- An optimized BRD4 inhibitor effectively eliminates NF-κB-driven triple-negative breast cancer cells
-
Acetylation of NF-κB's RelA subunit at lysine-310 (AcLys310) helps to maintain constitutive NF-κB activity in cancers such as triple-negative breast cancer (TNBC). Bromodomain-containing factor BRD4 binds to acetylated RelA to promote the activity of NF-κB. Hence, interfering with the acetylated RelA-BRD4 interaction is a potential strategy for treating NF-κB-driven TNBC. Here, a new compound 13a was obtained by structural optimization and modification of our previously reported compound. In comparison with the well-known BRD4 inhibitor (+)-JQ1, 13a showed more potent anticancer activity in NF-κB-active MDA-MB-231 cells. Mechanistically, 13a antagonized the protein–protein interaction (PPI) between BRD4 and acetylated RelA, decreased levels of IL-6, IL-8, Snail, Vimentin, and ZEB1, induced cell senescence and DNA damage, and weakened the adhesion, metastasis, and invasion ability of TNBC cells. Our results provide insights into avenues for the further development of potent BRD4-acetylated RelA PPI inhibitors. Moreover, our findings highlight the effectiveness and feasibility of blocking the interaction between BRD4 and acetylated RelA against NF-κB-active cancers, and of screening antagonists of this PPI.
- Yang, Guan-Jun,Song, Ying-Qi,Wang, Wanhe,Han, Quan-Bin,Ma, Dik-Lung,Leung, Chung-Hang
-
-
Read Online
- A New Approach to the Synthesis of Diethyl 2,3-Diisobutylsuccinate, a Component of Titanium–Magnesium Catalysts for Propylene Polymerization
-
A procedure was developed for preparing 2,3-dialkyl-substituted succinates by condensation of a succinic acid diester with two isobutyraldehyde molecules, followed by esterification and hydrogenation of the sum of dienes. Diethyl 2,3-diisobutylsuccinate of 75%–99% purity was prepared by this procedure in a good yield. The use of the synthesized diethyl 2,3-diisobutylsuccinate as a stereoregulating component of titanium–magnesium catalysts allows synthesis of polypropylene with broad molecular-mass distribution. The catalysts prepared using >95% pure diethyl 2,3-diisobutylsuccinate demonstrated the best characteristics and allowed polypropylene synthesis with high isotacticity index in a high yield.
- Barabanov, A. A.,Bukatov, G. D.,Mainagashev, I. Ya.,Mats’ko, M. A.,Nechepurenko, I. V.,Salakhutdinov, N. F.,Sergeev, S. A.,Volcho, K. P.,Zakharov, V. A.
-
p. 715 - 725
(2021/08/13)
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- O-to-S Substitution Enables Dovetailing Conflicting Cyclizability, Polymerizability, and Recyclability: Dithiolactone vs. Dilactone
-
Developing chemically recyclable polymers represents a greener alternative to landfill and incineration and offers a closed-loop strategy toward a circular materials economy. However, the synthesis of chemically recyclable polymers is still plagued with certain fundamental limitations, including trade-offs between the monomer's cyclizability and polymerizability, as well as between polymer's depolymerizability and properties. Here we describe the subtle O-to-S substitution, dithiolactone monomers derived from abundant feedstock α-amino acids can demonstrate appealing chemical properties different from those of dilactone, including accelerated ring closure, augmented kinetics polymerizability, high depolymerizability and selectivity, and thus constitute a unique class of polythioester materials exhibiting controlled molecular weight (up to 100.5 kDa), atactic yet high crystallinity, structurally diversity, and chemical recyclability. These polythioesters well addresses the formidable challenges of developing chemically recyclable polymers by having an unusual set of desired properties, including easy-to-make monomer from ubiquitous feedstock, and high polymerizability, crystallinity and precise tunability of physicochemical performance, as well as high depolymerizability and selectivity. Computational studies explain why O-to-S modification of polymer backbone enables dovetailing desirable, but conflicting, performance into one polymer structure.
- Wang, Yanchao,Li, Maosheng,Chen, Jinlong,Tao, Youhua,Wang, Xianhong
-
supporting information
p. 22547 - 22553
(2021/09/09)
-
- Synthesis, structure and reactivity of some chiral benzylthio alcohols, 1,3-oxathiolanes and their S-oxides
-
A series of amino acid-derived chiral benzylthio alcohols have been prepared and characterized. A chiral mercapto alcohol derived from S-leucine has been used to form three chiral 2,4-disubstituted 1,3-oxathiolanes. One of these has been oxidized to the S-oxide and another to the S,S-dioxide. The cis and trans isomers have been characterized by 1H NMR in each case and it appears that thermal epimerisation at C-2 is possible at the sulfoxide oxidation state. The X-ray structure of major trans diastereomer of 2-phenyl-4-isobutyl-1,3-oxathiolane S,S-dioxide shows an envelope conformation with oxygen at the flap and an internal angle at sulfur of just 93.8°. This compound fragments upon flash vacuum pyrolysis at 700°C to give SO2, benzaldehyde and 4-methylpent-1-ene.
- Aitken, R. Alan,Lightfoot, Philip,Thomas, Andrew W.
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p. 369 - 387
(2020/05/25)
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- Benzoxazinone-containing 3,5-dimethylisoxazole derivatives as BET bromodomain inhibitors for treatment of castration-resistant prostate cancer
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The bromodomain and extra-terminal proteins (BET) have emerged as promising therapeutic targets for the treatment of castration-resistant prostate cancer (CRPC). We report the design, synthesis and evaluation of a new series of benzoxazinone-containing 3,5-dimethylisoxazole derivatives as selective BET inhibitors. One of the new compounds, (R)-12 (Y02234), binds to BRD4(1) with a Kd value of 110 nM and blocks bromodomain and acetyl lysine interactions with an IC50 value of 100 nM. It also exhibits selectivity for BET over non-BET bromodomain proteins and demonstrates reasonable anti-proliferation and colony formation inhibition effect in prostate cancer cell lines such as 22Rv1 and C4-2B. The BRD4 inhibitor (R)-12 also significantly suppresses the expression of ERG, Myc and AR target gene PSA at the mRNA level in prostate cancer cells. Treatment with (R)-12 significantly suppresses the tumor growth of prostate cancer (TGI = 70%) in a 22Rv1-derived xenograft model. These data suggest that compound (R)-12 is a promising lead compound for the development of a new class of therapeutics for the treatment of CRPC.
- Xue, Xiaoqian,Zhang, Yan,Wang, Chao,Zhang, Maofeng,Xiang, Qiuping,Wang, Junjian,Wang, Anhui,Li, Chenchang,Zhang, Cheng,Zou, Lingjiao,Wang, Rui,Wu, Shuang,Lu, Yongzhi,Chen, Hongwu,Ding, Ke,Li, Guohui,Xu, Yong
-
supporting information
p. 542 - 559
(2018/05/24)
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- α-Aminoxy Oligopeptides: Synthesis, Secondary Structure, and Cytotoxicity of a New Class of Anticancer Foldamers
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α-Aminoxy peptides are peptidomimetic foldamers with high proteolytic and conformational stability. To gain an improved synthetic access to α-aminoxy oligopeptides we used a straightforward combination of solution- and solid-phase-supported methods and obtained oligomers that showed a remarkable anticancer activity against a panel of cancer cell lines. We solved the first X-ray crystal structure of an α-aminoxy peptide with multiple turns around the helical axis. The crystal structure revealed a right-handed 28-helical conformation with precisely two residues per turn and a helical pitch of 5.8 ?. By 2D ROESY experiments, molecular dynamics simulations, and CD spectroscopy we were able to identify the 28-helix as the predominant conformation in organic solvents. In aqueous solution, the α-aminoxy peptides exist in the 28-helical conformation at acidic pH, but exhibit remarkable changes in the secondary structure with increasing pH. The most cytotoxic α-aminoxy peptides have an increased propensity to take up a 28-helical conformation in the presence of a model membrane. This indicates a correlation between the 28-helical conformation and the membranolytic activity observed in mode of action studies, thereby providing novel insights in the folding properties and the biological activity of α-aminoxy peptides.
- Diedrich, Daniela,Moita, Ana J. Rodrigues,Rüther, Anja,Frieg, Benedikt,Reiss, Guido J.,Hoeppner, Astrid,Kurz, Thomas,Gohlke, Holger,Lüdeke, Steffen,Kassack, Matthias U.,Hansen, Finn K.
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p. 17600 - 17611
(2016/11/28)
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- Enantioselective construction of tetrasubstituted stereogenic carbons through bronsted base catalyzed michael reactions: α′-hydroxy enones as key enoate equivalent
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Catalytic and asymmetric Michael reactions constitute very powerful tools for the construction of new C-C bonds in synthesis, but most of the reports claiming high selectivity are limited to some specific combinations of nucleophile/electrophile compound types, and only few successful methods deal with the generation of all-carbon quaternary stereocenters. A contribution to solve this gap is presented here based on chiral bifunctional Bronsted base (BB) catalysis and the use of α′-oxy enones as enabling Michael acceptors with ambivalent H-bond acceptor/donor character, a yet unreported design element for bidentate enoate equivalents. It is found that the Michael addition of a range of enolizable carbonyl compounds that have previously demonstrated challenging (i.e., α-substituted 2-oxindoles, cyanoesters, oxazolones, thiazolones, and azlactones) to α′-oxy enones can afford the corresponding tetrasubstituted carbon stereocenters in high diastereo- and enantioselectivity in the presence of standard BB catalysts. Experiments show that the α′-oxy ketone moiety plays a key role in the above realizations, as parallel reactions under identical conditions but using the parent α,β-unsaturated ketones or esters instead proceed sluggish and/or with poor stereoselectivity. A series of trivial chemical manipulations of the ketol moiety in adducts can produce the corresponding carboxy, aldehyde, and ketone compounds under very mild conditions, giving access to a variety of enantioenriched densely functionalized building blocks containing a fully substituted carbon stereocenter. A computational investigation to rationalize the mode of substrate activation and the reaction stereochemistry is also provided, and the proposed models are compared with related systems in the literature.
- Badiola, Eider,Fiser, Bla,Gmez-Bengoa, Enrique,Mielgo, Antonia,Olaizola, Iurre,Urruzuno, Iaki,Garca, Jess M.,Odriozola, Jos M.,Razkin, Jess,Oiarbide, Mikel,Palomo, Claudio
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supporting information
p. 17869 - 17881
(2015/02/19)
-
- Enantioselective protonation of α-hetero carboxylic acid-derived ketene disilyl acetals under chiral ionic Bronsted acid catalysis
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Highly enantioselective protonation of α-halo and alkoxy carboxylic acid-derived ketene disilyl acetals is achieved by using P-spiro chiral diaminodioxaphosphonium barfate as a Bronsted acid catalyst, where the enantiofacial discrimination by the catalyst mainly stems from the recognition of the electronic difference between two substituents on the ketene disilyl acetal.
- Uraguchi, Daisuke,Kizu, Tomohito,Ohira, Yuki,Ooi, Takashi
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supporting information
p. 13489 - 13491
(2015/01/09)
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- Synthesis of enantiomerically enriched-bromonitriles from amino acids
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Two methods were investigated for the preparation of six chiral-bromonitriles with different optic purities. The nitrous deamination of amino acids gives-bromoacids, which react with chlorosulfonyl isocyanate followed by triethylamine to afford-bromonitriles with moderate enantiomeric excess. However, the dehydration of corresponding-bromoamids using thionyl chloride gives-bromonitriles with good enantiomeric excess up to 94%. The use of phosphoryl chloride instead of thionyl chloride results in more than 30% racemization as determined by high-performance liquid chromatograpic analysis.
- Tka, Najeh,Kraem, Jamil,Hassine, Bechir Ben
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p. 735 - 743
(2013/01/15)
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- Syntheses of hydrazino peptides and conjugates
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(α-Benzyloxycarbonyl-aminoacyl)benzotriazolides (Cbz = benzyloxycarbonyl) underwent a coupling reaction with α-hydrazino acids under microwave irradiation to form hybrid hydrazino dipeptides (42-71 %). Chiral acylations of β-N-Cbz-α-hydrazino acylbenzotriazolides were successfully carried out with N-, S-, O-, and C-nucleophiles in yields of 49-88 %. Benzyloxycarbonyl-protected hybrid hydrazino dipeptides and benzyloxycarbonyl-protected hydrazino aminoacyl conjugates with N-, S-, O-, and C-nucleophiles were prepared by using benzotriazole methodology. Copyright
- Panda, Siva S.,El-Nachef, Claudia,Bajaj, Kiran,Katritzky, Alan R.
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p. 4156 - 4162
(2013/07/19)
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- Stereoselective synthesis of γ-lactams from imines and cyanosuccinic anhydrides
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A reaction between imines and anhydrides has been developed with chiral disubstituted anhydrides and chiral imines. The synthesis of highly substituted γ-lactams with three stereogenic centers, including one quaternary center, proceeds at room temperature in high yield and with high diastereoselectivity in most cases. Enantiomerically pure alkyl-substituted anhydrides proceed with no epimerization, thus providing access to enantiomerically pure penta-substituted lactam products.
- Tan, Darlene Q.,Younai, Ashkaan,Pattawong, Ommidala,Fettinger, James C.,Cheong, Paul Ha-Yeon,Shaw, Jared T.
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supporting information
p. 5126 - 5129
(2013/10/22)
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- Enantio-and diastereoselective oxidation of N-alkylimines using chiral-bromonitriles and hydrogen peroxide system
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Chiral-bromonitriles were prepared with good chemical and optical yields starting from natural-amino acids by dehydrating the corresponding α-bromoamides with thionyl chloride. The combined system-bromonitriles/ hydrogen peroxide was examined for the enantio-and diastereoselective oxidation of N-alkylimines in basic media at room temperature. The oxidation of N-tertiobutylarylimines leads to optically active oxaziridines with moderate enantiomeric excess. However, the oxidation of (S)-1-phenylethylarylimines affords the corresponding oxaziridines with good diasteromeric excess up to 97/3 as proved by gaseous-phase chromatography.
- Tka, Najeh,Kraem, Jamil,Hassine, Bechir Ben
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scheme or table
p. 2994 - 3003
(2012/08/07)
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- IMPROVED SYNTHESIS OF OPTICALLY PURE (S) - 3-CYANO-5-METHYL-HEXANOIC ACID ALKYL ESTER, AN INTERMEDIATE OF (S)- PREGABALIN
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The present invention is directed towards synthesis of (S) - 3-cyano-5-methyl-hexanoic acid ethyl ester. A cost effective, eco-friendly process for preparation of enantiomerically pure (S)-3-cyano-5-methyl-hexanoic acid alkyl ester, intermediate of γ-amino acids, particularly (S)-pregabalin.
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Page/Page column 44
(2011/12/02)
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- An unusual conformation of α-haloamides due to cooperative binding with zincated porphyrins
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CD and NMR spectroscopic evidence of cooperative binding between an α-halogen atom and a carboxamide group with a zinc porphyrin leads to an unprecedented conformation for the determination of the absolute stereochemistry of α-haloamides (α-halocarboxylic acids derivatized with 1,4-phenylenediamine) through the use of exciton-coupled circular dichroism (ECCD). With the use of chiral lactams, whose rotomeric contributions are minimized, both ECCD and NMR spectroscopy demonstrate that the porphyrin favors binding to the side of the sterically more demanding halogen atom as compared to the smaller hydrogen atom. In all, the data is strongly suggestive of an unusual conformation not observed before for α-chiral amides. A mnemonic for determining the absolute stereochemistry of α-halogenated carboxylic acids is provided.
- Tanasova, Marina,Yang, Qifei,Olmsted, Courtney C.,Vasileiou, Chrysoula,Li, Xiaoyong,Anyika, Mercy,Borhan, Babak
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supporting information; experimental part
p. 4242 - 4253
(2011/02/25)
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- METHODS AND MATERIALS FOR PREPARING ORGANIC COMPOUNDS FROM PRIMARY AMINES
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Methods are disclosed for the conversion of primary amines to other functional groups. The methods can be used to prepare chiral organic compounds, including organic alcohols and organic halides. The methods can be carried out by treating a primary amine with an activating agent and a nitrosyl agent to produce the transformed compound along with nitrous oxide.
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Page/Page column 24-27
(2008/06/13)
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- Novel method of treatment of inflammatory skin conditions
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There is provided, inter alia, a method for the treatment or prevention of an inflammatory skin condition which is characterised by colonisation with Staphylococcus aureus, comprising the topical administration of an aureolysin inhibitor.
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Page/Page column 8
(2010/11/26)
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- USE OF AN AUREOLYSIN INHIBITOR FOR THE TREATMENT OF INFLAMMATORY SKIN CONDITIONS CHARACTERISED BY COLONISATION WITH STAPHYLOCOCCUS AUREUS
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There is provided, inter alia, a method for the treatment or prevention of an inflammatory skin condition which is characterised by colonisation with Staphylococcus aureus, comprising the topical administration of an aureolysin inhibitor.
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Page/Page column 17
(2010/11/26)
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- New scalable asymmetric aminomethylation reaction for the synthesis of β2-amino acids
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β-Amino acids are useful tools in the design of peptidomimetics, and the development of new methods for their syntheses, particularly the synthesis of β2-amino acids, remains an important challenge. Here we report a new scalable route based on the aminomethylation of silyl ketene N,O-acetals by Mannich-type iminium electrophiles. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Moumne, Roba,Denise, Bernard,Guitot, Karine,Rudler, Henri,Lavielle, Solange,Karoyan, Philippe
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p. 1912 - 1920
(2008/02/06)
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- Efficient synthesis of β2-amino acid by homologation of α-amino acids involving the reformatsky reaction and Mannich-type imminium electrophile
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Development of new methods for the synthesis of β-amino acids is important as polymers of these compounds are promising peptidomimetic candidates in medicinal chemistry. We report here our findings on a new and highly efficient general strategy for the synthesis of β2-amino acids by homologation of α-amino acids, involving the Reformatsky reaction and Mannich-type imminium electrophile.
- Moumne, Roba,Lavielle, Solange,Karoyan, Philippe
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p. 3332 - 3334
(2007/10/03)
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- THIAZOL-COMPOUNDS AS 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1 INHIBITORS
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The present invention relates to compounds with the formula (I), wherein R1, R2, R3, X, and Y are as defined herein, and also to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in medicine and for the preparation of a medicament which acts on the human 11-β-hydroxysteroid dehydrogenase type 1 enzyme.
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Page/Page column 150-151
(2008/06/13)
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- alpha-AMINO ACID PHENYL ESTER DERIVATIVES
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The present invention relates to alpha-amino acid phenyl ester derivatives having general formula (I) wherein R1 is (C1-3)alkyloxy; R2 is (C1-3)alkyl, (C1-3)alkyloxy or (C2-3)alkenyl; R3 is hydrogen, (C1-3)alkyl, (C1-3)alkyloxy or (C2-3)alkenyl; R4 is (C1-6)alkyl; R5 and R6 are independently (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl or aralkyl, each of which may be optionally substituted with (C1-3)alkyloxy, (C1-3)alkyloxycarbonyl, cyano or NR7R8; R7 and R8 are independently (C1-6)alkyl; or a pharmaceutically acceptable salt thereof. The invention also relates to pharmaceutical compositions comprising said derivatives, and to the use of these alpha-amino acid phenyl ester derivatives as hypnotics for the induction and maintenance of general anaesthesia.
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- Synthesis and characterization of chiral N-O turns induced by α-aminoxy acids
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Chiral α-aminoxy acids of various side chains were synthesized with high optical purity starting from chiral α-amino acids. The conformations of diamides 13a-e, 15, and 16 were probed by using NMR, FT-IR, and CD spectroscopic methods as well as X-ray crystallography. The right-handed turns with eight-membered-ring intramolecular hydrogen bonds between adjacent residues (called the N-O turns) were found to be preferred for D-aminoxy acid residues, and they were independent of the side chains. The rigid chiral N-O turns should have great potential in molecular design.
- Yang,Li,Ng,Yan,Qu,Wu
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p. 7303 - 7312
(2007/10/03)
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- Matrix metalloproteinase inhibitors
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A compound of formula (I), wherein W is —NHOH or —OH, R1is either free or protected hydroxymethyl or mercaptomethyl or derivatives thereof, R2is free or protected hydroxy, R3and R4is an organic group, R5/s
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- Design and synthesis of potent thiol-based inhibitors of endothelin converting enzyme-1
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Through directed screening of compounds prepared as metalloprotease inhibitors a compound, CGS 30084, that had potent endothelin converting enzyme-1 (ECE-1) in vitro inhibitory activity (IC50=77nM) was identified. Herein we report the synthesis and optimization of ECE-1 inhibitory activity of additional analogues from this lead. Compound 3c, the thioacetate methyl ester derivative of compound 4c, was found to be a long acting inhibitor of ECE-1 activity in rats after oral administration. (C) 2000 Elsevier Science Ltd.
- Fink, Cynthia A.,Moskal, Michael,Firooznia, Fariborz,Hoyer, Denton,Symonsbergen, David,Wei, Dongchu,Qiao, Ying,Savage, Paula,Beil, Michael E.,Trapani, Angelo J.,Jeng, Arco Y.
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p. 2037 - 2039
(2007/10/03)
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- CARBOSTYRIL DERIVATIVES AS MATRIX METALLOPROTEINASES INHIBITORS
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This invention provides a carbostyril derivative of the formula (1): STR1 where R 1, R 2, R 3, R 4, R 5, R 6 and n are as defined, or its salt. This carbostyril derivative or its salt possess an excellent matrix metalloproteinases inhibitory action.
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- COMPOUNDS CONTAINING A FUSED BICYCLE RING AND PROCESSES THEREFOR
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Compounds of the formula STR1 wherein X is O or S--(O) t ; n is one or two; m is zero or one; Y is CH 2, O, or S--(O) t provided that Y is O or S--(O) t only when m is one; and A is STR2 are dual inhibitors of NEP and ACE. Compounds wherein A is STR3 are selective ACE inhibitors. Also disclosed are methods of preparation and intermediates.
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- SUBSTITUTED AZEPINONE DUAL INHIBITORS OF ANGIOTENSIN CONVERTING ENZYME AND NEUTRAL EXDOPEPTIDASE
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Compounds of the formula STR1 are disclosed as possessing inhibitory activity against angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) and thus being useful as cardiovascular agents. Processes for preparing these compounds are also disclosed.
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-
- Asymmetric Synthesis of 2-Chloro- and 2-Bromo-alkanoic acids by Halogenation of α-D-Glucofuranose-Derived Silyl Ketene Acetals.
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Optically active (S)-2-bromo- and 2-chloro-alkanoic acids 6 and 7 have been obtained via the diastereoselective halogenation of chiral silyl ketene acetals 3a-f, and subsequent saponification of the resulting crude esters.Examples characterized by e.e. values up to 95percent are reported.The diastereoface selectivity is independent of the silyl ketene acetal E/Z configuration.
- Angibaud, P.,Chaumette, J. L.,Desmurs, J. R.,Duhamel, L.,Ple, G.,et al.
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p. 1919 - 1932
(2007/10/03)
-
- Bombesin analogs
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Agonists and Antagonist of bombesin are derivatives of naturally occurring bombesin possessing a methyl sulfide or a methyl amide bond connecting the two amino acids on the carboxy terminal end. Agonist and antagonist activities are confirmed using conventional competitive binding and biochemical assays as well as conventional physiological tests and the use of these derivatives in a variety of conditions. Use of these peptides include stimulating or antagonizing growth of tissues, especially lung, and a means for effecting treatment for digestional disorders. Treatment comprises administering to a patient in need thereof, an effective amount of a bombesin analog.
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-
- Synthesis and study of new α-haloacid ferroelectric liquid crystal derivatives. MM2 approach to the molecular structure-ferroelectric activity relationship
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In order to understand the structural factors that influence ferroelectric properties, three new series (F, Cl, and Br) of chiral naphthalene-ring derived compounds were synthesized, and their ferroelectric properties [spontaneous polarization (Ps) and response time (τ)] were evaluated in the pure compound. The chiral tails are α-halo acids derived from L-α-amino acids: L-α-alanine (1), L-leucine (2), L-isoleucine (3), and L-valine (4), with a fluorine, chlorine, or bromine atom in the chiral center. The highest Ps values were obtained for compounds containing a fluorine or chlorine atom in their asymmetric center and with chiral tail derived from L-isoleucine (3) (F-3, 102 nC/cm2; Cl-3, 100 nC/cm2). The steric requirements of the halogen atom and the bulky alkyl group in the asymmetric center determine the most stable conformations of these chiral tails, which have been studied by molecular mechanic empirical calculations, MM2. MM2 calculations prove to be a successful tool for understanding how the structure of the lateral chiral tail affects molecular arrangement and, as a consequence, the ferroelectric properties of the materials.
- Sierra,Serrano,Ros,Ezcurra,Zubía
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p. 7645 - 7651
(2007/10/02)
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- Peptide derivatives useful as antagonists of bombesin and gastrin-releasing peptide
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A method for controlling the growth of tumor tissues, especially small cell lung and prostatic carcinomas, and gastric acid secretion, causative and symptomatic of, peptic (esophageal, gastric, and duodenal) ulcers. Treatment comprises administering to a patient in need thereof, an effective amount of a bombesin/GRP type inhibitor. ψAntagonists of bombesin/GRP which are derivatives of naturally occurring bombesin/GRP possessing a thiomethylene or methylene sulfoxide bond connecting the two amino acids on the carboxy terminal end is modified are described. The antagonism is confirmed using conventional competitive binding and biochemical assays as well as conventional physiological tests and the use of these derivatives in a variety of conditions in which bombesin/GRP is implicated is also described.ψ
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-
- Phosphoramidate peptide inhibitors of human skin fibroblast collagenase
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An extensive series of N-(monoethylphosphoryl)peptides was synthesized and their inhibition of purified human skin fibroblast collagenase examined. At the cleavage site S1 all reported compounds have the (EtO)(OK)P(O) group and the peptide side chain extended toward the C-terminal end (up to P5') of the substrate sequence. These phosphoramidates with a tetrahedrally hybridized phosphorus atom are thought to be transition state analogue inhibitors. They exhibited fair inhibitory potency against this vertebrate collagenase having K(i) values in the micromolar range. The most potent of these, (EtO)(OK)P(O)-Ile-TrpNHCH3 (68), inhibits with a K(i) value of 1.5 μM and is nearly 100 times stronger than (EtO)(OK)P(O)-Ile-Ala-GlyOK (51) (K(i) of 140 μM), which has the sequence matching that of the α1(I) chain of collagen in P1', P2', P3' after the cleavage site. Several compounds were prepared in an attempt to identify the nature of the S2', S3', and S4' binding sites. Alanine at the P2' position was replaced by leucine, phenylalanine, tryptophan, or tyrosine derivatives, resulting in K(i) values in a significantly lower range, 1.0-40 μM, compared to 51. No upper size limitation or specificity has been found at this position, yet similar replacements at the P3' position, which is occupied naturally by a glycine residue, gave weaker inhibitors: (EtO)(OK)P(O)-Ile-Tyr(OBzl)-PheOK (57) had a K(i) of 120 μM. Hexapeptide derivatives had weaker activities in the 270 μM-2 mM range. All inhibitors were evaluated by using the synthetic thio peptolide spectrophotometric assay.
- Kortylewicz,Galardy
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p. 263 - 273
(2007/10/02)
-
- Nucleophilic Substitution Reactions of Alkyl Halides By Using New Polymer-Supported Reagents Containing Hemin
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A new polymer reagent consisting of hemin, divinylbenzene, and 2-methyl-5-vinylpyridine was synthesized by suspension copolymerization.Substitution reactions of primary, secondary, and tertiary alkyl halides with the hemin copolymer combined with cyanide, azide, and thiocyanate ions were given satisfactory yields.This reaction mechanism was revealed to be a SNi type on the basis of stereochemical study.The hemin copolymer was not only a polymer-supported reagent with functional capabilities, but also served to separate the product from the reaction mixture.
- Saito, Kiyoshi,Harada, Kaoru
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p. 2562 - 2566
(2007/10/02)
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- INHIBITORS OF HUMAN LEUCOCYTE ELASTASE. PEPTIDES INCORPORATING AN &α-AZANORVALINE RESIDUE OR A THIOMETHYLENE LINKAGE IN PLACE OF A PEPTIDE BOND
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Peptides containing an α-azanorvaline residue at the C-terminus and N- group at the N-terminus have been made as inhibitors of human leucocyte elastase.A number of analogues with an amide bond replaced by a thiomethylene group have also been prepared.The analogues were tested against leucocyte elastase using MeO-Suc-Ala-Ala-Pro-Val-p-nitroanilide as a substrate and the results were obtained as IC50 values.Both types of analogues inhibited the leucocyte elastase; the most potent of these was N--L-valyl-L-prolyl-α-azanorvaline phenyl ester ( 2 ) ( IC50 0.28 μM, Ki 0.02 μM ).
- Dutta, Anand S.,Giles, Michael, B.,Gormley, James J.,Williams, Joseph C.,Kusner, Edward J.
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p. 111 - 120
(2007/10/02)
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- The Determination of Small Amounts of Enantiomeric Impurities in α-Halo Carboxylic Acids
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The accurate determination of the enantiomeric composition of α-halo carboxylic acids is reported.Such data are of importance in the synthesis of chiral compounds and in mechanistic studies involving the title compounds.
- Watabe, K.,Chang, S.-C.,Gil-Av, E.,Koppenhoefer, B.
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p. 225 - 228
(2007/10/02)
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- Novel thiopeptolide substrates for vertebrate collagenase
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The disclosure relates to novel synthetic thiopeptolide substrates having high activity for the enzyme collagenase. These substrates have the following amino acid sequences: wherein R=H or N-protecting group, X=Leu, Ile, Phe, Val, Gln, Ala, Y=Leu, Ile, Phe, Val, Ala, Z=Leu, Ile, Phe, Val, Gln, Ala, and R1 =terminal amide, carboxyl or ester group.
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- Modified Di- and Tripeptides of the C-Terminal Portion of Oxytocin and Vasopressin as Possible Cognition Activation Agents
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A number of peptides and modified peptides were synthesized and studied for their ability to reverse electroconvulsive shock-induced amnesia in rodents.A few of these peptides were selected for secondary evaluation in tests of short-term memory in rats and aged rhesus monkeys.A number of the peptides and modified peptides were active in the amnesia reversal test.In selected secondary tests, however, the chosen compounds failed to show significant activity in enhancing memory.New methods for preparing methyleneamino and methyleneoxy isosters of peptides are reportrd.Other modified peptides also included methylenethio, methylenesulfonyl, and ethylene isosteres in place of the normal peptide amide bond.
- Nicolaides, E. D.,Tinney, F. J.,Kaltenbronn, J. S.,Repine, J. T.,DeJohn, D. A.,et al.
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p. 959 - 971
(2007/10/02)
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