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APPLICATION OF MONOCYCLIC BETA-LACTAM COMPOUND IN PHARMACY
An application of a compound represented by formula (I) and pharmaceutically acceptable salts thereof in preparation of a drug for treating pneumonia.
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Paragraph 0039; 0040

(2021/11/04)

In search of small molecules that selectively inhibit mboat4
Ghrelin is a 28-residue peptide hormone produced by stomach P/D1 cells located in oxyntic glands of the fundus mucosa. Post-translational octanoylation of its Ser-3 residue, catalyzed by MBOAT4 (aka ghrelin O-acyl transferase (GOAT)), is essential for the binding of the hormone to its receptor in target tissues. Physiological roles of acyl ghrelin include the regulation of food intake, growth hormone secretion from the pituitary, and inhibition of insulin secretion from the pancreas. Here, we describe a medicinal chemistry campaign that led to the identification of small lipopeptidomimetics that inhibit GOAT in vitro. These molecules compete directly for substrate binding. We further describe the synthesis of heterocyclic inhibitors that compete at the acyl coenzyme A binding site.
Ding, Hui,Harran, Patrick G.,Hollibaugh, Ryan A.,Liu, Haixia,Murzinski, Emily S.,Saha, Ishika,Strugatsky, David,Tontonoz, Peter
(2021/12/24)

Radical-Mediated Acyl Thiol-Ene Reaction for Rapid Synthesis of Biomolecular Thioester Derivatives
The thiol-ene ‘click’ reaction has emerged as a versatile process for carbon–sulfur bond formation with widespread applications in chemical biology, medicinal chemistry and materials science. Thioesters are key intermediates in a wide range of synthetic and biological processes and efficient methods for their synthesis are of considerable interest. Herein, we report the first examples of acyl-thiol-ene (ATE) for the synthesis of biomolecular thioesters, including peptide, lipid and carbohydrate derivatives. A key finding is the profound effect of the amino acid side chain on the outcome of the ATE reaction. Furthermore, radical generated thioesters underwent efficient S-to-N acyl transfer and desulfurisation to furnish ‘sulfur-free’ ligation products in an overall amidation process with diverse applications for chemical ligation and bioconjugation.
Lynch, Dylan M.,McLean, Joshua T.,McSweeney, Lauren,Milbeo, Pierre,Scanlan, Eoin M.
supporting information
p. 4148 - 4160
(2021/08/24)

A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA1), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration
Neuropathic pain (NP) is a complex chronic pain state with a prevalence of almost 10% in the general population. Pharmacological options for NP are limited and weakly effective, so there is a need to develop more efficacious NP attenuating drugs. Activation of the type 1 lysophosphatidic acid (LPA1) receptor is a crucial factor in the initiation of NP. Hence, it is conceivable that a functional antagonism strategy could lead to NP mitigation. Here we describe a new series of LPA1 agonists among which derivative (S)-17 (UCM-05194) stands out as the most potent and selective LPA1 receptor agonist described so far (Emax = 118%, EC50 = 0.24 μM, KD = 19.6 nM; inactive at autotaxin and LPA2-6 receptors). This compound induces characteristic LPA1-mediated cellular effects and prompts the internalization of the receptor leading to its functional inactivation in primary sensory neurons and to an efficacious attenuation of the pain perception in an in vivo model of NP.
González-Gil, Inés,Zian, Debora,Vázquez-Villa, Henar,Hernández-Torres, Gloria,Martínez, R. Fernando,Khiar-Fernández, Nora,Rivera, Richard,Kihara, Yasuyuki,Devesa, Isabel,Mathivanan, Sakthikumar,Del Valle, Cristina Rosell,Zambrana-Infantes, Emma,Puigdomenech, María,Cincilla, Giovanni,Sanchez-Martinez, Melchor,Rodríguez De Fonseca, Fernando,Ferrer-Montiel, Antonio V.,Chun, Jerold,López-Vales, Rubén,López-Rodríguez, María L.,Ortega-Gutiérrez, Silvia
supporting information
p. 2372 - 2390
(2020/01/02)

Method for preparing high-purity (R)-4-formyl-2,2-dimethyl-3-oxazoline tert-butyl carboxylate
The invention discloses a method for preparing high-purity (R)-4-formyl-2,2-dimethyl-3-oxazoline tert-butyl carboxylate. The method comprises the following steps: carrying out a reaction on D-serine and thionyl chloride in methanol to obtain a compound 2; carrying out a reaction on the compound 2 and Boc anhydride under triethylamine to obtain a compound 3; carrying out a reaction on the compound3 and 2,2-dimethoxypropane under the action of boron trifluoride diethyl ether to obtain a compound 4; and reducing the compound 4 and DIBAL-H are at a temperature of -60 DEG C to -80 DEG C to obtaina crude product, carrying out a reaction on the crude product and sodium sulfite to form salt, and purifying to obtain the high-purity (R)-4-formyl-2,2-dimethyl-3-oxazoline tert-butyl carboxylate. According to the invention, the salt forming is performed by using the properties of sodium sulfite and an aldehyde group, so that the purity of the salified product can reach 98%, the industrial standard is met, and the production operation is well facilitated.
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Paragraph 0061; 0067-0070

(2020/03/09)

MONOCYCLIC B-LACTAM COMPOUND FOR TREATING BACTERIAL INFECTION
Disclosed are a class of new monocyclic β-lactam compounds, an isomer thereof or pharmaceutically acceptable salts thereof, and a pharmaceutical composition comprising the compounds, and the use of same in preparing drugs for treating diseases associated
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Paragraph 0072

(2020/12/16)

Chiral combinatorial preparation and biological evaluation of unique ceramides for inhibition of sphingomyelin synthase
Enantiomers or diastereomers of chiral bioactive compounds often exhibit different biological and toxicological properties. Here, we report the efficient synthesis of four stereoisomers of sphingosine and derivatization of unique chiral ceramides through a combinatorial chemistry by solid-phase activated resin ester. In addition, to test the effectivity of stereochemistry of ceramide, we demonstrated a cell-based assay of sphingomyelin synthase inhibition in the presence ofchiral unique ceramides, which suggested that libraries of this sort will be a rich source of biologically active synthetic molecules.
Koolath, Sajeer,Monde, Kenji,Murai, Yuta,Suga, Yoshiko
supporting information

(2020/02/04)

Methods and intermediates for synthesizing SK1-I
The invention provides methods for synthesizing the compound (2R,3S,4E)-N-methyl-5-(4′-pentylphenyl)-2-aminopent-4-ene-1,3-diol, also known as SK1-I, and intermediate compounds used in its synthesis.
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Page/Page column 3

(2019/08/20)

Pseudoenantiomeric glycoclusters: Synthesis and testing of heterobivalency in carbohydrate-protein interactions
Multivalent carbohydrate-protein interactions are key events in cell recognition processes and have been extensively studied by means of synthetic glycomimetics. To date, frequently the valency, i.e. the multiplicity of the ligand attached to a polyvalent
Brekalo, Jasna,Despras, Guillaume,Lindhorst, Thisbe K.
supporting information
p. 5929 - 5942
(2019/06/24)

Generating Stereodiversity: Diastereoselective Fluorination and Highly Diastereoselective Epimerization of α-Amino Acid Building Blocks
Diastereoselective fluorination of N-Boc (R)- and (S)-2,2-dimethyl-4-((arylsulfonyl)methyl)oxazolidines and a previously unknown diastereoselective epimerization at the fluorine-bearing carbon atom α to the sulfone was realized. Diastereoselectivities of both reactions were excellent for benzothiazolyl sulfones, allowing access to two enantiomerically pure diastereomers from one chiral precursor. To demonstrate synthetic utility, the benzothiazolyl sulfones were converted to diastereomerically pure (S,S)- and (R,S)-benzyl sulfones via sulfinate salts and to amino acids. To understand the diastereoselectivities, DFT analysis was performed.
Wei, Wei,Khangarot, Rama Kanwar,Stahl, Lothar,Veresmortean, Cristina,Pradhan, Padmanava,Yang, Lijia,Zajc, Barbara
supporting information
p. 3574 - 3578
(2018/06/26)

FUSED MORPHOLINOPYRIMIDINES AND METHODS OF USE THEREOF
The present disclosure relates to Fused Morpholinopyrimidines, pharmaceutical compositions comprising an effective amount of a Fused Morpholinopyrimidine and methods for using a Fused Morpholinopyrimidine in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine.
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Paragraph 1068

(2017/05/14)

Structure-activity relationships of lysophosphatidylserine analogs as agonists of G-protein-coupled receptors GPR34, P2Y10, and GPR174
Lysophosphatidylserine (LysoPS) is an endogenous lipid mediator generated by hydrolysis of membrane phospholipid phosphatidylserine. Recent ligand screening of orphan G-protein-coupled receptors (GPCRs) identified two LysoPS-specific human GPCRs, namely, P2Y10 (LPS2) and GPR174 (LPS3), which, together with previously reported GPR34 (LPS1), comprise a LysoPS receptor family. Herein, we examined the structure-activity relationships of a series of synthetic LysoPS analogues toward these recently deorphanized LysoPS receptors, based on the idea that LysoPS can be regarded as consisting of distinct modules (fatty acid, glycerol, and l-serine) connected by phosphodiester and ester linkages. Starting from the endogenous ligand (1-oleoyl-LysoPS, 1), we optimized the structure of each module and the ester linkage. Accordingly, we identified some structural requirements of each module for potency and for receptor subtype selectivity. Further assembly of individually structure-optimized modules yielded a series of potent and LysoPS receptor subtype-selective agonists, particularly for P2Y10 and GPR174.
Ikubo, Masaya,Inoue, Asuka,Nakamura, Sho,Jung, Sejin,Sayama, Misa,Otani, Yuko,Uwamizu, Akiharu,Suzuki, Keisuke,Kishi, Takayuki,Shuto, Akira,Ishiguro, Jun,Okudaira, Michiyo,Kano, Kuniyuki,Makide, Kumiko,Aoki, Junken,Ohwada, Tomohiko
supporting information
p. 4204 - 4219
(2015/06/08)

FUSED MORPHOLINOPYRIMIDINES AND METHODS OF USE THEREOF
The present disclosure relates to Fused Morpholinopyrimidines, pharmaceutical compositions comprising an effective amount of a Fused Morpholinopyrimidine and methods for using a Fused Morpholinopyrimidine in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine.
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Paragraph 0776

(2015/08/03)

NIPECOTIC ACID DERIVATIVE AND USE THEREOF FOR MEDICAL PURPOSES
The present invention aims to provide a compound having an sEH-inhibiting activity and to provide a pharmaceutical having a therapeutic effect and a prophylactic effect on chronic renal disease and pulmonary hypertension based on the sEH-inhibiting action. The present invention provides nipecotic acid derivatives represented by the chemical formula below and pharmaceutically acceptable salts thereof.
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Paragraph 0186

(2015/03/03)

Docking model of the nicotinic acetylcholine receptor and nitromethylene neonicotinoid derivatives with a longer chiral substituent and their biological activities
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
p. 759 - 769
(2015/02/19)

Synthesis of novel 2,3,4-trisubstituted-oxazolidine derivatives and in Vitro cytotoxic evaluation
We have previously reported the discovery of cytotoxic and pro-Apoptotic hit compound 1,1-dimethylethyl (S)- 2,2-dimethyl-4-[(3-nitrophenoxy)methyl]-3- oxazolidinecarboxylate 1 against leukemia cells. In the present work we describe the synthesis of 25 derivatives of this hit varying the substituent at ring or stereochemistry of the oxazolidine ring and evaluated them against human cancer cells lines. Six compounds exerted significant activity against HL60 promyelocytic leukemia cells with IC50 in low micromolar range (4-18 μM) and three compounds displayed activity against MDA-MB231 breast cancer cells (25-37 μM). In vitro cytotoxicity on normal cells PBMC (human peripheral blood mononuclear cells) was also evaluated. Compounds 7e (p-NO2, S) and 7m (p-COOCH3, S) showed good antiproliferative activity against HL60 (4 and 5 μM) and MDA-MB231 (37 and 25 μM) without affecting lymphocyte proliferation in PBMC, indicating low toxicity to normal cells. Besides, compound 7e induced DNA fragmentation on about 100% of HL60 cells at 50 μM. In this case, it was more potent than 7m and lead 1. This indicated that compound 7e has a great pro-Apoptotic potential.
Andrade, Saulo F.,Campos, Edmar F.S.,Teixeira, Claudia S.,Bandeira, Cristiano C.,Lavorato, Stefania N.,Romeiro, Nelilma C.,Bertollo, Caryne M.,Oliveira, M?nica C.,Souza-Fagundes, Elaine M.,Alves, Ricardo J.
p. 609 - 618
(2014/11/07)

Stereoselective synthesis of lanthionine derivatives in aqueous solution and their incorporation into the peptidoglycan of Escherichia coli
The three diastereoisomers - (R,R), (S,S) and meso - of lanthionine were synthesized in aqueous solution with high diastereoselectivity (>99%). The (S) and (R) enantiomers of two differently protected sulfamidates were opened by nucleophilic attack of (R) or (S)-cysteine. Acidification and controlled heating liberated the free lanthionines. Using the same chemistry, an α-benzyl lanthionine was also prepared. The proposed method, which avoids the need of enrichment by recrystallization, opens the way to the labelling of these compounds with 35S. Furthermore, in vivo bioincorporation into Escherichia coli W7 was studied. No incorporation of α-benzyl lanthionine was observed. In contrast, meso-lanthionine can effectively replace meso-diaminopimelic acid in vivo, while in the presence of (R,R)-lanthionine the initial increase of bacterial growth was followed by cell lysis. In the future, meso-[35S]lanthionine could be used to study the biosynthesis of peptidoglycan and its turnover in relation to cell growth and division.
Denoel, Thibaut,Zervosen, Astrid,Gerards, Thomas,Lemaire, Christian,Joris, Bernard,Blanot, Didier,Luxen, Andre
p. 4621 - 4628
(2014/10/16)

Synthesis of d -abrines by palladium-catalyzed reaction of ortho-iodoanilines with N -Boc- N -methylalanyl-substituted acetaldehyde and acetylene
A novel strategy to N-Boc-N-methyl - tryptophans (abrine derivatives) was developed that relies on the palladium-catalyzed annulation of ortho-iodoanilines 12 with either N-Boc-N-methyl-propargylglycine 16 or aldehyde 11. Both 11 and 16 can be prepared from d-serine. An alternative route to propargylglycine 16 utilizes an enantioselective propargylation reaction of glycine imine 17.
Danner, Paulami,Morkunas, Marius,Maier, Martin E.
p. 2474 - 2477
(2013/07/04)

AMIDINE SUBSTITUTED BETA - LACTAM COMPOUNDS, THEIR PREPARATION AND USE AS ANTIBACTERIAL AGENTS
The present invention relates to novel β-lactam compounds of formula (I), their preparation and use. In particular, this invention relates to novel β-lactam compounds which are amidine substituted monobactam derivatives useful as antimicrobial agents and their preparation.
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Paragraph 00104; 00105

(2013/08/15)

Synthesis and biological evaluation (in Vitro and in Vivo) of cyclic arginine-glycine-aspartate (RGD) peptidomimetic-paclitaxel conjugates targeting integrin αvβ3
A small library of integrin ligand-paclitaxel conjugates 10-13 was synthesized with the aim of using the tumor-homing cyclo[DKP-RGD] peptidomimetics for site-directed delivery of the cytotoxic drug. All the paclitaxel-RGD constructs 10-13 inhibited biotinylated vitronectin binding to the purified αVβ3 integrin receptor at low nanomolar concentration and showed in vitro cytotoxic activity against a panel of human tumor cell lines similar to that of paclitaxel. Among the cell lines, the cisplatin-resistant IGROV-1/Pt1 cells expressed high levels of integrin αVβ3, making them attractive to be tested in in vivo models. cyclo[DKP-f3-RGD]-PTX 11 displayed sufficient stability in physiological solution and in both human and murine plasma to be a good candidate for in vivo testing. In tumor-targeting experiments against the IGROV-1/Pt1 human ovarian carcinoma xenotransplanted in nude mice, compound 11 exhibited a superior activity compared with paclitaxel, despite the lower (about half) molar dosage used.
Colombo, Raffaele,Mingozzi, Michele,Belvisi, Laura,Arosio, Daniela,Piarulli, Umberto,Carenini, Nives,Perego, Paola,Zaffaroni, Nadia,De Cesare, Michelandrea,Castiglioni, Vittoria,Scanziani, Eugenio,Gennari, Cesare
supporting information
p. 10460 - 10474
(2013/02/22)

Transformation of d-serine to highly functionalized cyclohexenecarboxylates in study of oseltamivir synthesis
In an attempted synthesis of oseltamivir, D-serine was used to prepare (R)-Garner aldehyde, which reacted with vinylzinc reagent to give an alcohol product predominating in the (1′R,4S)-isomer. After the alcohol was protected as p-methoxybenzyl ether, the N,O-acetal was hydrolyzed and oxidized to an aldehyde, which underwent Reformatsky-type reaction with ethyl α-(bromomethyl)acrylate by promotion of indium to give an addition product readily for ring-closure metathesis to afford 3-alkoxy-4-amido-5-hydroxy-1- cyclohexenecarboxylates. After activation of the 5-hydroxy group as methanesulfonate, an attempted substitution reaction with sodium azide gave unexpectedly a cyclic carbamate via an intramolecular nucleophilic attack of the 4-tert-butoxycarbamate group.
Lai, Joshua,Fang, Jim-Min
scheme or table
p. 426 - 435
(2012/08/07)

Catalytic asymmetric [4+2] annulation initiated by an aza-rauhut-currier reaction: Facile entry to highly functionalized tetrahydropyridines
Under control: The first example of chiral amino phosphine catalysts for the title reaction between vinyl ketones and N-sulfonyl-1-aza-1,3-dienes has been developed. Under ambient conditions, this protocol provides straightforward access to densely functionalized, enantioenriched tetrahydropyridines with high levels of sterecontrol in good to excellent yields. Copyright
Shi, Zugui,Yu, Peiyuan,Loh, Teck-Peng,Zhong, Guofu
supporting information; scheme or table
p. 7825 - 7829
(2012/09/08)

Total synthesis and complete structural assignment of thiocillin i
The total synthesis of the thiopeptide antibiotic, thiocillin I, is described. This work unequivocally defines the full structure (constitution and configuration) of the natural product as 1.
Aulakh, Virender S.,Ciufolini, Marco A.
supporting information; experimental part
p. 5900 - 5904
(2011/06/10)

Orthogonally protected glycerols and 2-aminodiols: Useful building blocks in heterocyclic chemistry
The efficient synthesis of orthogonally protected glycerols, 2-aminopropane-1,3-diols and 2-aminobutane-1,4-diols that can constitute useful tools in heterocyclic chemistry, is reported. These interesting tri-functionalized small synthons were easily prepared from serine or aspartic acid. In addition, these substrates can be readily transformed into their iodide derivatives in very good yields. ARKAT USA, Inc.
Ollivier, Anthony,Goubert, Marlene,Tursun, Ahmatjan,Canet, Isabelle,Sinibaldia, Marie-Eve
experimental part
p. 108 - 126
(2010/10/03)

Development of new stereodiverse diaminocyclitols as inhibitors of influenza virus neuraminidase
"Chemical Equation Presented" A concise and modular approach to synthesize a new type of cyclopentene-based diaminocyclitol library from D-serine and L-serine has been developed, and key steps in this synthesis are an aza-Claisen rearrangement, a ring-closing metathesis, and a Baylis-Hillman reaction. The developed chemistry may offer a unique way to investigate the neuraminidase (NA) mutation by systematically mapping the changes within its binding sites.
Cui, Yi,Jiao, Zhaodong,Gong, Jianxian,Yu, Quan,Zheng, Xiaofeng,Quan, Junmin,Luo, Ming,Yang, Zhen
supporting information; experimental part
p. 4 - 7
(2010/03/03)

Total synthesis of the large non-ribosomal peptide polytheonamide B
Polytheonamide B is by far the largest non-ribosomal peptide known at present, and displays extraordinary cytotoxicity (EC50 =68 pg ml -1 , mouse leukaemia P388 cells). Its 48 amino-acid residues include a variety of non-proteinogenic d- and l-amino acids, and the absolute stereochemistry of these amino acids alternate in sequence. These structural features induce the formation of a stable β-strand-type structure, giving rise to an overall tubular structure over 30A? in length. In a biological setting, this fold is believed to transport cations across the lipid bilayer through a pore, thereby acting as an ion channel. Here, we report the first chemical construction of polytheonamide B. Our synthesis relies on the combination of four key stages: syntheses of non-proteinogenic amino acids, a solid-phase assembly of four fragments of polytheonamide B, silver-mediated connection of the fragments and, finally, global deprotection. The synthetic material now available will allow studies of the relationships between its conformational properties, channel functions and cytotoxicity.
Inoue, Masayuki,Shinohara, Naoki,Tanabe, Shintaro,Takahashi, Tomoaki,Okura, Ken,Itoh, Hiroaki,Mizoguchi, Yuki,Iida, Maiko,Lee, Nayoung,Matsuoka, Shigeru
supporting information; scheme or table
p. 280 - 285
(2010/09/03)

4,4-Difluorinated analogues of l-arginine and NG-hydroxy-l-arginine as mechanistic probes for nitric oxide synthase
4,4-Difluoro-l-arginine and 4,4-difluoro-NG-hydroxy-l-arginine were synthesized and shown to be substrates for the inducible isoform of nitric oxide synthase (iNOS). Binding of both fluorinated analogues to the NOS active site was also investigated using a spectral binding assay employing a heme domain construct of the inducible NOS isoform (iNOSheme). 4,4-Difluoro-NG-hydroxy-arginine was found to bind at the NOS active site in a unique manner consistent with a model involving ligation of the FeIII heme center by the oxygen atom of the NG-hydroxy moiety.
Martin, Nathaniel I.,Woodward, Joshua J.,Winter, Michael B.,Marletta, Michael A.
supporting information; experimental part
p. 1758 - 1762
(2009/11/30)

The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K
Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclinical species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors.
Gauthier, Jacques Yves,Chauret, Nathalie,Cromlish, Wanda,Desmarais, Sylvie,Duong, Le T.,Falgueyret, Jean-Pierre,Kimmel, Donald B.,Lamontagne, Sonia,Leger, Serge,LeRiche, Tammy,Li, Chun Sing,Masse, Frederic,McKay, Daniel J.,Nicoll-Griffith, Deborah A.,Oballa, Renata M.,Palmer, James T.,Percival, M. David,Riendeau, Denis,Robichaud, Joel,Rodan, Gideon A.,Rodan, Sevgi B.,Seto, Carmai,Therien, Michel,Truong, Vouy-Linh,Venuti, Michael C.,Wesolowski, Gregg,Young, Robert N.,Zamboni, Robert,Black, W. Cameron
p. 923 - 928
(2008/12/22)

Examining the chirality, conformation and selective kinase inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino) piperidin-1-yl)-3-oxopropanenitrile (CP-690,550)
Here, we examine the significance that stereochemistry plays within the clinically relevant Janus kinase 3 (Jak3) inhibitor 1 (CP-690,550). A synthesis of all four enantiopure stereoisomers of the drug was carried out and an examination of each compound revealed that only the enantiopure 3R,4R isomer was capable of blocking Stat5 phosphorylation (Jak3 dependent). Each compound was profiled across a panel of over 350 kinases, which revealed a high level of selectivity for the Jak family kinases for these related compounds. Each stereoisomer retained a degree of binding to Jak3 and Jak2 and the 3R,4S and 3S,4R stereoisomers were further revealed to have binding affinity for selected members of the STE7 and STE20 subfamily of kinases. Finally, an appraisal of the minimum energy conformation of each stereoisomer and molecular docking at Jak3 was performed in an effort to better understand each compounds selectivity and potency profiles.
Jiang, Jian-Kang,Ghoreschi, Kamran,Deflorian, Francesca,Chen, Zhi,Perreira, Melissa,Pesu, Marko,Smith, Jeremy,Nguyen, Dac-Trung,Liu, Eric H.,Leister, William,Costanzi, Stefano,O'Shea, John J.,Thomas, Craig J.
supporting information; experimental part
p. 8012 - 8018
(2009/12/07)

Total synthesis of (-)-aplaminal
(Chemical Equation Presented) The total synthesis and assignment of absolute configuration of (-)-aplaminal (1), a cytotoxic metabolite from a sea hare possessing a triazobicyclo[3.2.1]octane skeleton, has been achieved. The synthesis entailed condensatio
Smith III, Amos B.,Liu, Zhuqing
supporting information; experimental part
p. 4363 - 4365
(2009/06/06)

A novel synthesis of highly substituted perhydropyrrolizines, perhydroindolizines, and pyrrolidines: Inhibition of the peptidyl-prolyl cis/trans isomerase (PPIase) Pin1
In this paper, we describe the synthesis and biological evaluation of highly substituted perhydropyrrolizines that inhibit the peptidyl-prolyl cis/trans isomerase (PPIase) Pin1, an oncogenic target. The enzyme selectively catalyzes the cis/trans isomeriza
Siegrist, Romain,Zuercher, Martina,Baumgartner, Corinne,Seiler, Paul,Diederich, Francois,Daum, Sebastian,Fischer, Gunter,Klein, Christian,Dangl, Markus,Schwaiger, Manfred
p. 217 - 259
(2008/02/09)

Novel peptidomimetic cysteine protease inhibitors as potential antimalarial agents
The synthesis of a new class of peptidomimetics 1a-j, based on a 1,4-benzodiazepine scaffold and on a C-terminal aspartyl aldehyde building block, is described. Compounds 1a-j provided significant inhibitory activity against falcipains 2A and 2B (FP-2A an
Micale, Nicola,Kozikowski, Alan P.,Ettari, Roberta,Grasso, Silvana,Zappalà, Maria,Jeong, Jong-Jin,Kumar, Ajay,Hanspal, Manjit,Chishti, Athar H.
p. 3064 - 3067
(2007/10/03)

Synthesis of fluorescent lactosylceramide stereoisomers
The intracellular distribution of synthetic glycosphingolipids (GSLs) bearing a fluorophore can be monitored in living cells by fluorescence microscopy. We reported previously that variation in the length of the long-chain base and in the structure of the carbohydrate-containing polar head group of (2S,3R) (or d-erythro-)-β-lactosylceramide (LacCer) did not alter the mechanism of endocytic uptake from the plasma membrane of various mammalian cell types [Singh, R.D., Puri, V., Valiyaveettil, J.T., Marks, D.L., Bittman, R., Pagano, R.E., 2003. Selective caveolin-1-dependent endocytosis of glycosphingolipids. Mol. Biol. Cell 14, 3254-3265]. To extend our examination of the molecular features in LacCer that are responsible for its uptake by the caveolar-requiring endocytic pathway, we have synthesized the three unnatural stereoisomers [(2R,3R)-, (2S,3S)-, and (2R,3S)] of dipyrromethene difluoride (BODIPY)-LacCer. These analogues will be used to probe the role of stereochemistry in the long-chain base of LacCer in the mechanism of endocytic uptake.
Liu, Yidong,Bittman, Robert
p. 58 - 69
(2007/10/03)

8-AZAPROSTAGLANDIN DERIVATIVES AND MEDICINAL USES THEREOF
The pharmaceutical composition comprising the compound of the invention having 8-azaprostaglandin skeleton represented by formula (I) (wherein, all the symbols have the same meanings as that of the specification.) a salt thereof, a solvate thereof or a cyclodextrin clathrate thereof, or a prodrug thereof and them as active ingredient have EP4 agonistic action and thus are considered useful for the prevention and/or treatment of immunological diseases, asthma, neuronal cell death, arthritis, lung failure, pulmonary fibrosis, pulmonary emphysema, bronchitis, chronic obstructive pulmonary disease, liver damage, acute hepatitis, nephritis, renal insufficiency, hypertension, myocardial ischemia, systemic inflammatory response syndrome, sepsis, hemophagous syndrome, macrophage activation syndrome, Still''s disease, Kawasaki disease, burn, systemic granulomatosis, ulcerative colitis, Crohn''s disease, hypercytokinemia at dialysis, multiple organ failure, shock and glaucoma, etc. Furthermore, the compounds also have an action of accelerating bone formation, so it is expected to be useful for the prevention and/or treatment of diseases associated with loss in bone mass, for example, primary osteoporosis, secondary osteoporosis, bone metastasis of cancer, hypercalcemia, Paget''s disease, bone loss, osteonecrosis, bone formation after bone operation, alternative treatment for bone grafting.
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Page/Page column 57

(2010/02/14)

Novel aliphatic compounds, process for their preparation and their usage
The present invention provides an aliphatic compound represented by the following formula (I) or pharmacologically acceptable salts thereof: where n denotes an integer of 1 to 11, and 1 denotes an integer of 1 to 16, the aliphatic compound being an optical isomer of the (2R,3S,2′S) configuration when the 8-position thereof is a double bond, or an optical isomer of the (2S,3R,2′RS) configuration when the 8-position is a single bond; methods for producing the compound or pharmacologically acceptable salts thereof; and uses of the compound in the treatment of cardiovascular diseases (e.g. arteriosclerosis, cardiac diseases), cancer, rheumatism, diabetic retinopathy, and respiratory diseases.
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Page/Page column 11-12

(2010/02/05)

Synthesis of 3-Aminochroman Derivatives by Radical Cyclization
(Equation presented) Enantiomerically pure 5-acetyl-3-amino-3,4-dihydro-2H- 1-benzopyran and methyl 3-amino-3,4-dihydro-2H-1-benzopyran-5-carboxylate were successfully synthesized starting from D- or L-serine. The formation of the benzopyran ring involved a radical cyclization step. The enantiomeric purities of the final aminochroman derivatives were determined by capillary electrophoresis using β-cyclodextrins as a chiral selector.
Pave, Gregoire,Usse-Versluys, Stephanie,Viaud-Massuard, Marie-Claude,Guillaumet, Gerald
p. 4253 - 4256
(2007/10/03)

Efficient radical cyclisation of secondary amides: An enantioselective synthesis of phenyl allokainoid
Cyclisation of various unsaturated haloamides with tributyltin hydride/AIBN has been explored. Substituted pyrrolidinones were isolated in good to excellent yield and the cyclisation of a serine-derived amide was utilised as the key step in an enantiosele
Bryans, Justin S.,Large, Jonathan M.,Parsons, Andrew F.
p. 3487 - 3490
(2007/10/03)

Efficient tin hydride-mediated radical cyclisation of secondary amides leading to substituted pyrrolidinones. Part 2. Application to the synthesis of aromatic kainic acid analogues
An enantioselective synthesis of phenyl allokainoid, starting from D-serine, is reported. Tin-mediated cyclisation of a secondary amide was used in the key step to produce a trisubstituted pyrrolidinone in excellent yield (ca. 80%). The predominant format
Bryans, Justin S.,Large, Jonathan M.,Parsons, Andrew F.
p. 2905 - 2910
(2007/10/03)

The synthesis of 4,5-methano congeners of α-kainic and α-allo-kainic acids as probes for glutamate receptors
The synthesis of diastereomeric 4,5-methano-L-proline 3-acetic acids is described starting from D-serine. The key reactions include a free-radical carbocyclization and an acid-catalyzed destannylative cyclopropanation of an iminium ion intermediate. Copyright (C) 1996 Elsevier Science Ltd.
Hanessian, Stephen,Ninkovic, Sacha,Reinhold, Ulrich
p. 8971 - 8974
(2007/10/03)

Grignard reactions to chiral oxazolidine aldehydes
Modest to high levels of asymmetric induction are observed with Grignard additions to Garner type aldehydes. The resultant secondary alcohols are important precursors of chiral building blocks for asymmetric synthesis and we have demonstrated that they can be readily converted into their respective γ-hydroxy-β-amino alcohols and β-hydroxyamino acids. Additionally, aryloxy ethers, important components of many natural products, can be obtained from these precursors.
Williams, Lorenzo,Zhang, Zhongda,Shao, Feng,Carroll, Patrick J.,Joullie, Madeleine M.
p. 11673 - 11694
(2007/10/03)

A practical stereoselective synthesis of (2S, 3S)-3-hydroxyleucine
A practical and convenient procedure is described for the preparation of gram quantities of (2S, 3S)-3-hydroxyleucine. The key step involves the triflate-mediated cyclization of spirooxazolidine 4 to the spirobicyclic compound 5, which is easily converted to the title compound in high yield.
Williams, Lorenzo,Zhang, Zhongda,Ding, Xiaobin,Joullie, Madeleine M.
p. 7031 - 7034
(2007/10/02)

Synthesis of conformationally restricted analogs of kainic acid. Is the conformation of the C4-substituent of kainoid important to its neuroexcitatory activity?
Conformationally restricted analogs of kainic acid, which have an azabicyclo[3.3.0]octane system, were synthesized through the intramolecular addition reaction of trimethylenemethane to the α,β-unsaturated ester. Every synthesized isomer showed very weak depolarizing activity. These results indicate that the plane of the isopropenyl group of kainic acid should be diagonal to the pyrrolidine ring to show potent activity.
Hashimoto, Kimiko,Ohfune, Yasufumi,Shirahama, Haruhisa
p. 6235 - 6238
(2007/10/02)

GUANIDINO COMPOUNDS AS REGULATORS OF NITRIC OXIDE SYNTHASE
Compounds of the formula:useful as regulators of nitric oxide synthase that indirectly modulate cyclic guanosine monophosphate (cGMP), pharmaceutical compositions thereof, for treating disorders of vascular smooth muscles, macrophages, neurons, platelets, bronchial smooth muscles, optic muscles and gastrointestinal smooth muscles, sickle cell anemia and diabetes.
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(2008/06/13)

Guanidino compounds as regulators of nitric oxide synthase
Compounds of the formula: STR1 useful as regulators of nitric oxide synthase that indirectly modulate cyclic guanosine monophosphate (cGMP), pharmaceutical compositions thereof, for treating disorders of vascular smooth muscles, macrophages, neurons, platelets, bronchial smooth muscles, optic muscles and gastrointestinal smooth muscles, sickle cell anemia and diabetes.
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(2008/06/13)

Total synthesis of balanol
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Nicolaou,Bunnage,Bunnage, Mark E.,Koide,Koide, Kazunori
p. 8402 - 8403
(2007/10/02)

1,1,-Dimethylethyl (S)- or (R)-4-formyl-2,2-dimethyl-3-oxazolidinecarboxylate: A useful serinal derivative
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Garner, Philip,Park, Jung Min
p. 18 - 18
(2017/05/23)

SYNTHESIS OF ACYCLIC ANALOGUES OF KAINOIDS AND NEUROEXCITATORY ACTIVITY
Four configurational isomers of 3-benzylglutamic acid, acyclic analogues of kainoids were synthesized to examine their structure-activity relationship.
Yanagida, Miwa,Hashimoto, Kimiko,Ishida, Michiko,Shinozaki, Haruhiko,Shirahama, Haruhisa
p. 3799 - 3802
(2007/10/02)

SYNTHESIS OF A MODEL DEPSIPEPTIDE SEGMENT OF LUZOPEPTINS (BBM 928), POTENT ANTITUMOR AND ANTIRETROVIRAL ANTIBIOTICS
A modified Rapoport procedure was used to synthesize a tripeptide containing N-methyl-3-hydroxyvaline, an unusual aminoacid found in Luzopeptins.
Ciufolini, Marco A.,Swaminathan, Shankar
p. 3027 - 3028
(2007/10/02)

The Synthesis and Configurational Stability of Differentially Protected β-Hydroxy-β-amino Aldehydes
Syntheses of 1,1-dimethylethyl (S)-4-formyl-2,2-dimethyl-3-oxazolidinecarboxylate (5) and 1,1-dimethylethyl (4S-trans)-4-formyl-2,2,5-trimethyl-3-oxazolidinecarboxylate (6) from commercially available serine and threonine derivatives are described.The method involves selective reduction of the corresponding oxazolidine esters 3 and 4 using diisobutylaluminum hydride at low temperature.These differentially protected β-hydroxy-α-amino aldehydes are also shown to be produced in 93-95 percent enantiomeric excess (via NMR and HPLC analysis of the Mosher esterderivatives 8 and epi-8)-thus making them useful as chiral, nonracemic synthons for asymmetric synthesis.
Garner, Philip,Park, Jung Min
p. 2361 - 2364
(2007/10/02)