- NOVEL PROCESS FOR PREPARING SOLRIAMFETOL HYDROCHLORIDE
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The present invention concerns a novel process for preparing solriamfetol hydrochloride.
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- Peptidotriazolamers Inhibit Aβ(1–42) Oligomerization and Cross a Blood-Brain-Barrier Model
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In peptidotriazolamers every second peptide bond is replaced by a 1H-1,2,3-triazole. Such foldamers are expected to bridge the gap in molecular weight between small-molecule drugs and protein-based drugs. Amyloid β (Aβ) aggregates play an important role in Alzheimer's disease. We studied the impact of amide bond replacements by 1,4-disubstituted 1H-1,2,3-triazoles on the inhibitory activity of the aggregation “hot spots” K16LVFF20 and G39VVIA42 in Aβ(1–42). We found that peptidotriazolamers act as modulators of the Aβ(1–42) oligomerization. Some peptidotriazolamers are able to interfere with the formation of toxic early Aβ oligomers, depending on the position of the triazoles, which is also supported by computational studies. Preliminary in vitro results demonstrate that a highly active peptidotriazolamer is also able to cross the blood-brain-barrier.
- Tonali, Nicolo,Hericks, Loreen,Schr?der, David C.,Kracker, Oliver,Krzemieniecki, Rados?aw,Kaffy, Julia,Le Joncour, Vadim,Laakkonen, Pirjo,Marion, Antoine,Ongeri, Sandrine,Dodero, Veronica I.,Sewald, Norbert
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p. 840 - 851
(2021/05/05)
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- PROCESS FOR PREPARATION OF SOLRIAMFETOL AND INTERMEDIATES THEREOF
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The present invention relates to a process for the preparation of dopamine and norepinephrine reuptake inhibitor (DNRI) compound Solriamfetol and pharmaceutically acceptable salts thereof, having the chemical name (R)-2-amino- 3-phenylpropyl carbamate (APC) by using novel intermediates. (I)
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Page/Page column 2; 8
(2021/08/20)
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- Enantioselective Rh-Catalyzed Hydroboration of Silyl Enol Ethers
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The asymmetric hydroboration of alkenes has proven to be among the most powerful methods for the synthesis of chiral boron compounds. This protocol is well suitable for activated alkenes such as vinylarenes and alkenes bearing directing groups. However, the catalytic enantioselective hydroboration of O-substituted alkenes has remained unprecedented. Here we report a Rh-catalyzed enantioselective hydroboration of silyl enol ethers (SEEs) that utilizes two new chiral phosphine ligands we developed. This approach features mild reaction conditions and a broad substrate scope as well as excellent functional group tolerance, and enables highly efficient preparation of synthetically valuable chiral borylethers.
- Dong, Wenke,Lei, Yaqin,Lin, Zhenyang,Ma, Honghui,Xu, Xin,Zhao, Wanxiang
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p. 10902 - 10909
(2021/07/31)
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- Direct Access to Primary Amines from Alkenes by Selective Metal-Free Hydroamination
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Direct and selective synthesis of primary amines from easily available precursors is attractive yet challenging. Herein, we report the rapid synthesis of primary amines from alkenes via metal-free regioselective hydroamination at room temperature. Ammonium carbonate was used as ammonia surrogate for the first time, allowing for efficient conversion of terminal and internal alkenes into linear, α-branched, and α-tertiary primary amines under mild conditions. This method provides a straightforward and powerful approach to a wide spectrum of advanced, highly functionalized primary amines which are of particular interest in pharmaceutical chemistry and other areas.
- Du, Yi-Dan,Chen, Bi-Hong,Shu, Wei
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supporting information
p. 9875 - 9880
(2021/03/29)
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- Auxiliary-controlled diastereoselective synthesis of a syn C-6-epimer of the ADAM 10 inhibitor GI254023X
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ADAM10 is a cell surface-expressed metalloprotease involved in various cell adhesion and proteolytic processes, in which biological studies have linked an over-expression of ADAM10 to the development and progression of various types of diseases including cancer. GI254023X is a hydroxamate metalloprotease inhibitor known for ADAM10 activity inhibition, but for which structure-activity based biological information for assessing anti-tumour and anti-inflammatory activity is lacking. In this work, an Evans’ asymmetric boron aldol reaction was used to synthesise a syn C-6-epimer of GI254023X intended for biological evaluation against the natural inhibitor.
- Nair, Shankari,Zeevaart, Jan Rijn,Hunter, Roger
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- Towards the Sarpagine-Ajmaline-Macroline Family of Indole Alkaloids: Enantioselective Synthesis of an N-Demethyl Alstolactone Diastereomer
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the strategy involving the use of functionalized tetrahydro-6H-cycloocta[b]indol-6-one is reported as a key intermediate for synthesis of members of the sarpagine-ajmaline-macroline family of monoterpene indole alkaloids. The desired tricycle was synthesized through the following key steps: 1) Evans’ syn-selective aldolization; 2) Liebeskind–Srogl cross-coupling using the phenylthiol ester of 3-chloropropanoic acid as a surrogate of acrylic thioester for the synthesis of 2,3-disubstituted indoles; and 3) ring-closing metathesis (RCM) for the formation of the eight-membered ring. An N-allylation followed by intramolecular 1,4-addition was planned for synthesis of the vobasine class of natural products. However, attempted cyclizations under a diverse set of conditions involving anionic, radical, and organopalladium/organonickel species failed to produce the bridged ring system. On the other hand, esterification of the pendant primary alcohol function with acetoacetic acid, followed by intramolecular Michael addition, afforded the desired tetracycle with excellent diastereoselectivity. Subsequent functional group manipulation and transannular cyclization of the amino alcohol afforded the N(1)-demethyl-3,5-diepi-alstolactone. We believe that the same synthetic route would afford the alstolactone should the amino alcohol with appropriate stereochemistry be used as the starting material.
- Dagoneau, Dylan,Wang, Qian,Zhu, Jieping
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supporting information
p. 4866 - 4873
(2020/04/15)
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- Benzphetamine hydrochloride preparation method
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The invention relates to the field of chemical pharmacy, particularly to a benzphetamine hydrochloride preparation method. According to the invention, the method avoids the use of ephedrine, pseudoephedrine, deoxyephedrine and other management and control products, has characteristics of inexpensive and easily-available raw materials and synthesis cost reducing, can obtain the high-purity target compound at high yield, and is suitable for industrial large-scale production.
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Paragraph 0090; 0091; 0092; 0093; 0094; 0095; 0096
(2020/01/25)
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- Copper(I) Phosphinooxazoline Complexes: Impact of the Ligand Substitution and Steric Demand on the Electrochemical and Photophysical Properties
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A series of seven homoleptic CuI complexes based on hetero-bidentate P^N ligands was synthesized and comprehensively characterized. In order to study structure–property relationships, the type, size, number and configuration of substituents at the phosphinooxazoline (phox) ligands were systematically varied. To this end, a combination of X-ray diffraction, NMR spectroscopy, steady-state absorption and emission spectroscopy, time-resolved emission spectroscopy, quenching experiments and cyclic voltammetry was used to assess the photophysical and electrochemical properties. Furthermore, time-dependent density functional theory calculations were applied to also analyze the excited state structures and characteristics. Surprisingly, a strong dependency on the chirality of the respective P^N ligand was found, whereas the specific kind and size of the different substituents has only a minor impact on the properties in solution. Most importantly, all complexes except C3 are photostable in solution and show fully reversible redox processes. Sacrificial reductants were applied to demonstrate a successful electron transfer upon light irradiation. These properties render this class of photosensitizers as potential candidates for solar energy conversion issues.
- Frey, Wolfgang,Giereth, Robin,Karnahl, Michael,Klo?, Marvin,Mengele, Alexander K.,Steffen, Andreas,Tschierlei, Stefanie
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p. 2675 - 2684
(2020/03/04)
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- Preparation method of benzphetamine hydrochloride
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The invention relates to the field of chemical pharmacy, and in particular relates to a preparation method of benzphetamine hydrochloride. According to the method, the use of controlled products suchas ephedrine, pseudoephedrine, deoxyephedrine and the like is avoided; the raw materials are cheap and easy to obtain, so that the synthesis cost is reduced; by using the preparation method disclosedby the invention, the high-purity target compound can be obtained at high yield, and industrial large-scale production is easy.
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Paragraph 0071; 0073-0079
(2020/01/25)
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- Synthesis method of (D)-2-benzyl-N,N-dimethylaziridine-1-sulfonamide
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The invention discloses a synthesis method of (D)-2-benzyl-N,N-dimethylaziridine-1-sulfonamide, which comprises the following steps: a. reducing D-phenylalanine to obtain D-phenylalaninol, b. performing esterification and ring-closing reactions on the D-phenylalaninol to obtain (D)-2-benzyl-N,N-dimethylaziridine; and c. carrying out a reaction on the (D)-2-benzyl-N,N-dimethylaziridine with dimethylamino sulfonyl chloride to generate the (D)-2-benzyl-N,N-dimethyl aziridine-1-sulfonamide. The product has high content and purity, enhances the yield of industrial production, shortens the half timeof industrial production, and effectively considers the problems of environmental protection, cost and yield.
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Paragraph 0004; 0010-0014
(2020/08/27)
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- Nucleophilic RhI Catalyzed Selective Isomerization of Terminal Aziridines to Enamides
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The selective isomerization of various terminal N-Boc protected aziridines to enamides was realized using the highly reactive nucleophilic rhodium catalyst C with the Lewis acid LiNTf2 as co-catalyst under moderate conditions. The reaction proceeds smoothly with only 1 molpercent catalyst loading and excellent yields were achieved. An intermediate containing an enamide with a non-conjugated terminal C=C double bond was detected during the course of the reaction, which isomerizes to form the thermodynamically favored 2-amido styrene. Mechanistic insight is gained based on these observations.
- Tian, Yingying,Kunz, Doris
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p. 4272 - 4275
(2020/07/04)
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- Chiral alpha-amido aldehyde and preparation method thereof
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The invention relates to chiral alpha-amido aldehyde and a preparation method thereof. The method comprises the following steps that alpha-dehydroamido aldehyde shown in the following general formula(1) and hydrogen carry out a reduction reaction in an organic solvent under the catalytic action of a diphosphine-rhodium complex, and a chiral alpha-amido aldehyde compound shown in the following general formula (2) is obtained. The synthetic route adopts an asymmetric catalytic hydrogenation method, the process is simple, efficient and green, and the method is very suitable for industrial mass production. The product chiral amido aldehyde can be further derived into a chiral ligand and a chiral drug intermediate.
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- Nickel-Catalyzed Asymmetric Hydrogenation of 2-Amidoacrylates
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Earth-abundant nickel, coordinated with a suitable chiral bisphosphine ligand, was found to be an efficient catalyst for the asymmetric hydrogenation of 2-amidoacrylates, affording the chiral α-amino acid esters in quantitative yields and excellent enantioselectivity (up to 96 % ee). The active catalyst component was studied by NMR and HRMS, which helped us to realize high catalytic efficiency on a gram scale with a low catalyst loading (S/C=2000). The hydrogenated products could be simply converted into chiral α-amino acids, β-amino alcohols, and their bioactive derivatives. Furthermore, the catalytic mechanism was investigated using deuterium-labeling experiments and computational calculations.
- Chen, Jianzhong,Gridnev, Ilya D.,Hu, Yawen,Li, Bowen,Zhang, Wanbin,Zhang, Zhenfeng
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supporting information
p. 5371 - 5375
(2020/02/15)
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- PROCESS FOR THE PREPARATION OF SOLRIAMFETOL AND SALT THEREOF
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The present invention relates to solriamfetol or novel salts thereof and its process for preparation. More particularly the present invention relates to solriamfetol dibenzoyl-D-tartaric acid salt or solriamfetol di-p-toluoyl-D-tartaric acid salt and their process for preparation. Further the present invention relates to use of solriamfetol dibenzoyl-D-tartaric acid salt or solriamfetol di-p-toluoyl-D-tartaric acid salt for the preparation of solriamfetol hydrochloride.
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Page/Page column 17; 20-21
(2020/03/05)
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- Discovery of a novel cathepsin inhibitor with dual autophagy-inducing and metastasis-inhibiting effects on breast cancer cells
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Drug resistance and cancer cells metastasis have been the leading causes of chemotherapy failure and cancer-associated death in breast cancer patients. In present, various active molecules either exhibiting novel mechanism of action such as inducing autophagy or inhibiting metastasis have been developed to address these problems. However, the compounds exhibiting such dual functions have rarely been described. Previous work in our group showed that TSA, as a synthetic analog of asperphenamate, induced autophagic cell death in breast cancer cells instead of apoptosis. Furthermore, the target enzyme of TSA was predicted to be cathepin L (Cat L) by natural product consensus pharmacophore strategy. Accumulated evidences have shown that cathepsins are closely associated with migration and invasion of breast cancer cells. It seemed likely that TSA-like molecules may possess the dual functions of inducing autophagy and inhibiting metastasis. Therefore, sixty optically active derivatives were firstly designed and synthesized by replacing the A-ring moiety of TSA with other substituted-phenyl sulfonyl groups. Further cathepsin inhibitory activity assay showed that (S, S) and (S, R) isomers displayed no activity against four kinds of cathepsins (L, S, K, B), while all derivatives tested were inactive toward K and B subtypes. Compound 6a with meta-bromo substituent displayed the greatest inhibitory activity, and its inhibitory capability against Cat L and S was 3.9 and 11.5-fold more potent than that of TSA, respectively. Molecular docking also exhibited that 6a formed more hydrogen bonds or π-π contacts with Cat L or S than TSA. In order to determine whether 6a could play dual roles, its anti-cancer mechanism was further investigated. On the one hand, MDC staining experiment and western blotting analysis validated that 6a can induce autophagy in MDA-MB-231 cells. On the other hand, its metastatic inhibitory ability was also confirmed by wound healing and transwell chamber experiment.
- Yuan, Lei,Liu, Jun,He, Wenhui,Bao, Youmei,Sheng, Lei,Zou, Chunyang,Hu, Baichun,Ge, Wentao,Liu, Yang,Wang, Jian,Lin, Bin,Li, Yanchun,Ma, Enlong
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p. 239 - 253
(2018/12/04)
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- Synthesis of a diastereomer of the marine macrolide lytophilippine A
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The synthesis of a diastereomer of lytophilippine A required 22 longest linear steps using known building blocks. Cross-metathesis/asymmetric aldol addition and regioselective esterification/ring-closing metathesis served as efficient combi tools for scaffold construction. Detailed NMR investigations in different solvent (systems) provide evidence for a deep-seated configurational misassignment of the molecule named lytophilippine A.
- Klüppel, André,Gille, Annika,Karayel, Ceren Ester,Hiersemann, Martin
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supporting information
p. 2421 - 2425
(2019/03/29)
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- Chemo- and Enantioselective Hydrogenation of α-Formyl Enamides: An Efficient Access to Chiral α-Amido Aldehydes
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In order to effectively synthesize chiral α-amino aldehydes, which have a wide range of potential applications in organic synthesis and medicinal chemistry, a highly chemo- and enantioselective hydrogenation of α-formyl enamides has been developed, catalyzed by a rhodium complex of a P-stereogenic bisphosphine ligand. Under different hydrogen pressures, the chiral α-amido aldehydes and β-amido alcohols were obtained in high yields (97–99 %) and with excellent chemo- and enantioselectivities (up to >99.9 % ee). The hydrogenation can be carried out on a gram scale and with a high substrate/catalyst ratio (up to 20 000 S/C), and the hydrogenated products were further converted into several important chiral products. Computations of the catalytic cycle gave a clear description for the R/S pathways, provided a reasonable explanation for the enantioselectivity, and revealed several other specific features.
- Zhang, Jian,Jia, Jia,Zeng, Xincheng,Wang, Yuanhao,Zhang, Zhenfeng,Gridnev, Ilya D.,Zhang, Wanbin
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p. 11505 - 11512
(2019/07/17)
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- Highly Efficient and Robust Enantioselective Liquid–Liquid Extraction of 1,2-Amino Alcohols utilizing VAPOL- and VANOL-based Phosphoric Acid Hosts
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The large-scale production of enantiopure compounds in a cost-effective and environmentally friendly manner remains one of the major challenges of modern-day chemistry. The resolution of racemates through enantioselective liquid–liquid extraction was developed as a suitable solution but has remained largely underused, owing to a lack of highly efficient and robust chiral hosts to mediate the process. This paucity of hosts can in part be attributed to a poor understanding of the underlying principles behind these processes hindering the design of more efficient selectors. A previously untested class of hosts, VAPOL and VANOL derived phosphoric acids, has been studied in depth for the efficient enantioselective liquid–liquid extraction of 1,2-amino alcohols. A systematic investigation of extraction parameters was conducted, revealing many key interactions and DFT calculations illustrate the binding modes for the 1:1 complexes that are involved in chiral recognition. The resulting, now-optimized, procedures are highly robust and easy to implement. They are also easily scalable, as demonstrated by U-tube experiments.
- Pinxterhuis, Erik B.,Gualtierotti, Jean-Baptiste,Wezenberg, Sander J.,de Vries, Johannes G.,Feringa, Ben L.
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p. 178 - 184
(2017/12/15)
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- Access towards enantiopure α,α-difluoromethyl alcohols by means of sulfoxides as traceless chiral auxiliaries
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A new methodology to access enantiopure α,α-difluoromethyl alcohols is hereby being described. The strategy relies on the use of an enantiopure aryl α,α-difluoromethyl sulfoxide employed as chiral and removable auxiliary for the stereoselective difluoromethylation of carbonyl derivatives. The obtained α,α-difluoro-β-hydroxysulfoxides displayed unprecedented diastereomeric ratios.
- Batisse, Chloé,Panossian, Armen,Hanquet, Gilles,Leroux, Frédéric R.
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supporting information
p. 10423 - 10426
(2018/09/21)
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- Polyether urea bridged chiral molecular tweezers and preparation and application thereof
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The invention discloses polyether urea bridged chiral molecular tweezers and preparation and application thereof. The polyether urea bridged chiral molecular tweezers are structurally shown as formula(I) or formula (II) shown in the description. The invention also provides application of the polyether urea bridged chiral molecular tweezers in the recognition of a chiral molecular guest; the chiral molecular guest is D/L-amino acid ester hydrochloride. The polyether urea bridged chiral molecular tweezers synthesized herein have certain property of chirally recognizing D/L-amino acid ester hydrochloride and are applicable to chiral recognition and separation of enantiomers.
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Paragraph 0032; 0033
(2018/11/22)
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- Thiourea polyether bridged chiral molecular tweezer and preparation and application thereof
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The invention discloses a thiourea polyether bridged chiral molecular tweezer and a preparation and an application thereof. The thiourea polyether bridged chiral molecular tweezer takes a thiourea polyether chain as a linking group, and the ent-beyerane skeleton is taken as a chiral arm, and a structure is as shown in a formula (I) or a formula (II). The present invention provides the applicationof the thiourea polyether bridged chiral molecular tweezer for identifying a chiral molecular object, wherein the chiral molecular object is D/L-amino acid ester hydrochloride. The synthesized molecular tweezer has certain chiral recognition performance for D/L-amino-acid ester hydrochloride, and can be used for chiral recognition and separation of enantiomers.
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Paragraph 0037-0038
(2019/01/08)
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- Regioselective Fluorination of α-Hydroxy-β-aminophosphonates by Using PyFluor
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We report a simple protocol for the synthesis of α-fluoro-β-aminophosphonates by the regioselective fluorination of α-hydroxy-β-aminophosphonates under mild conditions. The fluorination reactions were mediated by the PyFluor reagent and occurred with the retention of configuration. The main products of this reaction were a series of α-fluoro-β-aminophosphonates, which can be used as precursors in the preparation of medicinally important compounds (e.g., dipeptide analogues).
- Ka?mierczak, Marcin,Kubicki, Maciej,Koroniak, Henryk
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p. 3844 - 3852
(2018/07/31)
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- Highly efficient enantioselective liquid-liquid extraction of 1,2-amino-alcohols using SPINOL based phosphoric acid hosts
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Access to enantiopure compounds on large scale in an environmentally friendly and cost-efficient manner remains one of the greatest challenges in chemistry. Resolution of racemates using enantioselective liquid-liquid extraction has great potential to meet that challenge. However, a relatively feeble understanding of the chemical principles and physical properties behind this technique has hampered the development of hosts possessing sufficient resolving power for their application to large scale processes. Herein we present, employing the previously untested SPINOL based phosphoric acids host family, an in depths study of the parameters affecting the efficiency of the resolution of amino-alcohols in the optic of further understanding the core principles behind ELLE. We have systematically investigated the dependencies of the enantioselection by parameters such as the choice of solvent, the temperature, as well as the pH and bring to light many previously unsuspected and highly intriguing interactions. Furthermore, utilizing these new insights to our advantage, we developed novel, highly efficient, extraction and resolving protocols which provide remarkable levels of enantioselectivity. It was shown that the extraction is catalytic in host by demonstrating transport in a U-tube and finally it was demonstrated how the solvent dependency could be exploited in an unprecedented triphasic resolution system.
- Pinxterhuis, Erik B.,Gualtierotti, Jean-Baptiste,Heeres, Hero J.,De Vries, Johannes G.,Feringa, Ben L.
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p. 6409 - 6418
(2017/08/29)
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- Ligand, metal complex containing ligand, and reaction using metal complex containing ligand
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A hydrogen transfer reaction may be more efficiently promoted by using a metal complex represented by Formula (2): (wherein, R1 to R8 are the same or different, and each represents a hydrogen atom, a substituted or unsubstituted alkyl group or the like; or wherein; R1 and R2, R2 and R3, R3 and R4, R4 and R5, and R5 and R6 are respectively bonded to each other to form a bivalent hydrocarbon group; R9 are the same or different, and each represents an alkyl group or cycloalkyl group; M is ruthenium (Ru) or the like; X is a ligand; and n is 0, 1 or 2). More specifically, the metal complex enables a hydrogenation reaction of various substrates having a stable carbonyl group or the like to be advanced with a high yield under mild conditions.
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Page/Page column 46-50
(2016/10/31)
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- Design, synthesis and biological evaluation of novel asperphenamate derivatives
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A series of novel asperphenamate derivatives were designed and synthesized, including series I (the A-phenyl group replaced with various aromatic heterocycles) and series II (the acyl group substituted by sulfonyl group). All compounds have been screened for their antiproliferative activity in vitro against MCF-7, HeLa, and BEL-7402 cell lines by the standard MTT method. Structure-activity relationship studies displayed the heterocycle type played an important role in activity. Six-membered ring derivatives displayed more potency than five-membered ring and the sulfonyl group in A-ring region made an important contribution to activity. Among all derivatives, tosyl derivative 8c exhibited the greatest potency in three human cancer cell lines. Especially in MCF-7 cells, the cellular potency of 8c was approximately 3.0-fold more potent than that of cisplatin. Firstly, the mechanism of cell death induced by 8c in MCF-7 cells was investigated. The results showed that the cell death was induced by autophagy instead of apoptosis or cell cycle arrest. Further studies indicated that 8c might induce autophagic cell death in HeLa and BEL-7402 cell lines.
- Liu, Qingyin,Li, Wei,Sheng, Lei,Zou, Chunyang,Sun, Hongxin,Zhang, Chunfeng,Liu, Yang,Shi, Jiyue,Ma, Enlong,Yuan, Lei
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-
- PRODUCTION METHOD FOR COMPOUND COMPRISING AMINO GROUP AND/OR HYDROXYL GROUP
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Disclosed is a method for producing a compound having an amino group and/or a hydroxyl group from a substrate compound having an atomic group containing CO or CS by eliminating said atomic group. The substrate compound having an atomic group containing CO or CS (for example, an amide, a carbamate, or the like) is allowed to react with a compound expressed by formula (I) below, at a temperature of 120°C or lower, preferably in the presence of an ammonium salt, to eliminate said atomic group containing CO or CS. In formula (I) A may not be present, and in a case where A is present, A represents an alkyl group having 1 to 6 carbon atoms. ????????H2N-A-NH2?????(I)
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Paragraph 0092
(2015/01/18)
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- Enantioselective synthesis of putative lipiarmycin aglycon related to fidaxomicin/tiacumicin B
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An enantioselective synthesis of a putative lipiarmycin aglycon was accomplished and features: 1) Brown's enantioselective alkoxyallylboration and allylation of aldehydes, 2) chain elongation by iterative Horner-Wadsworth-Emmons olefination, 3) Evans' aldol reaction and 4) an enediene ring-closing metathesis. A neighboring-group-assisted chemoselective reductive desilylation was uncovered in this study and was instrumental to the realization of the present synthesis.
- Erb, William,Grassot, Jean-Marie,Linder, David,Neuville, Luc,Zhu, Jieping
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supporting information
p. 1929 - 1932
(2015/02/19)
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- Docking model of the nicotinic acetylcholine receptor and nitromethylene neonicotinoid derivatives with a longer chiral substituent and their biological activities
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In the present study, nitromethylene neonicotinoid derivatives possessing substituents that contain a sulfur atom, oxygen atom or aromatic ring at position 5 on the imidazolidine ring were synthesized to evaluate their affinity for the nicotinic acetylcholine receptor (nAChR) and their insecticidal activity against adult female houseflies. Comparing the receptor affinity of the alkylated derivative with the receptor affinity of compounds possessing either ether or thioether groups revealed that conversion of the carbon atom to a sulfur atom did not influence the receptor affinity, whereas conversion to an oxygen atom was disadvantageous for the receptor affinity. The receptor affinity of compounds possessing a benzyl or phenyl group was lower than that of the unsubstituted compound. Analysis of the three-dimensional quantitative structure-activity relationship using comparative molecular field analysis demonstrated that steric hindrance of the receptor should exist around the C3 of an n-butyl group attached at position 5 on the imidazolidine ring. A docking study of the nAChR-ligand model suggested that the ligand-binding region expands as the length of the substituent increases by brushing against the amino acids that form the binding region. The insecticidal activity of the compounds was positively correlated with the receptor affinity by considering log P and the number of heteroatoms, including sulfur and oxygen atoms, in the substituents, suggesting that the insecticidal activity is influenced by the receptor affinity, hydrophobicity, and metabolic stability of the compounds.
- Nagaoka, Hikaru,Nishiwaki, Hisashi,Kubo, Takuya,Akamatsu, Miki,Yamauchi, Satoshi,Shuto, Yoshihiro
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p. 759 - 769
(2015/02/19)
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- Probing o-diphenylphosphanyl benzoate (o-DPPB)-directed C - C bond formation: Total synthesis of dictyostatin
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Herein, we report a robust total synthesis of dictyostatin. This polyketide natural product has attracted much attention because of its impressive antiproliferative activity against several human cancer-cell lines. We accomplished its synthesis in a highly convergent manner from three fragments of equal complexity, which were prepared on multigram scale. The southern and northwestern subunits were constructed through application of our o-DPPB-directed hydroformylation and allylic substitution methodology, respectively. These methods generated the C6 and C14 stereocenters of dictyostatin with good diastereoselectivities and simultaneously allowed further elaboration of the fragments by Wittig olefination and Sharpless asymmetric epoxidation, respectively. The compelling performance of the hydroformylation and allylic substitution with regard to practicability, selectivity, and scale underline their value for the construction of propionate motifs.
- Wünsch, Sebastian,Breit, Bernhard
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supporting information
p. 2358 - 2363
(2015/02/05)
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- N-substituted benzenepropanamide or benzenepropenamide derivatives for use in the treatment of pain and inflammation
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Compounds for use in the treatment or prophylaxis of pain, including acute and chronic pain (e.g., nociceptive pain, neuropathic pain, headaches, migraine), represented by general formula (I) in which: the dotted line represents a single or a double bond; and R5 and R5′ are independently —H, —OH or —OR6, where R6 is a linear or branched C1-C4 alkyl; X is -0-, —CH2O—, —CH2CH2O—, —CH(CH3)CH2O— or —CH2CH(CH3)O—; Z is —CH2CH2O—, —CH(CH3)CH2O— or —CH2CH(CH3)O—; m is an integer of O or 1; and n is an integer of 0-50. The compounds of the invention are also effective for reducing inflammation and may be used alone or in combination with other analgesics.
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Page/Page column 8; 9
(2015/12/17)
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- Total synthesis and structural validation of cyclodepsipeptides solonamide A and B
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Microorganisms are an attractive source of new natural products with antimicrobial properties, and the marine environment constitutes a prolific resource of bioactive microorganisms. During a global research expedition (Galathea III), two depsipeptides, solonamide A and solonamide B, were isolated from the marine bacterium Photobacterium halotolerance and were found to inhibit virulence gene expression in the serious human pathogen, Staphylococcus aureus. They act by interfering with the agr quorum sensing system and show resemblance to the endogenous S. aureus quorum sensing peptide, autoinducing peptide I (AIP-I). To enable more comprehensive studies, we embarked on the chemical synthesis of solonamides A and B. The key synthetic steps were formation of the (R)-β-hydroxy-fatty-acids by stereo-selective aldol reactions and a cyclative macrolactamization, which proceeded under highly dilute conditions. Thus, the first total syntheses of the solonamides corroborated the originally assigned structures, and by changing the stereochemistry of the auxiliary in the aldol steps we gained access to the natural products as well as their β3-epimers.
- Kitir, Betül,Baldry, Mara,Ingmer, Hanne,Olsen, Christian A.
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p. 7721 - 7732
(2014/12/10)
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- Catalytic anions embedded into avidin: Importance of their chirality and the chiral environment on the stereocontrol of the aldol reaction
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Several catalytic anions bearing a pseudo-dipeptide scaffold, in combination with a biotinylated imidazolium cation, were prepared. The assembly of these salts with avidin resulted in the formation of stable biohybrid catalysts, active in ionic liquid/aqueous media for the aldol reaction. By using natural and non-natural amino alcohols as "side chains" for the proline derivative anion, we studied the cooperativity between the anion and its position in avidin. Taking advantage of the large freedom of movement of the anion inside avidin, we also investigated the substrate scope of this type of biohybrid catalyst.
- Gauchot, Vincent,Schmitzer, Andreea R.
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p. 2694 - 2701
(2014/04/17)
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- Synthesis of salicylic acid-based 1,3,4-oxadiazole derivatives coupled with chiral oxazolidinones: Novel hybrid heterocycles as antitumor agents
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A series of novel salicylic acid-based 1,3,4-oxadiazoles derivatives coupled with chiral oxazolidinones were synthesized to screen for their in vitro antitumor activity against five human cancer cell lines. Some of these compounds showed good antitumor activities with IC50values ranging from 31.19-57.21 μM. Among the tested compounds 11, 15, 19,23,24, and 34 showed broad-spectrum antitumor activity against all the cell lines. In particular, compound 19 revealed remarkable antitumor activity with IC50 = 31.19-41.87 μM. A431 was the most sensitive cell line against all the compounds studied, followed by HeLa, MCF-7, A549 and HepG2. Structures of newly synthesized compounds were confirmed by IR,1 H NMR, 13C NMR and HRMS spectral data
- Murty,Penthala, Raju,Nath, Lekshmi R.,Anto, Ruby John
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p. 1133 - 1142
(2015/03/31)
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- N-Substituted Benzenepropanamide and Benzenepropenamide For Use in the Prevention or the Treatment of Affective Disorders
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Compounds for use in the treatment or prophylaxis of an affective disorder, which compound is represented by formula I in which the dotted line represents a single or a double bond; and R5 and R5′ are independently —H, —OH or —OR6, where R6 is a linear or branched C1-C4 alkyl; X is —CH2O—; Z is —CH2OH2O—, —CH(CH3)CH2O— or —CH2CH(CH3)O—; m is 1; and n is an integer of 1-5; or a pharmaceutically acceptable salt, prodrug, metabolite, or hydrate thereof.
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Paragraph 0081-0084
(2014/09/30)
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- Bis(amidate)bis(amido) titanium complex: A regioselective intermolecular alkyne hydroamination catalyst
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An efficient and selective bis(amidate)bis(amido) titanium precatalyst for the anti-Markovnikov hydroamination of alkynes is reported. Hydroamination of terminal and internal alkynes with primary alkylamines, arylamines, and hydrazines is promoted by 5-10 mol % of Ti catalyst. Various functional groups are tolerated including esters, protected alcohols, and imines. The in situ generated complex shows comparable catalytic activity, demonstrating its synthetic versatility for benchtop application. Applications of this catalyst for the synthesis of amino alcohols and a one-pot procedure for indole synthesis are described. A mechanistic proposal that invokes turnover-limiting protonolysis is presented to rationalize the observed regioselectivities.
- Yim, Jacky C.-H.,Bexrud, Jason A.,Ayinla, Rashidat O.,Leitch, David C.,Schafer, Laurel L.
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p. 2015 - 2028
(2014/04/03)
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- A homogeneous chiral manganese(III)-salphe catalyst for enantioselective epoxidation of olefins
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A new chiral Mn(III)-Salphe catalyst was synthesized from natural amino acid (R)-phenylalanine and 3,5-di-tert-butyl-hydroxybenzaldehyde and applied to the asymmetric epoxidations of unfunctionalized olefins in ionic liquids. Satisfactory enantioselectivities (79% 4O Ac was unnecessary. We proposed that alcoholic hydroxyls in the Mn(III)-Salphe compound played the role of axial ligand. However, the reaction time was longer than when using Jacobsen's catalyst because of the structure of the Mn(III)-Salphe compound, in which coordination geometries by the two alcoholic hydroxyls with certain angles affected the substrate approaching the Mn(V) = 0 center. The chiral ligand was characterized by the combination of infrared, ultraviolet, and visible spectra and 1H NMR. Copyright
- Wei, Saili,Tang, Yuhai,Zhao, Ruiqin,Xu, Xiaoqian,Xu, Guojin,Yu, Yong,Zheng, Yuansuo
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p. 2134 - 2146
(2013/07/25)
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- Tunable ferrocenyl-phosphinite ligands for the ruthenium(II)-catalyzed asymmetric transfer hydrogenation of ketones
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We report here new examples of enantiomerically pure monodendate phosphinite ligands containing both a ferrocene moiety and NH bridging moiety adjacent to the stereocenter, as well as their ruthenium(II) dichloro complexes. The phosphinites based on ferrocenyl moiety possessing stereogenic center have been screened as ligands for ruthenium(II)-catalyzed transfer hydrogenation of aromatic ketones to give corresponding secondary alcohols using iso-PrOH as the hydrogen source in the presence of NaOH. Up to 99% conversion with 97% ee was obtained in the transfer hydrogenation of acetophenone derivatives. Furthermore, the catalytic properties of these catalysts based on ferrocenyl-phosphinite backbone are also discussed briefly. The structures of these ligand and their corresponding complexes have been elucidated by a combination of multinuclear NMR spectroscopy, IR spectroscopy and elemental analysis.
- I?ik, U?ur,Aydemir, Murat,Meri?, Nermin,Durap, Feyyaz,Kayan, Cezmi,Temel, Hamdi,Baysal, Akin
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p. 225 - 233
(2013/10/08)
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- New chiral ruthenium(II)-phosphinite complexes containing a ferrocenyl group in enantioselective transfer hydrogenations of aromatic ketones
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A new and versatile class of unsymmetrical ferrocenyl-phosphinite ligands possessing a stereogenic center has been prepared from commercially available, inexpensive aminoacids such as, d-, l-phenylglycine and d-, l-phenylalanine, through a concise synthetic procedure. These ligands are not very sensitive to air and moisture, and display good enantioselectivities in the ruthenium-catalyzed asymmetric transfer hydrogenation of acetophenone derivatives, in which up to 91% ee was obtained. A comparison of the catalytic properties of amino alcohols and other analogues based on a ferrocenyl backbone is also discussed briefly. The structures of these ligands and their corresponding complexes have been elucidated by a combination of multinuclear NMR spectroscopy, IR spectroscopy, and elemental analysis.
- Ak, Buenyamin,Elma, Duygu,Meric, Nermin,Kayan, Cezmi,Isik, Ugur,Aydemir, Murat,Durap, Feyyaz,Baysal, Akin
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p. 1257 - 1264
(2013/11/19)
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- Synthesis and biological evaluation of paleo-soraphens
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Synthesis can provide molecules such as paleo-soraphens A and B (see scheme) that are genetically encoded but not obtained from the natural source. Although it is unclear whether this is part of an evolutionary process or the consequence of the chemical synthesis, the biological evaluation of these genetically encoded natural products can shed light on how natural products are structurally optimized with respect to their biological profile. Copyright
- Lu, Hai-Hua,Raja, Aruna,Franke, Raimo,Landsberg, Dirk,Sasse, Florenz,Kalesse, Markus
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supporting information
p. 13549 - 13552
(2014/01/06)
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- N- SUBSTITUTED BENZENEPROPANAMIDE AND BENZENEPROPENAMIDE FOR USE IN THE PREVENTION OR THE TREATMENT OF AFFECTIVE DISORDERS
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Compounds for use in the treatment or prophylaxis of an affective disorder, which compound is represented by formula I in which the dotted line represents a single or a double bond; and R5 and R5' are independently -H, -OH or -OR6, where R6 is a linear or branched C1-C4 alkyl; X is -CH2O-; Z is -CH2ΟΗ2O-,-CH(CH3)CH2O- or -CH2CH(CH3)O-; m is 1; and n is an integer of 1-5; or a pharmaceutically acceptable salt, prodrug, metabolite, or hydrate thereof.
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Page/Page column 23
(2013/04/10)
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- Synthesis and in vitro antitumor activity of asperphenamate derivatives as autophagy inducer
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In an effort to improve the aqueous solubility and the antitumor activity of natural product asperphenamate, we have designed and synthesized three series of asperphenamate derivatives, including series I (simplifying molecular skeleton series), series II (introducing a hydroxyl group to A-phenyl ring series) and series III (disrupting molecular planarity series). All derivatives have displayed a significantly increased solubility compared with asperphenamate. Their growth inhibitory activities in vitro were screened by the standard MTT method in MCF-7, HeLa, and BEL-7402 cell lines. With the exception of the derivatives in series I, most of derivatives in series II and series III showed growth inhibitory activity. Among all derivatives, IM23b in series III showed the greatest potency in human breast cancer MCF-7 cells. The cellular potency of IM23b was approximately 1.5-fold more potent than that of cisplatin. The mechanism of cell death induced by IM23b in human breast cancer MCF-7 cells was further investigated. We concluded that the cell death was induced by autophagy instead of apoptosis or cell cycle arrest.
- Yuan, Lei,Li, Yanchun,Zou, Chunyang,Wang, Chao,Gao, Jian,Miao, Caixia,Ma, Enlong,Sun, Tiemin
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scheme or table
p. 2216 - 2220
(2012/04/18)
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- Bis(phosphinite) with C2-symmetric axis; Effects on the ruthenium(II)-catalyzed asymmetric transfer hydrogenation of acetophenone derivatives
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Chiral ruthenium catalyst systems generated in situ from [Ru(η6-p-cymene)(μ-Cl)Cl]complex and chiral Csymmetric bis(phosphinite) ligands based on amino alcohol derivatives were employed in the asymmetric transfer hydrogenation of aromatic ketones to give the corresponding optically active alcohols in high yield. The best results were obtained in the [Ru(η6-p-cymene)(μ-Cl)Cl]and (2S)-2-[benzyl(2-{benzyl[(2S)-1- [(diphenylphosphanyl)oxy]-3-phenyl propan-2-yl]amino}ethyl)amino]-3-phenylpropyl diphenylphosphinite or (2R)-2-[benzyl(2-{benzyl[(2R)-1-[(diphenylphosphanyl) oxy]-3-phenylpropan-2-yl]amino}ethyl)amino]-3-phenylpropyl diphenylphosphinite catalytic systems, which gave enantioselectivities of up to 93% ee and 99% conversion. Copyright
- Aydemir, Murat,Durap, Feyyaz,Kayan, Cezmi,Baysal, Akin,Turgut, Ylmaz
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p. 2777 - 2784
(2013/02/22)
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- Pyridine containing chiral macrocycles: Synthesis and their enantiomeric recognition for amino acid derivatives
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Four novel C2-symmetric enantiomerically pure, chiral pyridine-18-crown-6 type macrocycles containing lipophilic chains at the stereogenic centers were prepared. The enantioselectivity of the new ligands toward the enantiomers of d-,l-amino acid methyl ester derivatives were also determined by 1H NMR titration method. These novel macrocycles have been showed to be strong complexing agents for d- and l-amino acid methyl ester hydrochloride salts (with Kass up to 13590 M-1 and G 0 up to 23.3 kJ mol-1 and selectivity ratio: 80:20) by 1H NMR titration methods. These macrocyclic hosts exhibited enantioselective binding towards the d-enantiomer of valine methyl ester hydrochloride with Kd/Kl up to 5.08 in CDCl3 with 0.25% CD3OD.
- Deniz, Pinar,Turgut, Yilmaz,Togrul, Mahmut,Hosgoren, Halil
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scheme or table
p. 6227 - 6232
(2011/09/19)
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- Novel multifunctional peptidase inhibitors, especially for medical use
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The invention relates to compounds of the general formula (1) or the acid addition salts thereof with organic and/or inorganic acids; as well as to the use of the compounds of the general formula (1) in medicine.
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Page/Page column 40
(2011/04/18)
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- The first synthesis of β-amino phosphonates using cyclic sulfamidates
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Cyclic sulfamidates (prepared from α-amino acids and β-amino alcohols) have been used for the first time for the synthesis of novel β-amino phosphonates (chiral and achiral) by treatment with dialkyl phosphites using sodium hydride. 2-Substituted and 1,2-disubtituted β-amino phosphonates have efficiently been prepared following this method. The products are formed in high yield (79-84%) within 8-12 h.
- Das, Biswanath,Reddy, Cheruku Ravindra,Nagendra, Siddavatam,Lingaiah, Maram
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scheme or table
p. 3496 - 3498
(2011/07/08)
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- The tandem chain extension aldol reaction used for synthesis of ketomethylene tripeptidomimetics targeting hPEPT1
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The rationale for targeting the human di-/tripeptide transporter hPEPT1 for oral drug delivery has been well established by several drug and prodrug cases. The aim of this study was to synthesize novel ketomethylene modified tripeptidomimetics and to investigate their binding affinity for hPEPT1. Three related tripeptidomimetics of the structure H-Phe-ψ[COCH2]- Ser(Bz)-Xaa-OH were synthesized applying the tandem chain extension aldol reaction, where amino acid derived β-keto imides were stereoselectively converted to α-substituted γ-keto imides. In addition, three corresponding tripeptides, composed of amide bonds, were synthesized for comparison of binding affinities. The six investigated compounds were all defined as high affinity ligands (Ki-values 14C]Gly-Sar uptake in Caco-2 cells. Consequently, the ketomethylene replacement for the natural amide bond and α-side chain modifications appears to offer a promising strategy to modify tripeptidic structures while maintaining a high affinity for hPEPT1.
- Thorn, Karina,Nielsen, Carsten Uhd,Jakobsen, Palle,Steffansen, Bente,Zercher, Charles K.,Begtrup, Mikael
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scheme or table
p. 4597 - 4601
(2011/09/12)
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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; 58
(2010/12/31)
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- Total synthesis and anticancer activity studies of the stereoisomers of asperphenamate and patriscabratine
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All stereoisomers of asperphenamate 1a and patriscabratine 2a were achieved with a high yield, and total synthesis of 2a is firstly described here. The absolute configuration of patriscabratine was determined as (S,S). The compounds 1a-d and 2a-d have been tested by MTT assay in T47D, MDA-MB231, HL60, Hela and SGC-7901 cell lines in vitro. Among them, the (R,S) stereoisomer shows the strongest anticancer effects, while the (S,R) shows the weakest one.
- Yuan, Lei,Wang, Jin Hui,Sun, Tie Min
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scheme or table
p. 155 - 158
(2010/11/18)
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- Synthesis and antimicrobial activity of a series of optically active quaternary ammonium salts derived from phenylalanine
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We synthesized nine quaternary ammonium compounds (QUATs) starting from phenylalanine, N-alkyl-N,N-dimethyl-(1-hydroxy-3-phenylpropyl)-2-ammonium bromides, which were prepared as optically pure substances. Five compounds were prepared as S-enantiomers and four compounds as R-enantiomers. These compounds were evaluated by their activities against bacteria and fungi. Three microbial strains were used in the study: the gram-negative bacteria Escherichia coli, the gram-positive bacteria Staphylococcus aureus and the fungi Candida albicans. The activities were expressed as minimum bactericidal or fungicidal concentrations (MBC). The most active compounds were (2S)-N-tetradecyl-N,N-dimethyl-(1-hydroxy-3-phenylpropyl)-2-ammonium bromide and (2R)-N-tetradecyl-N,N-dimethyl-(1-hydroxy-3-phenylpropyl)-2-ammonium bromide, with MBC values exceeding those of commercial benzalkoniumbromide (BAB) used as standard. The relationships between structure and biological activity of the tested QUATs were quantified by the bilinear model (QSAR) and are discussed. Versita Warsaw and Springer-Verlag Berlin Heidelberg.
- Lukac, Milos,Lacko, Ivan,Bukovsky, Marian,Kyselova, Zuzana,Karlovska, Janka,Horvath, Branislav,Devinsky, Ferdinand
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scheme or table
p. 194 - 201
(2010/12/19)
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