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Crystallization method of Boc-amino acid
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a crystallization method of Boc amino acid. The preparation method comprises the following steps: (1) reacting free amino acid with di-tert-butyl dicarbonate, carrying out post-treatment to obtain a Boc-protected amino acid reaction solution, and carrying out reduced pressure distillation to remove a solvent until the solvent is dry, thereby obtaining a colorless or light yellow transparent oily substance; (2) adding a seed crystal into the obtained oily substance, standing for a period of time at normal temperature, curing the oily substance to be white, and then adding a weak polar solvent for pulping; (3) pulping for a period of time, filtering, washing, and drying under reduced pressure to obtain the product. According to the method, crystallized Boc amino acid cannot be separated out and crystallized by a conventional method, so that the purity of the product is improved, and meanwhile, the product has certain stability and can be stored for a long time without being decomposed.
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Paragraph 0030-0038

(2021/04/17)

Synthesis ofN-Boc-α-amino Acids from Carbon Dioxide by Electrochemical Carboxylation ofN-Boc-α-aminosulfones
Electrochemical reduction ofN-Boc-α-aminosulfones in DMF using an undivided cell equipped with a Pt plate cathode and an Mg rod anode under atmospheric pressure of bubbling carbon dioxide through the solution under constant current conditions resulted in a reductive C-S bond cleavage with elimination of benzenesulfinate ion generating the corresponding anion species followed by fixation of carbon dioxide to give the correspondingN-Boc-α-amino acids in moderate to good yields.
Senboku, Hisanori,Minemura, Yoshihito,Suzuki, Yuto,Matsuno, Hidetoshi,Takakuwa, Mayu
p. 16077 - 16083
(2021/10/12)

Discovery of M3Antagonist-PDE4 Inhibitor Dual Pharmacology Molecules for the Treatment of Chronic Obstructive Pulmonary Disease
In this paper, we report the discovery of dual M3 antagonist-PDE4 inhibitor (MAPI) compounds for the inhaled treatment of pulmonary diseases. The identification of dual compounds was enabled by the intuition that the fusion of a PDE4 scaffold derived from our CHF-6001 series with a muscarinic scaffold through a common linking ring could generate compounds active versus both the transmembrane M3 receptor and the intracellular PDE4 enzyme. Two chemical series characterized by two different muscarinic scaffolds were investigated. SAR optimization was aimed at obtaining M3 nanomolar affinity coupled with nanomolar PDE4 inhibition, which translated into anti-bronchospastic efficacy ex vivo (inhibition of rat trachea contraction) and into anti-inflammatory efficacy in vitro (inhibition of TNFα release). Among the best compounds, compound 92a achieved the goal of demonstrating in vivo efficacy and duration of action in both the bronchoconstriction and inflammation assays in rat after intratracheal administration.
Armani, Elisabetta,Rizzi, Andrea,Capaldi, Carmelida,De Fanti, Renato,Delcanale, Maurizio,Villetti, Gino,Marchini, Gessica,Pisano, Anna Rita,Pitozzi, Vanessa,Pittelli, Maria Gloria,Trevisani, Marcello,Salvadori, Michela,Cenacchi, Valentina,Puccini, Paola,Amadei, Francesco,Pappani, Alice,Civelli, Maurizio,Patacchini, Riccardo,Baker-Glenn, Charles A.G.,Van De Po?l, Hervé,Blackaby, Wesley P.,Nash, Kevin,Amari, Gabriele
supporting information
p. 9100 - 9119
(2021/07/19)

COMPOUNDS USEFUL IN HIV THERAPY
The invention relates to compounds of Formula (I), (Ia), (Ib), (II) or (III), salts thereof, pharmaceutical compositions thereof, as well as therapeutic methods of treatment and prevention.
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Page/Page column 194

(2020/06/19)

One-Pot C-H Arylation/Lactamization Cascade Reaction of Free Benzylamines
An efficient method has been developed for the synthesis of seven-membered biaryl lactams involving Pd-catalyzed, native amine-directed, ortho-arylation of benzylamines followed by in situ lactamization. This cascade sequence is enabled by the use of 2-iodobenzoates, which facilitates C-H arylation from the free amine under conditions that typically require an improved directing group approach. This reaction is characterized by a broad substrate scope with good functional group tolerance. The need for an ester versus carboxylic acid-functionalized coupling partner is also explored, as is the potential for synthesizing eight-membered biaryl lactams. Various applications are also investigated, including access to the aza-brassinolide core.
Chand-Thakuri, Pratibha,Landge, Vinod G.,Kapoor, Mohit,Young, Michael C.
p. 6626 - 6644
(2020/07/14)

Asymmetric Dearomative Cascade Multiple Functionalizations of Activated N-Alkylpyridinium and N-Alkylquinolinium Salts
An enantioselective cascade reaction of N-alkylpyridinium and -quinolinium salts with o-hydroxybenzylideneacetones to access fused polyheterocycles through cross dienamine-mediated addition followed by trapping of the dearomatized enamine-type intermediates and aminal formation has been developed. A cascade assembly of N-benzyl-4-methylpyridinium salt and cyclic 2,4-dienones is further disclosed to give bridged frameworks via repetitive dearomatization and aromatization activation.
Chen, Ying-Chun,Du, Wei,Song, Xue,Yan, Ru-Jie
supporting information
p. 7617 - 7621
(2020/10/09)

ALLOSTERIC EGFR INHIBITORS AND METHODS OF USE THEREOF
The disclosure relates to compounds that act as an allosteric inhibitors of epidermal growth factor receptor (EGFR); pharmaceutical compositions comprising the compounds; and methods of treating or preventing kinase-mediated disorders, including cancer and other proliferation diseases.
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Page/Page column 62-63; 90

(2021/01/22)

Carbon Dioxide-Mediated C(sp2)-H Arylation of Primary and Secondary Benzylamines
C-C bond formation by transition metal-catalyzed C-H activation has become an important strategy to fabricate new bonds in a rapid fashion. Despite the pharmacological importance of ortho-arylbenzylamines, however, effective ortho-C-C bond formation of free primary and secondary benzylamines using PdII remains an outstanding challenge. Presented herein is a new strategy for constructing ortho-arylated primary and secondary benzylamines mediated by carbon dioxide (CO2). The use of CO2 with Pd is critical to allowing this transformation to proceed under relatively mild conditions, and mechanistic studies indicate that it (CO2) is directly involved in the rate-determining step. Furthermore, the milder temperatures furnish free amine products that can be directly used or elaborated without the need for deprotection. In cases where diarylation is possible, an interesting chelate effect is shown to facilitate selective monoarylation.
Kapoor, Mohit,Chand-Thakuri, Pratibha,Young, Michael C.
supporting information
p. 7980 - 7989
(2019/05/22)

Structural modification of histone deacetylase inhibitors with a phenylglycine scaffold
During the discovery of histone deacetylase inhibitors (HDACIs) as antitumor drugs, a series of potent phenylglycine-based HDACIs were developed. However, further development is restricted by the poor solubility. Therefore, structural modifications were performed in the present study in the development of potent HDACIs with improved pharmacokinetic properties. The synthesized molecules were designed by the substitution of fatty linkers for aromatic linkers, and showed good solubility profiles. Among the compounds derived, molecule HD9 showed a potent enzyme-inhibitory effect (IC50 values of 76 nmol/l) and in-vitro antiproliferative activities (IC50 values of 0.51, 0.83, and 0.76 μmol/l against U937, K562, and HL60 cells, respectively). Molecule HD9 showed selectivity of HDAC3 over HDAC6 in the isoform selectivity assays. Molecular docking studies showed good binding patterns of molecule HD9 to the active site of HDAC3. Results from the present work indicated that molecule HD9 is a promising lead compound for the tumor therapy.
Zhang, Lei,Zhang, Li,Bian, Jiang,Jiang, Qixiao,Gao, Jianjun,Song, Weiguo
p. 145 - 156
(2018/03/08)

Synthesis of Tripeptide Derivatives with Three Stereogenic Centers and Chiral Recognition Probed by Tetraaza Macrocyclic Chiral Solvating Agents Derived from d -Phenylalanine and (1 S,2 S)-(+)-1,2-Diaminocyclohexane via 1H NMR Spectroscopy
Enantiomers of a series of tripeptide derivatives with three stereogenic centers (±)-G1-G9 have been prepared from d- and l-α-amino acids as guests for chiral recognition by 1H NMR spectroscopy. In the meantime, a family of tetraaza macrocyclic chiral solvating agents (TAMCSAs) 1a-1d has been synthesized from d-phenylalanine and (1S,2S)-(+)-1,2-diaminocyclohexane. Discrimination of enantiomers of (±)-G1-G9 was carried out in the presence of TAMCSAs 1a-1d by 1H NMR spectroscopy. The results indicate that enantiomers of (±)-G1-G9 can be effectively discriminated in the presence of TAMCSAs 1a-1d by 1H NMR signals of multiple protons exhibiting nonequivalent chemical shifts (ΔΔδ) up to 0.616 ppm. Furthermore, enantiomers of (±)-G1-G9 were easily assigned by comparing 1H NMR signals of the split corresponding protons with those attributed to a single enantiomer. Different optical purities (ee up to 90%) of G1 were clearly observed and calculated in the presence of TAMCSAs 1a-1d, respectively. Intermolecular hydrogen bonding interactions were demonstrated through theoretical calculations of enantiomers of (±)-G1 with TAMCSA 1a by means of the hybrid functional theory with the standard basis sets of 3-21G of the Gaussian 03 program.
Feng, Lei,Gao, Guangpeng,Zhao, Hongmei,Zheng, Li,Wang, Yu,Stavropoulos, Pericles,Ai, Lin,Zhang, Jiaxin
p. 13874 - 13887
(2018/11/23)

Dynamic Kinetic Resolution of N-Protected Amino Acid Esters via Phase-Transfer Catalytic Base Hydrolysis
Asymmetric base hydrolysis of α-chiral esters with synthetic small-molecule catalysts is described. Quaternary ammonium salts derived from quinine were used as chiral phase-transfer catalysts to promote the base hydrolysis of N-protected amino acid hexafluoroisopropyl esters in a CHCl3/NaOH (aq) via dynamic kinetic resolution, providing the corresponding products in moderate to good yields (up to 99%) with up to 96:4 er. Experimental and computational mechanistic studies using DFT calculation and pseudotransition state (pseudo-TS) conformational search afforded a TS model accounting for the origin of the stereoselectivity. The model suggested π-stacking and H-bonding interactions play essential roles in stabilizing the TS structures.
Yamamoto, Eiji,Wakafuji, Kodai,Furutachi, Yuho,Kobayashi, Kaoru,Kamachi, Takashi,Tokunaga, Makoto
p. 5708 - 5713
(2018/05/30)

Diastereo- and Enantioselective Synthesis of β-Aminoboronate Esters by Copper(I)-Catalyzed 1,2-Addition of 1,1-Bis[(pinacolato)boryl]alkanes to Imines
Reported herein is an efficient copper(I)-catalytic system for the diastereo- and enantioselective 1,2-addition of 1,1-bis[(pinacolato)boryl]alkanes to protected imines to afford synthetically valuable enantioenriched β-aminoboron compounds bearing contiguous stereogenic centers. The reaction exhibits a broad scope with respect to protected imines and 1,1-bis[(pinacolato)boryl]alkanes, thus providing β-aminoboronate esters with excellent diastereo- and enantioselectivity. The synthetic utility of the obtained β-aminoboronate ester was also demonstrated.
Kim, Jeongho,Ko, Kwangwook,Cho, Seung Hwan
supporting information
p. 11584 - 11588
(2017/09/12)

A chiral 2-phenyl pyrrolidine synthetic method
The invention discloses a synthetic method of chiral 2-phenylpyrrolidine. The synthetic method comprises the following steps: (1) butoxycarbonyl protective reaction: carrying out reaction on chiral 2-amino-phenylacetic acid and di-tert-butyl dicarbonate to obtain chiral 2-( butoxycarbonyl amino)-2-phenylacetic acid; (2) condensation and reduction reaction: carrying out condensation on the chiral 2-(butoxycarbonyl amino)-2-phenylacetic acid and 2, 2-dimethyl-1, 3-dioxane-4, 6-dione, and carrying out reduction by virtue of sodium borohydride to obtain chiral 2-(2, 2-dimethyl-4, 6-dicarbonyl-1, 3-dioxane-5-yl)-1-phenyl ethyl tert-butyl carbamate; (3) de-protection and heating ring closure reaction: carrying out de-protection and heating ring closure reaction on the chiral 2-(2, 2-dimethyl-4, 6-dicarbonyl-1, 3-dioxane-5-yl)-1-phenyl ethyl tert-butyl carbamate to obtain chiral 5-phenylpyrrolidine-2-ketone; and (4) reduction reaction: reducing the chiral 5-phenylpyrrolidine-2-ketone by virtue of lithium aluminium hydride to obtain the chiral 2-phenylpyrrolidine. The synthetic method is simple in operation, high in yield and cheap and easily acquired in raw materials and is suitable for industrial production.
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Paragraph 0050; 0051

(2017/02/02)

Phenylglycine-containing cinnamamide histone deacetylase inhibitor, and preparation method and application thereof
The invention relates to a phenylglycine-containing cinnamamide histone deacetylase inhibitor, and a preparation method and application thereof. The structure of the compound is disclosed as Formula I. The invention also relates to a pharmaceutical composition containing the compound disclosed as Formula I. The compound provided by the invention is used for preparing drugs for preventing and treating mammal diseases related to histone deacetylase activity abnormal expression.
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Paragraph 0039; 0103; 0104

(2016/10/09)

PXD101 analogs with L-phenylglycine-containing branched cap as histone deacetylase inhibitors
Histone deacetylases (HDACs) allow histones to wrap DNA more tightly and finally lead to the repression of some tumor suppressor genes. Histone deacetylase inhibitors (HDACIs) have been proved to have effects on tumorigenesis and tumor progression. In this study, we reported the design, synthesis, and in vitro activity evaluation of novel PXD101 analogs with L-phenylglycine-containing cap as HDACIs. Our results showed that HDACs inhibitory activities of compounds 10k, 10r, and 10s were not only superior to the first approved HDACI SAHA, but also comparable to their parent compound PXD101, a recently approved HDACI in 2014. However, all 6 selected PXD101 analogs exhibited moderate in vitro antiproliferative activities, less potent than PXD101 and SAHA. Representative compound 10s showed similar HDACs isoform selective profile to PXD101, which demonstrated that introduction of L-phenylglycine-containing branched cap group could not change the isoform selectivity of PXD101 dramatically.
Li, Jingyao,Li, Xiaoyang,Wang, Xue,Hou, Jinning,Zang, Jie,Gao, Shuai,Xu, Wenfang,Zhang, Yingjie
p. 574 - 584
(2016/10/06)

ERK INHIBITORS
The present invention provides a compound of Formula (I) or the pharmaceutically acceptable salts, esters, and prodrugs thereof, which are ERK2 inhibitors. The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula (I) and a pharmaceutically acceptable carrier. The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula (I) and an effective amount of at least one other pharmaceutically active ingredient (such as, for example, a chemotherapeutic agent), and a pharmaceutically acceptable carrier.
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Page/Page column 82; 83

(2016/07/05)

Mechanism of Oxidative Amidation of Nitroalkanes with Oxygen and Amine Nucleophiles by Using Electrophilic Iodine
Recently, we developed a direct method to oxidatively convert primary nitroalkanes into amides that entailed mixing an iodonium source with an amine, base, and oxygen. Herein, we systematically investigated the mechanism and likely intermediates of such methods. We conclude that an amine-iodonium complex first forms through N-halogen bonding. This complex reacts with aci-nitronates to give both α-iodo- and α,α-diiodonitroalkanes, which can act as alternative sources of electrophilic iodine and also generate an extra equimolar amount of I+ under O2. In particular, evidence supports α,α-diiodonitroalkane intermediates reacting with molecular oxygen to form a peroxy adduct; alternatively, these tetrahedral intermediates rearrange anaerobically to form a cleavable nitrite ester. In either case, activated esters are proposed to form that eventually reacts with nucleophilic amines in a traditional fashion.
Li, Jing,Lear, Martin J.,Kwon, Eunsang,Hayashi, Yujiro
p. 5538 - 5542
(2016/04/20)

PROCESS FOR PREPARING LEVOMILNACIPRAN
The present invention refers to a new process for preparing levomilnacipran, in particular to a process for the resolution of racemic tw-milnacipran with a derivative of optically active phenylglycine.
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Page/Page column 6; 7

(2015/07/07)

ERK INHIBITORS
Disclosed are the ERK inhibitors of formula (1.0) and the pharmaceutically acceptable salts thereof. Also disclosed are methods of treating cancer using the compounds of formula (1.0). This invention provides compounds that are ERK inhibitors (i.e., ERK2 inhibitors). This invention also provides a pharmaceutical composition comprising an effective amount of at least one (e.g., 1) compound of formula (1.0) and a pharmaceutically acceptable carrier.
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Page/Page column 72

(2015/07/07)

Oxidative Amidation of Nitroalkanes with Amine Nucleophiles using Molecular Oxygen and Iodine
The formation of amides and peptides often necessitates powerful yet mild reagent systems. The reagents used, however, are often expensive and highly elaborate. New atom-economical and practical methods that achieve such goals are highly desirable. Ideally, the methods should start with substrates that are readily available in both chiral and non-chiral forms and utilize cheap reagents that are compatible with a wide variety of functional groups, steric encumberance, and epimerizable stereocenters. A direct oxidative method was developed to form amide and peptide bonds between amines and primary nitroalkanes simply by using I2 and K2CO3 under O2. Contrary to expectations, a 1:1 halogen-bonded complex forms between the iodonium source and the amine, which reacts with nitronates to form α-iodo nitroalkanes as precursors to the amides.
Li, Jing,Lear, Martin J.,Kawamoto, Yuya,Umemiya, Shigenobu,Wong, Alice R.,Kwon, Eunsang,Sato, Itaru,Hayashi, Yujiro
p. 12986 - 12990
(2015/11/02)

HETEROARYL DERIVATIVES
Compounds of formula (I) described herein are both phosphodiesterase 4 (PDE4) enzyme inhibitors and muscarinic M3 receptor antagonists and are useful for the prevention and/or treatment of diseases of the respiratory tract characterized by airway obstruction.
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Paragraph 0502; 0503; 0504

(2015/06/17)

HETEROARYL DERIVATIVES FOR THE TREATMENT OF RESPIRATORY DISEASES
The invention relates to novel compounds of formula (I) which are both phosphodiesterase 4 (PDE4) enzyme inhibitors and muscarinic M3 receptor antagonists, methods of preparing such compounds, compositions containing them and therapeutic use thereof.
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Page/Page column 116; 117

(2015/06/18)

Dual Catalytic Decarboxylative Allylations of α-Amino Acids and Their Divergent Mechanisms
The room temperature radical decarboxylative allylation of N-protected α-amino acids and esters has been accomplished via a combination of palladium and photoredox catalysis to provide homoallylic amines. Mechanistic investigations revealed that the stability of the α-amino radical, which is formed by decarboxylation, dictates the predominant reaction pathway between competing mechanisms.
Lang, Simon B.,O'Nele, Kathryn M.,Douglas, Justin T.,Tunge, Jon A.
supporting information
p. 18589 - 18593
(2016/01/25)

Histone deacetylase inhibitors with enhanced enzymatic inhibition effects and potent in vitro and in vivo antitumor activities
In the present work, a series of small molecules were designed and synthesized based on structural optimization. A significant improvement in the enzyme inhibitory activity of these compounds was discovered. Moreover, the tested compounds have moderate preference for classa I HDACs over HDAC6, as demonstrated by enzyme selectivity assays. In vitro antiproliferation assay results show that representative compounds can selectively inhibit the growth of non-solid lymphoma and leukemic cells such as U937, K562, and HL60. In the in vivo antitumor assay, (S)-4-(2-(5-(dimethylamino)naphthalene-1-sulfonamido)-2- phenylacetamido)-N-hydroxybenzamide (D17) showed better performance than SAHA in blocking U937 tumor growth. Western blot analysis revealed that representative molecules can block the function of both class I HDACs and HDAC6. More importantly, our western blot results reveal that the levels of some oncogenic proteins (p-Akt in the PI3K/AKT/mTOR signal pathway, c-Raf and p-Erk in the MAPK signal pathway) were dramatically down-regulated by our compounds in the U937 cell line rather than MDA-MB-231 cells. This distinction in cellular mechanism might be an important reason why the U937 cell line was found to more sensitive to our HDAC inhibitors than the MDA-MB-231 cell line.
Zhang, Lei,Zhang, Yingjie,Chou, C. James,Inks, Elizabeth S.,Wang, Xuejian,Li, Xiaoguang,Hou, Jinning,Xu, Wenfang
p. 638 - 648
(2014/03/21)

Discovery of a series of small molecules as potent histone deacetylase inhibitors
A series of small molecules were designed and synthesized based on our previous virtual screening approach, which was performed to discover potent histone deacetylase inhibitors (HDACIs) with novel structures. The derived compounds were tested by Hela cell nucleus extract for enzyme inhibition assay. Tumor cell growth inhibition assays were performed using a series of tumor cell lines. Molecule 4h has the best performance among these compounds with enzyme inhibition IC50 of 0.14 μM and tumor cell growth inhibition IC50 of 1.85 (U937), 2.02 (HL60), 2.67 (K562). Docking studies showed that multiple H-bonds and hydrophobic interactions make 4h binding to the active site of HDAC. 4h has the advantage of low molecular weight, so a variety of structural modifications can be performed in our further studies.
Zhang, Lei,Wang, Xuejian,Li, Xiaoguang,Xu, Wenfang
p. 333 - 337
(2014/06/09)

Three-component asymmetric catalytic ugi reaction - Concinnity from diversity by substrate-mediated catalyst assembly
The first chiral catalyst for the three-component Ugi reaction was identified as a result of a screen of a large set of different BOROX catalysts. The BOROX catalysts were assembled in situ from a chiral biaryl ligand, an amine, water, BH3×SMe2, and an alcohol or phenol. The catalyst screen included 13 different ligands, 12 amines, and 47 alcohols or phenols. The optimal catalyst system (LAP 8-5-47) provided α-amino amides from an aldehyde, a secondary amine, and an isonitrile with excellent asymmetric induction. The catalytically active species is proposed to be an ion pair that consists of the chiral boroxinate anion and an iminium cation. Harmonious arrangement of parts: A screen of BOROX catalysts that were generated in situ from 13 different ligands and 47 alcohols led to the identification of an effective combination for the catalytic asymmetric three-component Ugi reaction. Experimental results suggest that the catalyst is a chiral polyborate anion, which then forms an ion pair with the iminium cation that is generated from aldehyde and secondary amine.
Zhao, Wenjun,Huang, Li,Guan, Yong,Wulff, William D.
supporting information
p. 3436 - 3441
(2014/04/03)

Discovery of a series of hydroximic acid derivatives as potent histone deacetylase inhibitors
To develop potent histone deacetylase inhibitors as antitumor agents, structural modification was performed. The synthesized molecules were tested by enzymatic inhibition assay and anti-proliferation assay. Several molecules show improved activities in the enzymatic inhibition assay. However, in the MTT assays, all these derived molecules have limited performance compared with SAHA. The IC50 values of molecule ((S)-N-(6-(hydroxyamino)-6-oxohexyl)-4-(3-(2-oxo-1-phenyl-2-((3-(trifluoromethyl)phenyl)amino)ethyl)ureido)benzamide, L8) which has the best enzymatic inhibition activity (with an IC50 value of 11.7nm and 967nm against Hela nucleus extract and HDAC8, respectively) were calculated compared with SAHA. Molecular docking was performed to predict the binding mode of molecule L8 in the active site of HDAC2 and HDAC8. Hydrophobic interaction, chelate binding, electrostatic attraction and H-bond interaction in combination make contribution to the ligand-receptor interactions.
Zhang, Lei,Wang, Xuejian,Li, Xiaoguang,Zhang, Lihui,Xu, Wenfang
p. 582 - 589
(2014/08/05)

Synthesis and biological evaluation of new pleuromutilin derivatives as antibacterial agents
Several pleuromutilin derivatives possessing thiadiazole moieties were synthesized via acylation reactions under mild conditions. The in vitro antibacterial activities of the derivatives against methicillin-resistant S. aureus, methicillin-resistant S. epidermidis, S. aureus, S. epidermidis, E. coli, and B. cereus were tested by the agar dilution method and Oxford cup assay. All the screened compounds displayed potent activity. Compound 6d was the most active antibacterial agent because of its lowest MIC value and largest inhibition zone. Docking experiments were performed to understand the possible mode of the interactions between the derivatives and 50S ribosomal subunit. Moreover, the absorption, distribution, metabolism, excretion and toxicity properties of the synthesized compounds were analyzed after prediction using the Advanced Chemistry Development/Percepta Platform available online.
Shang, Ruo-Feng,Wang, Guan-Hua,Xu, Xi-Ming,Liu, Si-Jie,Zhang, Chao,Yi, Yun-Peng,Liang, Jian-Ping,Liu, Yu
p. 19050 - 19065
(2015/02/05)

COSMETIC USES AND METHODS FOR INDOLINE GRANZYME B INHIBITOR COMPOSITIONS
Cosmetic uses and methods for indoline granzyme B inhibitor compounds in compositions with a cosmetically acceptable carrier. Uses and methods for treating, reducing or inhibiting the appearance of ageing in the skin are provided. Also provided are compositions and formulation for cosmetic uses and methods of maintaining a youthful appearance, reducing an appearance of ageing, inhibiting an appearance of ageing, reducing a rate of an appearance of ageing, reducing a skin inelasticity, reducing a rate of increasing skin inelasticity, maintaining a skin elasticity, and increasing the density of hair follicles of a skin of a subjecl. The uses and methods comprise applying/administering an indoline granzyme B inhibitor to a skin, or a portion of a skin of the subject.
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Page/Page column 57; 134

(2014/10/15)

ANTI-PCSK9 COMPOUNDS AND METHODS FOR THE TREATMENT AND/OR PREVENTION OF CARDIOVASCULAR DISEASES
Disclosed are compounds that modulate the physiological action of the proprotein convertase subtilisin kexin type 9 (PCSK9), and methods of using these modulators to reduce LDL-cholesterol levels and/or for the treatment and/or prevention of cardiovascular disease (CVD), including treatment of hypercholesterolemia.
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Page/Page column 32

(2014/10/04)

Design, synthesis and biological evaluation of novel L-isoserine tripeptide derivatives as aminopeptidase N inhibitors
Aminopeptidase N (APN/CD13) is one of the essential proteins for tumour invasion, angiogenesis and metastasis as it is over-expressed on the surface of different tumour cells. Based on our previous work that L-isoserine dipeptide derivatives were potent APN inhibitors, we designed and synthesized L-isoserine tripeptide derivatives as APN inhibitors. Among these compounds, one compound 16l (IC50=2.51±0.2 M) showed similar inhibitory effect compared with control compound Bestatin (IC50=6.25±0.4 M) and it could be used as novel lead compound for the APN inhibitors development as anticancer agents in the future.
Pan, Huili,Yang, Kanghui,Zhang, Jian,Xu, Yingying,Jiang, Yuqi,Yuan, Yumei,Zhang, Xiaopan,Xu, Wenfang
p. 717 - 726
(2013/07/26)

Synthesis and antibacterial evaluation of novel pleuromutilin derivatives
A series of novel pleuromutilin derivatives possessing thioether moiety has been synthesized via acylation reaction under mild conditions. Their in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Escherichia coli, and Streptococcus agalactiae were tested by agar dilution method and Oxford cup assay. Among the 17 compounds screened, 14-O-[(4-methoxybenzamide-2- methylpropane-2-yl) thioacetate] mutilin 4i, 14-O-[(2-aminobenzamide-2- methylpropane-2-yl) thioacetate] mutilin 5a and 14-O-[(4-aminobenzamide-2- methylpropane-2-yl) thioacetate] mutilin 5c were resulted as most active antibacterial agents.
Shang, Ruofeng,Liu, Yu,Xin, Zhijun,Guo, Wenzhu,Guo, Zhiting,Hao, Baocheng,Jianping, Liang
p. 231 - 238
(2013/07/27)

One-step synthesis of racemic α-amino acids from aldehydes, amine components, and gaseous CO2 by the aid of a bismetal reagent
α-Amino acids are essential resources for human life and are highly useful as building blocks for organic synthesis. The core framework of an α-amino acid can be divided into three basic components: an aldehyde, an amine, and carbon dioxide (CO2). We report herein that a one-step synthesis of α-amino acids has been successfully achieved from these three basic and inexpensive chemicals with a single operation, in which the mixture of an aldehyde, a sulfonamide, and gaseous CO2 was heated at 100 °C in the presence of Bu3Sn-SnBu3 and CsF. In this one-pot sequential protocol, two important intermediates (imine and α-amino stannane) are involved and the stannyl anion generated in situ plays a crucial role, particularly for the efficient stannylation of the imine in the presence of proton sources and for promoting retrostannylation of the undesired α-alkoxy stannane owing to its high stability and tolerance of the presence of proton sources. This methodology enabled the synthesis of a wide range of racemic arylglycine derivatives in high yields. Go retro! α-Amino acids are essential resources for human life and are highly useful as building blocks for organic synthesis. The core framework of an α-amino acid is retrosynthesized to an aldehyde, an amine, and carbon dioxide. A one-step synthesis of α-amin Copyright
Mita, Tsuyoshi,Higuchi, Yuki,Sato, Yoshihiro
p. 1123 - 1128
(2013/02/23)

Highly enantioselective nitro-mannich reaction catalyzed by cinchona alkaloids and N-benzotriazole derived ammonium salts
The catalytic enantio- and diastereoselective nitro-Mannich reaction of α-amido sulfones in the mixed solvent of toluene/H2O has been realized using a phase-transfer catalyst (PTC) derived from cinchona alkaloids and N-benzotriazole. It performed well over a wide range of substrates to give the desired products in good yields (up to 94%) with excellent enantioselectivities (up to 99% ee) and diastereoselectivities (up to 99:1).
Wei, Yu,He, Wei,Liu, Yulong,Liu, Peng,Zhang, Shengyong
supporting information; experimental part
p. 704 - 707
(2012/04/10)

One-pot synthesis of α-amino acids from CO2 using a bismetal reagent with Si-B bond
In the presence of 1.1 equiv of PhMe2Si-Bpin, 5 equiv of CsF, and 20 mol % of TsOH·H2O, precursors of N-Boc-imines can be converted into the corresponding α-aryl or α-alkenyl glycine derivatives under gaseous CO2 in moderate-to-high yields with a single operation. α-Isobutenyl glycine thus obtained can be further derivatized into various types of α-amino acids including N-Boc-leucine, serine, and glycine derivatives in short steps.
Mita, Tsuyoshi,Chen, Jianyang,Sugawara, Masumi,Sato, Yoshihiro
supporting information
p. 6202 - 6205
(2013/02/23)

Synthesis of arylglycine and mandelic acid derivatives through carboxylations of α-amido and α-acetoxy stannanes with carbon dioxide
Incorporation reactions of carbon dioxide (CO2) with N-Boc-α-amido and α-acetoxy stannanes were developed using CsF as a mild tin activator. Monoprotected α-amido stannanes could be used, and the corresponding arylglycine derivatives were obtained in moderate-to-high yields under 1 MPa (10 atm) of CO2 pressure. α-Acetoxy stannanes also underwent carboxylation to afford mandelic acid derivatives in excellent yields under ambient CO2 pressure. Both transformations enabled the synthesis of α-tertiary and α-quaternary carboxylic acid derivatives. In addition, the chirality of (S)-N-tert-butylsulfonyl-α- amido stannanes was transferred with up to 90% inversion of configuration at 100 °C.
Mita, Tsuyoshi,Sugawara, Masumi,Hasegawa, Hiroyuki,Sato, Yoshihiro
experimental part
p. 2159 - 2168
(2012/06/01)

GLYCINE DERIVATIVES AND THEIR USE AS MUSCARINIC RECEPTOR ANTAGONISTS
The present invention relates to alkaloid aminoester derivatives acting as muscarinic receptor antagonists, processes for their preparation, compositions comprising them and therapeutic uses thereof.
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(2012/06/15)

GLYCINE DERIVATIVES AND MEDICINAL COMPOSITIONS THEREOF
Alkaloid aminoester derivatives according to formula (I) and (VI) act as muscarinic receptor antagonists.
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(2012/06/16)

Maintaining potent HTLV-I protease inhibition without the P3-cap moiety in small tetrapeptidic inhibitors
The human T cell lymphotropic/leukemia virus type 1 (HTLV-I) causes adult T cell lymphoma/leukemia. The virus is also responsible for chronic progressive myelopathy and several inflammatory diseases. To stop the manufacturing of new viral components, in our previous reports, we derived small tetrapeptidic HTLV-I protease inhibitors with an important amide-capping moiety at the P3 residue. In the current study, we removed the P3-cap moiety and, with great difficulty, optimized the P3 residue for HTLV-I protease inhibition potency. We discovered a very potent and small tetrapeptidic HTLV-I protease inhibitor (KNI-10774a, IC50 = 13 nM).
Nguyen, Jeffrey-Tri,Kato, Keiko,Kumada, Henri-Obadja,Hidaka, Koushi,Kimura, Tooru,Kiso, Yoshiaki
scheme or table
p. 1832 - 1837
(2011/05/05)

Design and synthesis of several small-size HTLV-I protease inhibitors with different hydrophilicity profiles
The human T cell leukemia/lymphotropic virus type 1 (HTLV-I) is clinically associated with adult T cell leukemia/lymphoma, HTLV-I associated myelopathy/tropical spastic paraparesis, and a number of other chronic inflammatory diseases. To stop the replication of the virus, we developed highly potent tetrapeptidic HTLV-I protease inhibitors. In a recent X-ray crystallography study, several of our inhibitors could not form co-crystal complexes with the protease due to their high hydrophobicity. In the current study, we designed, synthesized and evaluated the HTLV-I protease inhibition potency of compounds with hydrophilic end-capping moieties with the aim of improving pharmaceutic and pharmacokinetic properties.
Nguyen, Jeffrey-Tri,Kato, Keiko,Hidaka, Koushi,Kumada, Henri-Obadja,Kimura, Tooru,Kiso, Yoshiaki
supporting information; experimental part
p. 2425 - 2429
(2011/06/17)

Highly enantioselective fluorescent recognition of amino acid derivatives by unsymmetrical salan sensors
Novel unsymmetrical salan fluorescent sensors 2a and 2b have been designed and synthesized. The chiral recognition of N-Boc-protected amino acids by 2a and 2b has been investigated. Sensor 2a possesses higher sensitivity and enantioselectivity than sensor 2b does. Job analysis and nonlinear regression results show that 2a can form a 1:1 stoichiometric complex with a N-Boc-protected amino acid. The obtained response selectivities and the association constants indicate that 2a is a highly enantioselective and sensitive fluorescent sensor toward N-Boc-protected amino acids.
Yang, Xia,Shen, Kang,Liu, Xuechao,Zhu, Chengjian,Cheng, Yixiang
scheme or table
p. 4611 - 4614
(2011/10/01)

One-pot synthesis of α-amino acids from imines through CO2 incorporation: An alternative method for strecker synthesis
Itas a gas: A novel one-pot process for the synthesis of α-amino acids from imine equivalents using CO2 gas as a carbon source has been developed. This reaction was made possible by the reagent combination of TMSSnBu3 and CsF (see scheme). Three successive reactions (imine formation, stannylation, and carboxylation) proceeded in the same flask under these conditions to give products in up to 79 % yield. Boc=tert-butoxycarbonyl, TMS=trimethylsilyl.
Mita, Tsuyoshi,Chen, Jianyang,Sugawara, Masumi,Sato, Yoshihiro
p. 1393 - 1396
(2011/04/22)

Discovery of small molecules that enhance astrocyte differentiation in rat fetal neural stem cells
1,3,4-Oxadiazole derivatives were found to enhance astrocyte differentiation in rat fetal neural stem cells (NSCs). Differentiation activity was assessed by immunocytochemistry and analysis of mRNA expression of astrocyte markers, GFAP and S100. Compounds 7 and 8 showed approximately a two-fold increase in astrocyte differentiation without engagement of neuronal differentiation and detectable cytotoxicity.
Chang, Dong Jo,Jeong, Mi Young,Song, Jiho,Jin, Chang Yun,Suh, Young-Ger,Kim, Hyun-Jung,Min, Kyung Hoon
supporting information; scheme or table
p. 7050 - 7053
(2012/01/13)

Enantiomeric resolution of α-amino acid derivatives on two diastereomeric chiral stationary phases based on chiral crown ethers incorporating two different chiral units
Two diastereomeric chiral stationary phases (CSPs) were applied to the liquid chromatographic resolution of various racemic a-amino methyl esters, α-amino N,N-diethylamides and α-amino N-propylamides. The CSP incorporating (R)-3,3' -diphenyl-1,1' -binaphtyl and (R,R)-tartaric acid unit as chiral barriers did not show any chiral recognition. In contrast, the CSP incorporating (R)-3,3'-diphenyl-1,1'-binaphtyl and (S,S)-tartaric acid unit as chiral barriers was found to show excellent chiral recognition especially for the two enantiomers of a-amino N-propylamides. Some of a-amino methyl esters and α-amino N,N-diethylamides were also resolved on the CSP incorporating (R)-3,3'-diphenyl-1,1'-binaphtyl and (S,S)-tartaric acid unit. From these results it was concluded that the two chiral units composing the diastereomeric CSPs can show "matched" or "mismatched" effect on the chiral recognition according to their absolute stereochemistry.
Kim, Hee Jin,Choi, Hee Jung,Cho, Yoon Jae,Hyun, Myung Ho
body text
p. 1551 - 1554
(2010/10/20)

Water soluble synthetic dieptide-based biodegradable nanoporous materials
Two water-soluble synthetic dipeptides, β-alanyl-l-phenylglycine and its retro analogue l-phenylglycyl-β-alanine form a new class of dipeptide-based nanoporous materials, which are composed of a hybrid of α and β-amino acids. These materials adsorb N2 gas with adsorption capacity of 173 cc g-1 and 71 cc g-1 and BET surface area of 56.76 m2g-1 and 41.73 m2g-1 for these dipeptides, respectively. Moreover, these nanoporous materials are found to be biodegradable towards soil bacterial consortium making them an interesting class of eco-friendly dipeptide-based nanoporous materials.
Guha, Samit,Chakraborty, Tushar,Banerjee, Arindam
experimental part
p. 1139 - 1145
(2010/05/17)

A practical synthesis of optically active arylglycines via catalytic asymmetric Strecker reaction
A practical procedure for catalytic asymmetric synthesis of optically active arylglycine derivatives via optically active α-aminonitriles has been developed. The N-benzhydryl α-arylaminonitrile intermediates were prepared in excellent yield (89-99%) and enantiomeric purity (96 to >98% ee) by enantioselective cyanation of aldimines with TMSCN/iPrOH in the presence of 2.5 mol % of an easily prepared Ti/chiral amino alcohol complex at 0 °C, without requiring slow addition of the cyanating agent. The easily racemized α-aminonitrile intermediates were efficiently hydrolyzed by an aqueous HCl/TFA mixture to give the arylglycine derivatives in good yield (60-92%) and moderate to excellent enantiomeric purity (85-98% ee).
Banphavichit, Vorawit,Mansawat, Woraluk,Bhanthumnavin, Worawan,Vilaivan, Tirayut
experimental part
p. 5849 - 5854
(2009/12/01)

COMPOUNDS HAVING ACTIVITY IN INCREASING ION TRANSPORT BY MUTANT-CFTR AND USES THEREOF
The invention provides compositions, pharmaceutical preparations and methods for increasing activity of a mutant cystic fibrosis transmembrane conductance regulator protein (mutant-CFTR). The compositions pharmaceutical preparations and methods are useful for the study and treatment of disorders associated with mutant-CFTR, such as cystic fibrosis. The compositions and pharmaceutical preparations of the invention may comprise one or more phenylglycine-containing compounds of the invention, or an analog or derivative thereof
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(2009/05/28)

1,8-Naphthyridine-3-carboxamide derivatives with anticancer and anti-inflammatory activity
A number of 1-propargyl-1,8-naphthyridine-3-carboxamide derivatives (15-35) have been synthesized and screened for their in vitro cytotoxicity and anti-inflammatory activity. Compounds 22, 31 and 34 have shown high cytotoxicity against a number of cancer cell lines, while compound 24 showed significant anti-inflammatory activity.
Kumar, Vivek,Jaggi, Manu,Singh, Anu T.,Madaan, Alka,Sanna, Vinod,Singh, Pratibha,Sharma, Pramod K.,Irchhaiya, Raghuveer,Burman, Anand C.
experimental part
p. 3356 - 3362
(2009/10/23)

Thiazolone-acylsulfonamides as novel HCV NS5B polymerase allosteric inhibitors: Convergence of structure-based drug design and X-ray crystallographic study
A novel series of thiazolone-acylsulfonamides were designed as HCV NS5B polymerase allosteric inhibitors. The structure based drug designs (SBDD) were guided by docking results that revealed the potential to explore an additional pocket in the allosteric site. In particular, the designed molecules contain moieties of previously described thiazolone and a newly designed acylsulfonamide linker that is in turn connected with a substituted aromatic ring. The selected compounds were synthesized and demonstrated low μM activity. The X-ray complex structure was determined at a 2.2 A resolution and converged with the SBDD principle.
Yan, Shunqi,Appleby, Todd,Larson, Gary,Wu, Jim Z.,Hamatake, Robert K.,Hong, Zhi,Yao, Nanhua
p. 1991 - 1995
(2008/02/04)

Chemo-enzymatic dynamic kinetic resolution of amino acid thioesters
The L-forms of racemic-N-protected-β,γa,aunsaturated a-amino acid thioesters were found to be substrates for the subtilisin-catalysed hydrolysis to the corresponding acids. The D-enantiomer was continuously racemised in the presence of an organic base. The combined reactions in a biphasic system allowed the deracemisation of the amino acid derivatives based on a dynamic kinetic resolution. Excellent yields and enantioselectivities were achieved.
Arosio, Dario,Caligiuri, Antonio,D'Arrigo, Paola,Pedrocchi-Fantoni, Giuseppe,Rossi, Cristina,Saraceno, Caterina,Servi, Stefano,Tessaro, Davide
p. 1345 - 1348
(2008/09/16)