitor aiming at impeding such membrane fusion may emerge as a broad-spectrum antiviral agent against a wide range of viral infections. Mycobacterium survives inside the phagosome by inhibiting phagosome–lysosome fusion with the help of a coat protein coronin 1. Structural analysis of coronin 1 and other WD40-repeat protein suggest that the trp-asp (WD) sequence is placed at distorted β-meander motif (more exposed) in coronin 1. The unique structural feature of coronin 1 was explored to identify a simple lipo-peptide sequence (myr-WD), which effectively inhibits membrane fusion by modulating the interfacial order, water penetration, and surface potential. The mycobacterium inspired lipo-dipeptide was successfully tested to combat type 1 influenza virus (H1N1) and murine coronavirus infections as a potential broad-spectrum antiviral agent.
Sardar, Avijit,Lahiri, Aritraa,Kamble, Mithila,Mallick, Amirul I.,Tarafdar, Pradip K.
supporting information
p. 6101 - 6106
(2021/02/01)

Dynamic Kinetic Cross-Electrophile Arylation of Benzyl Alcohols by Nickel Catalysis
Catalytic transformation of alcohols via metal-catalyzed cross-coupling reactions is very important, but it typically relies on a multistep procedure. We here report a dynamic kinetic cross-coupling approach for the direct functionalization of alcohols. The feasibility of this strategy is demonstrated by a nickel-catalyzed cross-electrophile arylation reaction of benzyl alcohols with (hetero)aryl electrophiles. The reaction proceeds with a broad substrate scope of both coupling partners. The electron-rich, electron-poor, and ortho-/meta-/para-substituted (hetero)aryl electrophiles (e.g., Ar-OTf, Ar-I, Ar-Br, and inert Ar-Cl) all coupled well. Most of the functionalities, including aldehyde, ketone, amide, ester, nitrile, sulfone, furan, thiophene, benzothiophene, pyridine, quinolone, Ar-SiMe3, Ar-Bpin, and Ar-SnBu3, were tolerated. The dynamic nature of this method enables the direct arylation of benzylic alcohol in the presence of various nucleophilic groups, including nonactivated primary/secondary/tertiary alcohols, phenols, and free indoles. It thus offers a robust alternative to existing methods for the precise construction of diarylmethanes. The synthetic utility of the method was demonstrated by a concise synthesis of biologically active molecules and by its application to peptide modification and conjugation. Preliminary mechanistic studies revealed that the reaction of in situ formed benzyl oxalates with nickel, possibly via a radical process, is an initial step in the reaction with aryl electrophiles.
Guo, Peng,Wang, Ke,Jin, Wen-Jie,Xie, Hao,Qi, Liangliang,Liu, Xue-Yuan,Shu, Xing-Zhong
supporting information
p. 513 - 523
(2021/01/12)

Silver-Mediated [3 + 2] Cycloaddition of Azomethine Ylides with Trifluoroacetimidoyl Chlorides for the Synthesis of 5-(Trifluoromethyl)imidazoles
A silver-mediated [3 + 2] cycloaddition of azomethine ylides with trifluoroacetimidoyl chlorides for the rapid assembly of 5-(trifluoromethyl)imidazoles has been developed. Notable features of the reaction include readily accessible reagents, a broad substrate scope, and high efficiency. The protocol can be successfully applied to construct the analogue of the specific allosteric modulator of GABAA receptors. The silver species could be recycled by a simple operation.
Yang, Hefei,Lu, Shu-Ning,Chen, Zhengkai,Wu, Xiao-Feng
supporting information
p. 4361 - 4370
(2021/03/09)

Eco-friendly synthesis of peptides using fmoc-amino acid chlorides as coupling agent under biphasic condition
Background: Agro-waste derived solvent media act as a greener process for the peptide bond formation using Nα-Fmoc-amino acid chloride and amino acid ester salt with in situ neutralization and coupling under biphasic condition. The Fmoc-amino acid chlorides are prepared by the reported procedure of freshly distilled SOCl2 with dry CH2Cl2. The protocol found many added ad-vantages such as neutralization of amino acid ester salt and not required additional base for the neu-tralization, and directly coupling take place with Fmoc-amino acid chloride gave final product dipeptide ester in good to excellent yields. The protocol occurs with complete stereo chemical integrity of the configuration of substrates. Here, we revisited Schotten-Baumann condition, instead of using inorganic base. Objective: To develop green protocol for the synthesis of peptide bond using Fmoc-amino acid chloride with amino acid esters salt. Methods: The final product isolated is analyzed in several spectroscopic and analytical techniques such as FT-IR,1H-,13C-NMR, Mass spectrometry and RP-HPLC to check stereo integrity and puri-ty of the product. Conclusion: The present method developed greener using natural agro-waste (lemon fruit shell ash) derived solvent medium for the reaction and not required chemical entity.
Kantharaju, Kamanna,Khatavi, Santosh Y.
p. 699 - 707
(2021/08/23)

Ribose conversion with amino acids into pyrraline platform chemicals-expeditious synthesis of diverse pyrrole-fused alkaloid compounds
One-pot conversion of sustainable d-ribose with l-amino acid, methyl esters produced pyrrole-2-carbaldehydes 5 in reasonable yields (32-63%) under pressurized conditions of 2.5 atm at 80 °C. The value-added pyrraline compounds 5 as platform chemicals were utilized for quick installation of poly-heterocyclic cores for the development of pyrrole-motif natural and artificial therapeutic agents. A pyrrole-fused piperazin-2-one scaffold 6 was prepared by reductive amination of pyrralines 5 with benzylamine. While further cyclization of pyrralines 5 with ethane-1,2-diamine produced pyrrolo-piperazin-2-ones 7 with an extra imidazolidine ring, the reaction with 2-amino alcohols derived from natural l-amino acids, alanine, valine, and phenylalanine, respectively provided pyrrolo-piperazin-2-ones 8, 9, and 10 with oxazolidine as the third structural core. Cell viability and an anti-inflammatory effect of the synthesized compounds were briefly tested by the MTT method and the Griess assay, among which 8h and 10g exhibited significant anti-inflammatory effects with negligible cell toxicity.
Cho, Soohyeon,Gu, Lina,In, Ik Joon,Kim, Hakwon,Koo, Sangho,Lee, Taehoon,Wu, Bo
p. 31511 - 31525
(2021/11/30)

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)

Amino acid conjugates of 2-mercaptobenzimidazole provide better anti-inflammatory pharmacology and improved toxicity profile
Benzimidazole is an important pharmacophore for clinically active drugs against inflammation and treatment of pain, however, it is associated with gastrointestinal side effects. Here we synthesized benzimidazole based agents with significant analgesic/anti-inflammatory potential but with less gastrointestinal adverse effects. In this study, we synthesized novel, orally bioavailable 2-mercaptobenzimidazole amino acid conjugates (4a–4o) and screened them for analgesic, anti-inflammatory and gastro-protective effects. The synthesized 2-mercaptbenzimidazole derivatives were characterized for their structure using FTIR, 1H NMR and 13C NMR spectroscopic techniques. The 2-mercaptobenzimidazole amino acid conjugates have found to possess potent analgesic, anti-inflammatory and gastroprotective activities, particularly with compound 4j and 4k. Most of the compounds exhibited remarkable anti-ulcer and antisecretory effects. Molecular docking studies were carried out to study the binding affinities and interactions of the synthesized compounds with target proteins COX-2 (PDB ID: 3LN1) and H+/K+-ATPase (PDB ID: 5Y0B). Our results support the clinical promise of these newly synthesized 2-mercaptobezimidazol conjugates as a component of therapeutic strategies for inflammation and analgesia, for which the gastric side effects are always a major limitation.
Khan, Muhammad T.,Nadeem, Humaira,Khan, Arif-ullah,Abbas, Muzaffar,Arif, Muazzam,Malik, Nadia Shamshad,Malik, Zulkifal,Javed, Ibrahim
p. 1057 - 1072
(2020/08/13)

A Novel N-Substituted Valine Derivative with Unique Peroxisome Proliferator-Activated Receptor γbinding Properties and Biological Activities
A proprietary library of novel N-Aryl-substituted amino acid derivatives bearing a hydroxamate head group allowed the identification of compound 3a that possesses weak proadipogenic and peroxisome proliferator-Activated receptor γ(PPARI) activating properties. The systematic optimization of 3a, in order to improve its PPARγagonist activity, led to the synthesis of compound 7j (N-Aryl-substituted valine derivative) that possesses dual PPARI/PPARα agonistic activity. Structural and kinetic analyses reveal that 7j occupies the typical ligand binding domain of the PPARγagonists with, however, a unique high-Affinity binding mode. Furthermore, 7j is highly effective in preventing cyclin-dependent kinase 5-mediated phosphorylation of PPARγserine 273. Although less proadipogenic than rosiglitazone, 7j significantly increases adipocyte insulin-stimulated glucose uptake and efficiently promotes white-To-brown adipocyte conversion. In addition, 7j prevents oleic acid-induced lipid accumulation in hepatoma cells. The unique biochemical properties and biological activities of compound 7j suggest that it would be a promising candidate for the development of compounds to reduce insulin resistance, obesity, and nonalcoholic fatty liver disease.
Peiretti, Franck,Montanari, Roberta,Capelli, Davide,Bonardo, Bernadette,Colson, Cécilia,Amri, Ez-Zoubir,Grimaldi, Marina,Balaguer, Patrick,Ito, Keiichi,Roeder, Robert G.,Pochetti, Giorgio,Brunel, Jean Michel
p. 13124 - 13139
(2020/12/02)

Structure-Based Design of Inhibitors Selective for Human Proteasome β2c or β2i Subunits
Subunit-selective proteasome inhibitors are valuable tools to assess the biological and medicinal relevance of individual proteasome active sites. Whereas the inhibitors for the β1c, β1i, β5c, and β5i subunits exploit the differences in the substrate-binding channels identified by X-ray crystallography, compounds selectively targeting β2c or β2i could not yet be rationally designed because of the high structural similarity of these two subunits. Here, we report the development, chemical synthesis, and biological screening of a compound library that led to the identification of the β2c- and β2i-selective compounds LU-002c (4; IC50 β2c: 8 nM, IC50 β2i/β2c: 40-fold) and LU-002i (5; IC50 β2i: 220 nM, IC50 β2c/β2i: 45-fold), respectively. Co-crystal structures with β2 humanized yeast proteasomes visualize protein-ligand interactions crucial for subunit specificity. Altogether, organic syntheses, activity-based protein profiling, yeast mutagenesis, and structural biology allowed us to decipher significant differences of β2 substrate-binding channels and to complete the set of subunit-selective proteasome inhibitors.
Xin, Bo-Tao,Huber, Eva M.,De Bruin, Gerjan,Heinemeyer, Wolfgang,Maurits, Elmer,Espinal, Christofer,Du, Yimeng,Janssens, Marissa,Weyburne, Emily S.,Kisselev, Alexei F.,Florea, Bogdan I.,Driessen, Christoph,Van Der Marel, Gijsbert A.,Groll, Michael,Overkleeft, Herman S.
supporting information
p. 1626 - 1642
(2019/02/19)

Preparation and biological evaluation of soluble tetrapeptide epoxyketone proteasome inhibitors
A series of novel tetrapeptidyl epoxyketone inhibitors of 20S proteasome was designed and synthesized. To fully understand the SAR, various groups at R1, R2, R3, R4 and R5 positions, including aromatic and aliphatic substituents were designed, synthesized and biologically assayed. Based on the enzymatic results, seven compounds were selected to evaluate their cellular activities and soluble compound 36 showed strong potency against human multiple myeloma (MM) cell lines. Microsomal stability results indicated that compound 36 was more stable in mice, rat and human microsomes than marketed carfilzomib. The in vivo activities of this compound were evaluated with the xenograft mice models of MM cell lines ARH77 and RPMI-8226 with luciferase expression and the T/C value of the two models were 49.5% and 37.6%, respectively. To evaluate the potential cardiovascular toxicity, inhibition of hERG ion channel in HEK293 cells by compound 36 and carfilzomib was carried out. The results indicated that 36 had no binding affinity for the hERG ion channel while carfilzomib could bind it with IC50 of 92.1 μM.
Lei, Meng,Zhang, Haoyang,Miao, Hang,Du, Xiao,Zhou, Hui,Wang, Jia,Wang, Xueyuan,Feng, Huayun,Shi, Jingmiao,Liu, Zhaogang,Shen, Jian,Zhu, Yongqiang
p. 4151 - 4162
(2019/08/07)

Synthesis, Characterization, and Reactivity of an Ethynyl Benziodoxolone (EBX)-Acetonitrile Complex
The synthesis of a crystalline ethynyl-1,2-benziodoxol-3(1H)-one (EBX)-acetonitrile complex is described. EBX has been widely used as an active species for a variety of reactions; however, its high instability has so far prevented its isolation. The EBX-acetonitrile is self-assembled into a double-layered honeycomb structure through weak hypervalent iodine secondary interactions and hydrogen bonding. The N-ethynylation of a variety of sulfonamides using the EBX-acetonitrile complex as a substrate under mild conditions is also described.
Yudasaka, Masaharu,Shimbo, Daisuke,Maruyama, Toshifumi,Tada, Norihiro,Itoh, Akichika
supporting information
p. 1098 - 1102
(2019/05/16)

Structure-Activity Relationships of Fish Oil Derivatives with Antiallergic Activity in Vitro and in Vivo
A series of unsaturated fatty acids in fish oil and their corresponding ethanolamide metabolites were explored to find active fish oil components of antiallergic activity in vitro. Ethanolamides of omega-3 fatty acids (α-linolenic acid, EPA, and DHA) were found to possess promising antiallergic activity, whereas free fatty acids and ethanolamides of other fatty acids exhibited no or weak potency. Based on this finding, structure-activity relationships of DHA-ethanolamide (DHEA) derivatives were investigated to yield better fatty acid derivatives with enhanced antiallergic activity in vitro and in vivo. When the ethanolamide moiety of DHEA was replaced by the substituted sulfonamide functionality, highly promising potency was provided in vitro. Compound 59 showed improved antiallergic activity in vivo over DHEA. The results indicate that optimized DHEA derivatives have enhanced antiallergic activity in vitro and in vivo, and the resulting structures will be an important basis for further development of bioavailable derivatives with promising allergy suppressive activity.
Kim, In-Hae,Kanayama, Yoshiki,Nishiwaki, Hisashi,Sugahara, Takuya,Nishi, Kosuke
p. 9576 - 9592
(2019/11/11)

Preparation method of high-purity glycine methyl ester hydrochloride
A preparation method of high-purity glycine methyl ester hydrochloride specifically comprises the steps that 1, glycine and absolute methanol are added into a reaction kettle and uniformly stirred andmixed; 2, hydrogen chloride gas is introduced, and the reaction temperature of a system is increased to be 40-60 DEG C; 3, hydrogen chloride gas is continuously introduced for 0-20 minutes when crystal is separated out in the system due to a thermal reaction; 4, the stirring rate is controlled and gradiently reduced until the temperature of the system is lower than or equal to 10 DEG C, and suction filtration and drying are carried out to obtain the white crystalline powder glycine methyl ester hydrochloride. According to the method, the glycine and the absolute methanol serve as raw materials, the introducing amount and introducing stage of the hydrogen chloride gas are controlled, and amino acid methyl ester hydrochloride with the purity higher than 99% is prepared at a time through a gradient cooling crystallization method, so that the problems of instant crystallization of the solvent-free reaction system, equipment stirring locking, high filtration energy consumption and the likeare effectively solved. According to the method, the reaction equipment is simple, reaction conditions are mild, crystallization is easy to control, and the product yield can reach 95%.
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Paragraph 0012-0018

(2019/07/29)

Continuous synthesis method of glycine methyl ester hydrochloride
A continuous synthesis method of glycine methyl ester hydrochloride specifically includes the steps that glycine and anhydrous methanol are added into a mixing kettle, and under the stirring condition, hydrogen chloride gas is introduced until the glycine is completely dissolved; the uniformly mixed material is continuously pumped into a reaction kettle, the temperature of a reaction system is maintained to be 55-60 DEG C, a seed crystal heat preservation reaction is added, the stirring speed is controlled, and continuously separated crystals are deposited at the bottom of the reaction kettle;then the crystals are subjected to centrifugation, washing and drying to obtain white crystal powder, and centrifugal mother liquor is pumped into the mixing kettle for cyclic utilization; while thecontinuous feeding reaction is carried out, a negative pressure system of 0.02-0.04 MPa is built in the reaction kettle, and water generated by the reaction is discharged by excessive methanol in thesystem during the reaction. According to the method, the process route is simple, the utilization rate of the reaction equipment is high, the product yield can reach 93% or above, the purity is higherthan 98%, no waste is generated, and automatic industrial production is easy to realize.
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Paragraph 0015; 0016

(2019/07/29)

Administration of ferrocene-modified amino acids induces changes in synaptic transmission in the CA1 area of the hippocampus
A series of ferrocene-modified amino acid methyl esters with pyrazole linker was prepared in good to quantitative yields starting from easy accessible ferrocene pyrazole carbaldehyde and amino acids in racemic and enantio enriched forms under reductive amination conditions (NaBH (OAc)3, reflux, 3 hr). The resulting enantiomers were resolved using analytical HPLC on modified cellulose or amylose as chiral selectors. In vivo electrophysiological experiments were performed in the CA1 field of the hippocampus on 3a Fc-Gly, (L)-3b Fc-Ala, and (D)-3b Fc-Ala compounds. An increasing in the amplitudes of responses of local potentials (up to 25%) of the CA1 region in the studied groups was found after intraperitoneal administration of ferrocene compounds 3a and (D)-3b compared with control rats treated with saline.
Dobryakova, Yulia V.,Ilyin, Mikhail M.,Markevich, Vladimir A.,Rodionov, Alexey N.,Simenel, Alexander A.,Snegur, Lubov V.
(2020/01/24)

Rhodium-Catalyzed Enantioselective Synthesis of Oxazinones via an Asymmetric Ring Opening-Lactonization Cascade of Oxabicyclic Alkenes
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
supporting information
p. 7549 - 7553
(2019/10/02)

Synthesis of ergosterol peroxide conjugates as mitochondria targeting probes for enhanced anticancer activity
Inspired by the significant bioactivity of ergosterol peroxide, we designed and synthesized four fluorescent coumarin and ergosterol peroxide conjugates 8a-d through the combination of ergosterol peroxide with 7-N,N-diethylamino coumarins fluorophore. The cytotoxicity of synthesized conjugates against three human cancer cells (HepG2, SK-Hep1, and MCF-7) was evaluated. The results of fluorescent imaging showed that the synthesized conjugates 8a-d localized and enriched mainly in mitochondria, leading to significantly enhanced cytotoxicity over ergosterol peroxide. Furthermore, the results of biological functions of 8d showed that it could suppress cell colony formation, invasion, and migration; induce G2/M phase arrest of HepG2 cells, and increase the intracellular ROS level.
Bu, Ming,Li, Hongling,Wang, Haijun,Wang, Jing,Lin, Yu,Ma, Yukun
(2019/09/19)

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
supporting information
p. 10833 - 10847
(2019/12/25)

Synthesis and Biological Evaluation of a Series of Novel Celastrol Derivatives with Amino Acid Chain
The synthesis of celastrol analogues containing amino acid ester at the C(29) position and their evaluation for cytotoxic activities in?vitro were reported. The MTT test showed that a set of derivatives with lower IC50 values than that of the positive control group cisplatin and the parent compound celastrol, which exhibited greater antiproliferative activities. The most potent title compounds 2a and 2e exhibited cytotoxic activities in?vitro against HeLa and A549 cell lines with IC50 values of 0.371 and 0.237?μm, 0.235 and 0.109?μm, respectively. The apoptosis assay demonstrated that 2a and 2e can induces of A549 cell apoptosis in low concentrations. These results showed that 2a and 2e may be promising for further research as antitumor agents.
Pang, Chaohai,Luo, Jinhui,Liu, Chunhua,Wu, Xuejin,Wang, Dingyong
(2018/05/04)

Identification of a fluorescent small-molecule enhancer for therapeutic autophagy in colorectal cancer by targeting mitochondrial protein translocase TIM44
Objective As the modulation of autophagic processes can be therapeutically beneficial to cancer treatment, the identification of novel autophagic enhancers is highly anticipated. However, current autophagy-inducing anticancer agents exert undesired side effects owing to their non-specific biodistribution in off-target tissues. This study aims to develop a multifunctional agent to integrate cancer targeting, imaging and therapy and to investigate its mechanism. Design A series of mitochondria-targeting near-infrared (NIR) fluorophores were synthesised, screened and identified for their autophagy-enhancing activity. The optical properties and biological effects were tested both in vitro and in vivo. The underlying mechanism was investigated using inhibitors, small interfering RNA (siRNA), RNA sequencing, mass spectrometry and human samples. Results We have screened and identified a new NIR autophagy-enhancer, IR-58, which exhibits significant tumour-selective killing effects. IR-58 preferentially accumulates in the mitochondria of colorectal cancer (CRC) cells and xenografts, a process that is glycolysis-dependent and organic anion transporter polypeptide-dependent. IR-58 kills tumour cells and induces apoptosis via inducing excessive autophagy, which is mediated through the reactive oxygen species (ROS)-Akt-mammalian target of rapamycin (mTOR) pathway. RNA sequencing, mass spectrometry and siRNA interference studies demonstrate that translocase of inner mitochondrial membrane 44 (TIM44)-superoxide dismutase 2 (SOD2) pathway inhibition is responsible for the excessive ROS, autophagy and apoptosis induced by IR-58. TIM44 expression correlates positively with CRC development and poor prognosis in patients. Conclusions A novel NIR small-molecule autophagy-enhancer, IR-58, with mitochondria-targeted imaging and therapy capabilities was developed for CRC treatment. Additionally, TIM44 was identified for the first time as a potential oncogene, which plays an important role in autophagy through the TIM44-SOD2-ROS-mTOR pathway.
Huang, Yinghui,Luo, Shenglin,Wang, Yang,He, Jintao,Luo, Peng,Chen, Zelin,Liu, Tao,Tan, Xu,Shi, Chunmeng,Zhou, Jie,Ou, Juanjuan,Miao, Hongming,Liang, Houjie
p. 307 - 319
(2018/07/31)

A potential greener protocol for peptide coupling reactions using recyclable/reusable ionic liquid [ C 4-DABCO ] [ N(CN) 2 ]
Abstract : Development of greener methodologies in synthetic organic chemistry has brought awareness in recent decades due to the ecological performance of green solvent media and catalytic systems. Here, we carried out the peptide bond formation reaction in one of the environmentally secure solvents, ‘ionic liquids’ in the presence of coupling reagent and in the absence of external base at room temperature, affording dipeptides in good to excellent yields. GRAPHICAL ABSTRACT: SYNOPSIS We carried out the peptide bond formation reaction in ionic liquids in the presence of a coupling reagent at room temperature, in the absence of an external base, affording dipeptides in good to excellent yields.
Konwar, Manashjyoti,Khupse, Nageshwar D,Saikia, Prakash J,Sarma, Diganta
(2018/05/15)

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.
p. 2292 - 2305
(2018/05/14)

HEMIAMINAL-TAG FOR PROTEIN LABELING AND PURIFICATION
The invention pertains to the synthesis, isolation, and characterization of hemiaminal for selective labeling of peptides, proteins, antibodies, and organic fragments with -C(=0) CH2NH2 and derivatives with -CH2NH2 group over -C(=0) CHRNH2 group (where R≠H). The invention also pertains to the method of single-site immobilization of proteins through N-terminus Gly on solid phase. The invention includes late-stage tagging of N-terminus Gly with an affinity tag, 19F NMR probe, and a fluorophore and a method for metal-free protein purification and isolation of analytically pure proteins.
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Page/Page column 22

(2018/06/30)

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.
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Paragraph 0084; 0085; 0123; 0124; 0143; 0144

(2018/07/30)

Synthesis method of N-benzyl matrinyl glycine
The invention relates to the field of chemical industry, in particular to a synthesis method of N-benzyl matrinyl glycine. The synthesis method comprises the following steps: preparing glycine methylester hydrochloride, namely weigh 3g of glycine, adding 150mL of anhydrous methanol, heating in an oil bath with the temperature of 65-70 DEG C, continuously inflating dry Hcl gas, dissolving all theglycine in about 60min, continuing inflating Hcl gas for 15min, stopping a reaction, concentrating under reduced pressure, adding a residue into acetone, and stirring to obtain 4.93g of a white solid;preparing N-benzyl matrinic acid, namely weighing 2.48g of matrine, adding into a 250-mL round-bottomed flask, adding sodium hydroxide with the concentration of 10%, performing a reflux reaction while stirring, detecting the progress of the reaction until the completion of the reaction, adjusting the pH to 7-8 by using a sulfuric acid solution with the centration of 20% in an ice bath, concentrating under reduced pressure, dissolving the residue by using methanol while heating, performing suction filtration while a solution is hot, concentrating a filtrate under reduced pressure to 1/4 of thevolume, adding acetone, vigorously stirring, separating out a precipitate, and performing suction filtration to obtain 2.23g of a white solid N-benzyl matrinic acid. By the synthesis method, the operation is simple, a reaction condition is mild, the reaction time is short, the yield is high, the reproducibility is good, and the product quality and the anti-tumor activity can be improved.
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Paragraph 0007; 0008

(2018/07/30)

Synthesis and characterization of selenium(I/II) and tellurium(IV) derivatives of amino acids
The direct reaction between Te metal and methyl 2-(2-bromoacetamido)propanoate (27) at room temperature, yields the first example of organotellurium(IV) derivative (MeOC(O)CH(Me)NHCOCH2)2TeBr2 (31). Similarly, reaction of Te with methyl 2-(2-bromoacetamido)acetate (26) and methyl 2-(2-bromoacetamido)-3-phenylpropanoate (28) in presence of NaI in acetone gives MeOC(O)CH2NHCOCH2I (29), MeOC(O)CH(R)NHCOCH2)2TeI2 (R = H (30) and CH2Ph (32). Treatment of 26/27/28 with Li2Te2/Li2Se2 readily provides the [MeOC(O)CH(CH3)NHCOCH2]2Te2, (33); [MeOC(O)CH2NHCOCH2]2Se2, (34); [MeOC(O)CH(CH2Ph)NHCOCH2]2Se2, (35) and [Figure presented] (36). Similarly the reaction of (2,6-dimethyl-4-tert-butylC6H2)SeNa with 28 readily provide the [MeOC(O)CH(CH2Ph)NHCOCH2]SeC6H2-2,6-dimethyl-4-tert-butyl), (37) in good yield. Molecule [MeOC(O)CHNH(Boc)CH2]2Se2, (38) and [NaOC(O)CHNH(Boc)CH2Te(2,4,6-Me3C6H2] (39) were prepared by the treatment of Li2Se2/2,4,6-Me3C6H2TeNa with methyl 3-bromo-2-((tert-butoxycarbonyl)amino)propanoate and N-(t-Boc)-L-serine β-lactone respectively. These compounds are purified by chromatography and characterized by a number of analytical techniques such as (1H, 13C, 77Se and 125Te NMR) spectroscopy, mass spectrometry and elemental analysis. The single crystal X-ray studies of 29, 30, 31, 36 and 38 revealed the presence of characteristic O?Se/Te, secondary bonding interactions. A detailed analysis of the crystal structures of the compound reveals interesting supramolecular assembly.
Singh, Puspendra,Singh, Harkesh B.,Butcher, Ray J.
supporting information
p. 1 - 9
(2018/09/21)

Synthesis of 4-N-α-coumaryl amino acids and investigation of their antioxidant, antimicrobial activities and fluorescence spectra
An efficient metal-free approach for the synthesis of N-coumaryl amino acids and the first one-step synthesis of 4-hydrazinocoumarin from 4-hydroxycoumarin was developed. The nucleophilic addition of amino acid methyl esters to 4-tosylcoumarins produced a series of 4-N-α-coumaryl amino acids in good to excellent yields without racemization. The antioxidant activities of the synthesized compounds were investigated using DPPH and FRAP methods. 4-Hydrazinocoumarin and N-coumaryl tyrosine had the best antioxidant activity. The antimicrobial activities of the compounds against Gram-positive was stronger than Gram-negative. 4-Hydrazinocoumarin showed the best antibacterial effect.
Ghalehshahi, Hajar Golshadi,Balalaie, Saeed,Aliahmadi, Atousa,Moghimi, Roya
p. 1461 - 1470
(2018/08/03)

Surface-enhanced Raman scattering of alkyne-conjugated MoS2: A comparative study between metallic and semiconductor phases
Raman enhancement on nonmetallic flat two-dimensional (2D) nanomaterial surfaces has attracted a great deal of attention since the discovery of graphene-enhanced Raman scattering. Molybdenum disulfide (MoS2) is a flat 2D nanomaterial with unique electronic and physical properties that can be applied in surface-enhanced Raman spectroscopy (SERS). Herein, we report a lithium-exfoliated MoS2 (Li-MoS2) has a metallic phase content of about 70%, which is three times higher than the metallic phase content of 20% in thioglycolic acid-exfoliated MoS2 (T-MoS2). Li-MoS2 therefore displays a 2-3 fold increase in the Raman signal for rhodamine 6G (R6G) used as an analyte. Furthermore, the conjugation of a thiol-terminated alkyne with Li-MoS2 also provided a greater SERS signal at 2123 cm-1 than that of T-MoS2. A defect-rich metallic MoS2 monolayer can therefore be used as the perfect substrate for surface-enhanced Raman scattering, although pristine MoS2 hardly exhibits an SERS effect. This study proved that (1) defect-rich metallic MoS2, (2) dipole-dipole interactions, and (3) the enhanced charge transfer effect of MoS2 monolayers are the three primary and essential parameters for enhancing the Raman signals of analytes on MoS2. Key observations include the fact that some alkyne groups were directly coordinated to the edges of Li-MoS2 defect sites, which shifted the alkyne signal to 2153 cm-1 in alkyne spectral mapping. More importantly, to quantify the SERS performance of Li-MoS2, SERS imaging of live cells was demonstrated using the unique alkyne signal at 2123 cm-1.
Anbazhagan, Rajeshkumar,Vadivelmurugan, Adhisankar,Tsai, Hsieh-Chih,Jeng, Ru-Jong
p. 1071 - 1082
(2018/02/10)

4,5-Disubstituted N-Methylimidazoles as Versatile Building Blocks for Defined Side-Chain Introduction
Fungerin is a 1,4,5-trisubstituted imidazole natural product characterised by a broad spectrum of antifungal activities. We planned to develop flexible strategies to access to such compounds. Imidazoles bearing suitable anchor groups at C-4 and C-5 allow the introduction of various substituted side-chains, generating libraries of fungerin derivatives for biological tests. Starting from commercially available reactants, two N-methyl 4,5-substituted imidazole core units were synthesised. Derivatives of type 1 contained two orthogonally protected C-1 anchors. Selective side-chain introduction was achieved through a sequence of Grignard coupling at C-5 to replace a tosylate and a Horner olefination through an aldehyde attached to C-4. Two target fungerin derivatives were synthesised. Since the organometallic substitution of the C-5-CH2-positioned leaving group proved to suffer from limitations concerning potential competing side-reactions, a type 2 imidazole core was built up. These structures had a halogen centre at C-4 and a hydroxyethyl anchor at C-5. Now, selective side-chain introduction allowed us to use Julia olefination to form the allyl side-chain at C-5 and Heck reactions to introduce the C-4 acryl substituents. Eight derivatives, including fungerin, were synthesised by this latter strategy, without producing any regioisomers. The second approach had the advantage that various side-chains could be coupled at C-4 and C-5 in two final steps. Thus, this strategy represents a versatile way to build up libraries of fungerin derivatives for biological testing.
Przybyla, Daniel,Nubbemeyer, Udo
supporting information
p. 695 - 703
(2017/02/05)

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)

Novel thiazolidinedione-5-acetic-acid-peptide hybrid derivatives as potent antidiabetic and cardioprotective agents
Thiazolidinediones (TZDs) are one of the important clinically established antidiabetic agents. Amino-acid and peptides have an advantage of better target selectivity and specificity. As hybrids, they also improved absorption and showed better bioavailability, which in turn makes them safer. Hence, here an effort has been made to synthesize hybrids of thiazolidinedione with amino-acids and peptides and evaluate their antidiabetic and cardioprotective effect in streptozotocin-nicotinamide (STZ-NA) induced Type 2 diabetes mellitus (T2DM) rat models. A series of 14 thiazolidinedione-5-acetic acid hybrids with of different amino-acids and peptide combinations were synthesized, characterized and further screened for antidiabetic and cardioprotective activity. Among all, six compounds T1 (SSDMA1), T4 (SSDMA4), T5 (SSDMA5), T7 (SDMA13), T9 (SSDMA15) and T13 (SSDMA49) showed better antioxidant activity and comparable % glucose uptake by yeast cells. Hence, the in vivo antidiabetic screening was done for these six compounds. Among all six T1, T7, T13 showed significant blood glucose level decrease compared to standard pioglitazone HCl. Also T1, T7 and T13 showed better antioxidant activity with lower IC50 value than standard ascorbic acid, and hence in vivo cardioprotective studies were done for these. The ECG studies showed that T1 (SSDMA1) and T7 (SSDMA13) were better effective than SDMA49 (T13) in restoring the normal functioning of the heart, thus may help in preventing the development of diabetic cardiomyopathy (DCM) and controlling T2DM.
Maji,Samanta
p. 1163 - 1172
(2017/02/23)

An azobenzene-based photoswitchable crystal growth modifier
An aspartic acid functionalised azobenzene derivative is found to be a light-switchable crystal growth modifier of calcite. UV irradiation of the molecule reversibly switches it to the cis isomer, which is a significantly less effective crystal growth inhibitor than the trans isomer. Visible light, or heat switches the inhibitor back “on”. Extended irradiation degrades the inhibitor such that it is irreversibly switched “off”. It was shown that the trans isomer is preferentially absorbed on to the crystal surface, which is consistent with its greater efficacy as an inhibitor.
Nealon, Gareth L.,Brown, David H.,Jones, Franca,Parkinson, Gordon,Ogden, Mark I.
p. 1286 - 1293
(2017/03/09)

A chrysin preparation of amino acid derivatives (by machine translation)
The invention discloses a chrysin amino acid derivative and its preparation method, dialogue chrysin 7 bit synthesizing different series of chrysin derivatives, the specific synthetic route for chrysin first with supplies immunoglobulin molecules thickener of ester reaction, obtained after the hydrolysis of 7 - O - carboxysomes alkylation chrysin derivatives, with different types of amino acid alkyl ester salt reaction, through the amide condensation to obtain chrysin amino acid alkyl esters, then hydrolyze chrysin amino acid derivatives. The invention relates to amino acid with the chrysin molecule, on the one hand improve the solubility of the chrysin, on the one hand and the killing effect of the normal cell; amino acid is the basic unit of a protein, as an important active molecule in the human body, the process involved in various life activities, non-toxic and harmless to the human body; amino acid has good solubility, and tumor cells to amino acid than normal cell high demand. (by machine translation)
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Paragraph 0055

(2017/08/23)

Aromatic substitution spiro indolyl diketopiperazine compound and synthesis method thereof
The invention discloses an aromatic substitution spiro indolyl diketopiperazine compound and a synthesis method thereof. Glycine is used as a raw material and subjected to esterification reaction with methyl alcohol and thionyl chloride to obtain methyl glycinate hydrochloride, methyl glycinate hydrochloride and aromatic aldehyde are subjected to condensation reaction to obtain Schiff base, isatin is used as a raw material and subjected to reduction reaction under the action of hydrazine hydrate to obtain indoline-2-ketone, indoline-2-ketone and benzaldehyde are subjected to Knoevenagel reaction under piperidine catalysis to obtain 3-phenylidene-1,3-dihydro-2H-indol-2 ketone, 3-phenylidene-1,3-dihydro-2H-indol-2 ketone and Schiff base are subjected to 1,3-dipole cycloaddition reaction under catalysis of chiral ligand (S)-TF-BiphamPhos/AgoAc to obtain spiro pyrrolidine, and protecting group removal and ring closure are carried out on spiro pyrrolidine and N-(9-fluorene methoxycarbonyl)-L-prolyl chloride through base catalysis to obtain the target product. The method has the advantages of being simple in path, high in yield, high in diastereoselectivity and single in product spatial configuration, and the raw materials are low in price and easy to obtain.
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Paragraph 0040; 0043

(2017/08/28)

Total synthesis and biological evaluation of spirotryprostatin A analogs
Based on the spirotryprostatin A structure, a series of compounds belonging to spiro-indolyl diketopiperazine structural class were designed and synthesized, which embody an oxindole with an all-carbon quaternary stereocenter. The total synthesis can efficiently be accessed in a seven-step reaction sequence with 18–28% overall yield from commercially available materials, and a highly enantioselective 1,3-dipolar cycloaddition, N-acylation of the resulting stereochemically complex spiro[pyrrolidin-3,3′-oxindole]s core with Fmoc-L-pro-Cl and spontaneous ring closure upon N-deprotection were obtained. The synthesized compounds 13a–e and 15a–e were evaluated for their antibacterial activities. The result showed that compounds 13b and 15b were active only against Gram-positive bacteria, and selective antibacterial activity was exhibited by compounds 13d and 13e against Streptococcus lactis. Further, all the remaining compounds showed a certain degree of antibacterial activity. In addition, the structure–activity relationship is also discussed.
Ma, Yangmin,Fan, Chao,Jia, Bin,Cheng, Pei,Liu, Jia,Ma, Yuqiang,Qiao, Ke
p. 737 - 746
(2017/10/17)

Ferrocene-modified amino acids: synthesis and in vivo bioeffects on hippocampus
A method for the ferrocene modification of amino acids of natural and synthetic origin has been developed. In the in vivo studies, the hippocampal electrical activity under the action of ferrocenyl(phenylpyrazolyl)glycine (1) was assessed. A meaningful rise (up to 25% compared to the control) in the response amplitudes of the focal potentials of the hippocampal region СА1 after intraperitoneal administration of compound 1 at the dose of 2.0 mg kg–1 was established.
Rodionov,Snegur,Simenel,Dobryakova, Yu. V.,Markevich
p. 136 - 142
(2017/07/05)

Understanding the speciation of Ln(III) complexes with octadentate tripodal ligands
Two new dissymmetrical tripodal ligands bearing three multidentate pyridine moieties (L5 and L6) have been synthesised and the speciation of their Ln(iii) complexes in solution has been studied. The complexation behaviour with selected Ln(iii) has been investigated by combining ESMS, spectrophotometric and NMR titrations. For both ligands LX (X = 5, 6), the Ln2(LX)3 species are abundantly present at stoichiometry in the form of unconventional low-symmetrical complexes. However, the complexes with L5 at [Ln]/[L5] ～1 are much better defined and allow the corresponding 1H-NMR spectrum to be completely assigned. Indeed, the latter points out that the structure of complexes [Ln2(L5)2]6+ in solution is best described as an unsaturated dinuclear helicate, where the tridentate sites are wrapped about the metallic cations, and the bidentate strand does not coordinate. Compared to L4 and L6, the prolongation of the spacer in L5 (glycine moiety) has in fact allowed thermodynamic and kinetic stabilities to increase, especially for the Lu(iii) complexes. Finally, the structure of dinuclear species [Ln2(LX)2]6+ (X = 4-6) is apparently independent of the structure of the bidentate moieties, which are involved in complexation in metal excess only.
Aroussi, Badr El,Hamacek, Josef
p. 4390 - 4399
(2017/07/10)

Dipeptide boric acid composed of carboxylic acid and alpha-amino acid as well as ester compound thereof, and preparation method and application of dipeptide boric acid and ester compound thereof
The invention belongs to the field of drug synthesis and in particular relates to a series of novel peptide boric acids as well as an ester compound or pharmaceutical salt thereof, and a preparation method and application of the peptide boric acids as well as the ester compound or pharmaceutical salt thereof in pharmacodynamics. A structure of the peptide boric acid and the ester compound or pharmaceutical salt thereof is shown in a formula I (described in the specification). The compound provided by the invention can be used for preparing a proteasome inhibitor and can further be used for treating solid tumours and blood tumours, wherein the solid tumours are selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, gastrointestinal stromal tumor, nasopharynx cancer and leukemia; and the blood tumours are selected from multiple myeloma, mantle cell lymphoma and histiocytic lymphoma.
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Paragraph 0122; 0123; 0124; 0125; 0126

(2016/12/01)

Photo-activated CO-releasing molecules (PhotoCORMs) of robust sawhorse scaffolds [μ2-OOCR1, η1-NH2CHR2(C=O] OCH3, Ru(i)2CO4]
A class of sawhorse-type ruthenium(i) complexes featuring a stable CORM sphere with diverse carboxylic and amino acid derivatives were synthesized and validated as lead structures for photo-activated CO-releasing molecules (PhotoCORMs). The CO release of these CORMs was triggered by 365 nm UV irradiation. Cell viability studies indicated that 3a and 3f were non-toxic both in the dark and in UV light, making them excellent lead structures for therapeutic CORMs.
Yang, Shuhong,Chen, Mengjiao,Zhou, Lingling,Zhang, Guofang,Gao, Ziwei,Zhang, Weiqiang
supporting information
p. 3727 - 3733
(2016/03/05)

Role of the phenolic OH moiety of GluN2B-selective NMDA antagonists with 3-benzazepine scaffold
In order to analyze the role of the phenolic OH moiety of ifenprodil (1) and 3-benzazepin-1,7-diol 2 for the affinity and selectivity at GluN2B subunit containing NMDA receptors, the 3-benzazepin-1-ols 3 were designed, synthesized and pharmacologically evaluated and furthermore, the molecular interactions of the phenylbutyl derivative 3c with the GluN2B receptor were investigated. In order to avoid decarbonylation during the intramolecular Friedel-Crafts acylation of 11, the N-atom has to be protected with a trifluoromethylsulfonyl group. The second key step of the synthesis was the removal of the N-triflyl group, which was realized by K2CO3induced elimination of trifluoromethanelsulfinate (F3CSO2-). In receptor binding studies with the radioligand [3H]ifenprodil the 3-benzazepin-1-ol 3c revealed a GluN2B affinity of 73 nM indicating that the phenolic OH moiety of 1 and 2 is not essential but favorable for high GluN2B affinity. In docking studies 3-benzazepin-1-ol 3c shows the same binding pose as ifenprodil-keto 1A in the X-ray crystal structure. H-bond interactions and lipophilic interactions of 3c and 1A are very similar.
Dey, Sougata,Schepmann, Dirk,Wünsch, Bernhard
supporting information
p. 889 - 893
(2016/05/24)

Phosphoramidate protides of five flavones and their antiproliferative activity against HepG2 and L-O2 cell lines
A series of flavone-7-phosphoramidate derivatives were synthesized and tested for their antiproliferative activity in vitro against human hepatoma cell line HepG2 and human normal hepatic cell line L-O2. Compound 8d, 16d and 17d, incorporating the amino acid alanine, exhibited high inhibitory activity on HepG2 cell line with IC50 values of 9.0 μmol/L, 5.5 μmol/L and 6.6 μmol/L. The introduction of acyl groups played a pivotal role in the selective inhibition toward human hepatoma HepG2 cells, except for compound 8a, 9a and 16b. Compound 8d, 16d and 17d could significantly induce G2/M arrest in HepG2 cells. Specially, Compound 16d could lead early apoptosis in HepG2 cells.
Li, Yue-Qing,Yang, Fei,Wang, Liu,Cao, Zhi,Han, Tian-Jiao,Duan, Zhe-Ang,Li, Zhen,Zhao, Wei-Jie
p. 196 - 208
(2016/05/02)

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
p. 542 - 555
(2016/10/06)

Oxiracetam synthesis technology
The invention belongs to the field of pharmaceutical chemicals and particularly relates to an oxiracetam synthesis technology, ethyl acetoacetate and glycine are taken as the raw materials, the ethyl acetoacetate is changed into 4-halogeneated ethyl acetoacetate by halogenation reaction, the 4-halogeneated ethyl acetoacetate and glycine ester formed by the glycine are cyclized to form 2,4-dioxo-1-pyrrolidine acetate, and 4-hydroxy-2-oxo-1-pyrrolidineacetamide is obtained after hydrolysis and aminolysis. According to the oxiracetam synthesis technology, the related raw materials are easy to obtain, and the synthesis technology is simple and has good industrial values.
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Paragraph 0032

(2017/02/28)

INHIBITORS OF HEPATITIS C VIRUS POLYMERASE
The present invention provides, among other things, compounds represented by the general Formula I: (I) and pharmaceutically acceptable salts thereof, wherein L and A (and further substituents) are as defined in classes and subclasses herein and compositions (e.g., pharmaceutical compositions) comprising such compounds, which compounds are useful as inhibitors of hepatitis C virus polymerase, and thus are useful, for example, as medicaments for the treatment of HCV infection.
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Paragraph 401; 409

(2016/10/11)

Synthesis and biological evaluation of novel phosphoramidate derivatives of coumarin as chitin synthase inhibitors and antifungal agents
A series of novel phosphoramidate derivatives of coumarin have been designed and synthesized as chitin synthase (CHS) inhibitors. All the synthesized compounds have been screened for their chitin synthase inhibition activity and antimicrobial activity in vitro. The bioactive assay manifested that most of the target compounds exhibited good efficacy against CHS and a variety of clinically important fungal pathogens. In particular, compound 7t with IC50 of 0.08 mM against CHS displayed stronger efficiency than the reference Polyoxin B with IC50 of 0.16 mM. In addition, the apparent Ki values of compound 7t was 0.096 mM while the Km of Chitin synthase prepared from Candida tropicalis was 3.86 mM for UDP-Nacetylglucosamine, and the result of the Ki showed that the compounds was a non-competitive inhibitor of the CHS. As far as the antifungal activity is concerned, compounds 7o, 7r and 7t were highly active against Aspergillus flavus with MIC values in the range of 1 μg/mL to 2 μg/Ml while the results of antibacterial screening showed that these compounds have negligible actions to the tested bacteria. These results indicated that the design of these compounds as antifungal agents was rational.
Ji, Qinggang,Ge, Zhiqiang,Ge, Zhixing,Chen, Kaizhi,Wu, Hualong,Liu, Xiaofei,Huang, Yanrong,Yuan, Lvjiang,Yang, Xiaolan,Liao, Fei
p. 166 - 176
(2015/12/04)

Catalysts and temperature driven melt polycondensation reaction for helical poly(ester-urethane)s based on natural L-amino acids
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
p. 1065 - 1077
(2016/03/12)

γ-Glutamyl-dipeptides: Easy tools to rapidly probe the stereoelectronic properties of the ionotropic glutamate receptor binding pocket
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
p. 8486 - 8492
(2016/11/28)

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
supporting information
p. 1185 - 1190
(2016/12/18)