- Multitargeting application of proline-derived peptidomimetics addressing cancer-related human matrix metalloproteinase 9 and carbonic anhydrase II
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A series of D-proline peptidomimetics were evaluated as dual inhibitors of both human carbonic anhydrases (hCAs) and human gelatinases (MMP2 and MMP9), as these enzymes are both involved in the carcinogenesis and tumor invasion processes. The synthesis and enzyme inhibition kinetics of D-proline derivatives containing a biphenyl sulfonamido moiety revealed an interesting inhibition profile of compound XIV towards MMP9 and CAII. The SAR analysis and docking studies revealed a stringent requirement of a trans geometry for the two arylsulfonyl moieties, which are both necessary for inhibition of MMP9 and CAII. As MMP9 and CAII enzymes are both overexpressed in gastrointestinal stromal tumor cells, this molecule may represent an interesting chemical probe for a multitargeting approach on gastric and colorectal cancer.
- Lenci, Elena,Angeli, Andrea,Calugi, Lorenzo,Innocenti, Riccardo,Carta, Fabrizio,Supuran, Claudiu T.,Trabocchi, Andrea
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Read Online
- Chiral suprastructures of asymmetric oligothiophene-hybrids induced by a single proline
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Oligothiophene-proline hybrids were synthesized via click-reaction showing intriguing self-assembly behavior in an aqueous environment by forming chiral superstructures, whose helicity is controlled by the configuration of the amino acid moiety. This journal is The Royal Society of Chemistry 2013.
- Digennaro, Angela,Wennemers, Helma,Joshi, Gururaj,Schmid, Sylvia,Mena-Osteritz, Elena,Baeuerle, Peter
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Read Online
- INHIBITORS OF CYCLIN DEPENDNT KINASE 7 (CDK7)
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The present invention provides novel compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., leukemia, melanoma, multiple myeloma), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of cyclin-dependent kinase 7 (CDK7), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject.
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- Enantioselective synthesis and physicochemical properties of libraries of 3-amino- and 3-amidofluoropiperidines
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The enantioselective syntheses of 3-amino-5-fluoropiperidines and 3-amino-5,5-difluoropiperidines were developed using the ring enlargement of prolinols to access libraries of 3-amino- and 3-amidofluoropiperidines. The study of the physicochemical properties revealed that fluorine atom(s) decrease(s) the pKa and modulate(s) the lipophilicity of 3-aminopiperidines. The relative stereochemistry of the fluorine atoms with the amino groups at C3 on the piperidine core has a small effect on the pK a due to conformationnal modifications induced by fluorine atom(s). In the protonated forms, the C-F bond is in an axial position due to a dipole-dipole interaction between the N-H+ and C-F bonds. Predictions of the physicochemical properties using common software appeared to be limited to determine correct values of pKa and/or differences of pK a between cis- and trans-3-amino-5-fluoropiperidines.
- Orliac, Aurelie,Routier, Julie,Burgat Charvillon, Fabienne,Sauer, Wolfgang H. B.,Bombrun, Agnes,Kulkarni, Santosh S.,Gomez Pardo, Domingo,Cossy, Janine
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supporting information
p. 3813 - 3824
(2014/04/03)
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- HETEROCYCLIC COMPOUNDS AND METHODS FOR THEIR USE
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The present invention relates to heterocyclic compounds useful for antagonising angiotensin II Type 2 (AT2) receptor. More particularly the invention relates to pyrrolidine and azetidine compounds, compositions containing them and their use in methods of treating or preventing disorders or diseases associated with AT2 receptor function including neuropathic pain, inflammatory pain, conditions associated with neuronal hypersensitivity, impaired nerve conduction velocity, cell proliferation disorders, disorders associated with an imbalance between bone resorption and bone formation and disorders associated with aberrant nerve regeneration.
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Page/Page column 116
(2013/07/19)
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- D-Proline-based peptidomimetic inhibitors of anthrax lethal factor
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In this work we reported the generation of d-proline-derived hydroxamic acids as inhibitors of anthrax lethal factor (LF), taking advantage of a pyrrolidine ring as the central scaffold and a hydroxamate group as the Zn 2+ chelating agent. The
- Calugi, Chiara,Trabocchi, Andrea,Lalli, Claudia,Guarna, Antonio
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- Novel pyrrolidone derivatives for use as MetAP-2 inhibitors
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Compounds of the formula (I), in which R, X, Y, Z, R3 and R4 have the meanings indicated in claim 1, are inhibitors of methionine aminopeptidase and can be employed for the treatment of tumours.
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Page/Page column 19
(2011/11/06)
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- Synthesis and stereochemical effects of pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines as EGFR and ErbB-2 inhibitors
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A novel class of pyrrolidinyl-acetyleneic thieno[3,2-d]pyrimidines has been identified which potently inhibit the EGFR and ErbB-2 receptor tyrosine kinases. Synthetic modifications of the pyrrolidine carbamate moiety result in a range of effects on enzyme and cellular potency. In addition, the impact of the absolute stereochemical configuration on cellular potency and oral mouse pharmacokinetics is described.
- Stevens, Kirk L.,Alligood, Krystal J.,Alberti, Jennifer G. Badiang,Caferro, Thomas R.,Chamberlain, Stanley D.,Dickerson, Scott H.,Dickson, Hamilton D.,Emerson, Holly K.,Griffin, Robert J.,Hubbard, Robert D.,Keith, Barry R.,Mullin, Robert J.,Petrov, Kimberly G.,Gerding, Roseanne M.,Reno, Michael J.,Rheault, Tara R.,Rusnak, David W.,Sammond, Douglas M.,Smith, Stephon C.,Uehling, David E.,Waterson, Alex G.,Wood, Edgar R.
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scheme or table
p. 21 - 26
(2009/04/10)
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- Catalysis of 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives in enantioselective anti-Mannich-type reactions: Importance of the 3-acid group on pyrrolidine for stereocontrol
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The development of enantioselective anti-selective Mannich-type reactions of aldehydes and ketones with imines catalyzed by 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives is reported in detail. Both (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid and (R)-3-pyrrolidinecarboxylic acid efficiently catalyzed the reactions of aldehydes with α-imino esters under mild conditions and afforded anti-Mannich products with high diastereo- and enantioselectivities (anti/syn up to 99:1, up to >99% ee). For the reactions of ketones with α-imino esters, (R)-3-pyrrolidinecarboxylic acid was an efficient catalyst (anti/syn up to >99:1, up to 99% ee). Evaluation of a series of pyrrolidine-based catalysts indicated that the acid group at the β-position of the pyrrolidine ring of the catalyst played an important role in forwarding the carbon-carbon bond formation and in directing anti-selectivity and enantioselectivity.
- Zhang, Haile,Mitsumori, Susumu,Utsumi, Naoto,Imai, Masanori,Garcia-Delgado, Noemi,Mifsud, Maria,Albertshofer, Klaus,Cheong, Paul Ha-Yeon,Houk,Tanaka, Fujie,Barbas III, Carlos F.
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p. 875 - 886
(2008/09/20)
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- Heterocyclic cyclopentyl tetrahydroisoquinoline and tetrahydropyridopyridine modulators of chemokine receptor activity
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The present invention is directed to compounds of the formula I: Wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, X, n and the broken lines are as defined herein which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptor CCR-2.
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Page/Page column 64
(2008/06/13)
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- Synthetic study of optically active 3-azabicyclo[3.3.0]octane-2,6,8- tricarboxylic acid
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Synthesis of (1R,2S,5S,6R,8S)-3-azabicyclo[3.3.0]octane-2,6,8-tricarboxylic acid (2) from trans-4-hydroxy-L-proline (5) was attempted. A Diels-Alder reaction of 3,4-dehydroproline derivative 9 and cyclopentadiene afforded a single stereoisomer 11. The Diels-Alder adduct was smoothly converted to the hydrochloride of 2 (24) via RuO4 oxidation. Although some racemization of the material or product was observed during the synthetic processes, the amino acid 24 proved to be optically pure.
- Arakawa, Yasushi,Ohnishi, Masafumi,Yoshimura, Norikazu,Yoshifuji, Shigeyuki
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p. 1015 - 1020
(2007/10/03)
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- Inhibitors of factor Xa and other serine proteases involved in the coagulation cascade
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The present invention provides compounds of Formula (I): wherein A, B, C, G, and W1 have any of the values defined in the specification, and pharmaceutically acceptable salt thereof, that are useful to treat thrombotic disorders. Also disclosed are pharmaceutical compositions comprising one or more compounds of Formula I, processes for preparing compounds of Formula I, and intermediates useful for preparing compounds of Formula I.
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- 4-Substituted D-glutamic acid analogues: The first potent inhibitors of glutamate racemase (MurI) enzyme with antibacterial activity
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The first potent inhibitors of glutamate racemase (MurI) enzyme that show whole cell antibacterial activity are described. Optically pure 4-substituted D-glutamic acid analogues with (2R,4S) stereochemistry and bearing aryl-, heteroaryl-, cinnamyl-, or biaryl-methyl substituents represent a novel class of glutamate racemase inhibitors. Exploration of the D-Glu core led to the identification of lead compounds (-)-8 and 10. 2-Naphthylmethyl derivative 10 was found to be a potent competitive inhibitor of glutamate racemase activity (Ki = 16 nM, circular dichroism assay; IC50 = 0.1 μg/mL high-performance liquid chromatography (HPLC) assay). Thorough structure-activity relationship (SAR) studies led to benzothienyl derivatives such as 69 and 74 with increased potency (IC50 = 0.036 and 0.01 μg/mL, respectively, HPLC assay). These compounds showed potent whole cell antibacterial activity against S. pneumoniae PN-R6, and good correlation with the enzyme assay. Compounds 69, 74 and biaryl derivative 52 showed efficacy in an in vivo murine thigh infection model against Streptococcus pneumoniae. Data described herein suggest that glutamate racemase may be a viable target for developing new antibacterial agents.
- De Dios, Alfonso,Prieto, Lourdes,Martín, Jose Alfredo,Rubio, Almudena,Ezquerra, Jesus,Tebbe, Mark,López De Uralde, Beatriz,Martín, Justina,Sánchez, Ana,LeTourneau, Deborah L.,McGee, James E.,Boylan, Carole,Parr Jr., Thomas R.,Smith, Michele C.
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p. 4559 - 4570
(2007/10/03)
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- Oligonucleotide analogs with an amino acid or a modified amino alcohol residue
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The present invention provides various novel oligonucleotide analogs having one or more properties that make the subject compounds superior to conventional oligonucleotides for use in procedures employing oligonucleotides. The compounds of the invention are oligonucleotide analogs in which the furanose ring of a naturally occurring nucleic acid is replaced with an amino acid or a modified amino alcohol residue. Some embodiments of the novel compounds of the invention are particularly useful for the antisense control of gene expression. The compounds of the invention may also be used as nucleic acid hybridization probes or as primers. Another aspect of the invention is to provide monomeric precursors of the oligonucleotide analogs of the invention. These monomeric precursors may be used to synthesize the subject polynucleotide analogs. Another aspect of the invention is to provide formulations of the subject polynucleotide analogs that are designed for the treatment or prevention of disease conditions. Yet another aspect of the invention is to provide methods for treating or preventing diseases, particularly viral infections and cell growth disorders. The subject disease treatment methods comprise the step of administering an effective amount of the subject polynucleotide analogs for use as antisense inhibitors.
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- 2,7-Diazabicyclo[3.3.0]octanes as novel h5-HT(1D) receptor agonists
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The conformational restriction of a (benzylamino)methyl substituted pyrrolidine to form 2,7-diazabicyclo[3.3.0]octanes has led to a series of compounds with high affinity at the h5-HT(1D) receptor as well as dramatically increased concentrations in the hepatic portal vein following oral administration.
- Russell, Michael G. N.,Beer, Margaret S.,Stanton, Josephine A.,Sohal, Bindi,Mortishire-Smith, Russell J.,Castro, Jose L.
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p. 2491 - 2496
(2007/10/03)
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- Stereoselective synthesis of unnatural aminoacids cis-4-hydroxyproline and bulgecinine
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A new stereoselective synthesis of both (2R,4R)- and (2S,4S)-4-hydroxy-proline and (+)- and (-)-bulgecinine was performed starting from synthons 1 or 1', respectively. The synthetic route has been established via a novel assisted cleavage of a disubstituted amide in mild conditions and successive stereocontrolled iodocyclization.
- Madau, Alessandra,Porzi, Gianni,Sandri, Sergio
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p. 825 - 830
(2007/10/03)
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- Ac-31>-CCK4 Analogs: Synthesis and Implications for the CCK-B Receptor-Bound Conformation
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It has been reported that substitution of the Met31 residue in Boc-CCK4 (Boc-Trp30-Met31-Asp32-Phe33-NH2, CCK33 numbering) by trans-3-propyl-L-proline yields a highly potent and selective CCK-B agonist.To further explore the structural requirements of the Met31 side chain in the receptor-bound conformation of CCK4, we have synthesized several Ac-CCK4 analogs containing substitution of Met31 by 3- and 4-(alkylthio)-substituted proline derivatives.To this end we have developed novel synthetic routes to enantiomerically pure N-Boc-4-cis- and -trans-(methylthio)prolines and racemic N-Boc-3-cis- and -trans-prolines.The protected mercaptoprolines were incorporated into Ac-CCK4 analogs using SPPS and were alkylated using various electrophiles following cleavage from the solid support.Binding assays reveal that 3-(alkylthio)prolines analogs have higher affinities at the CCK-B receptor than the corresponding 4-(alkylthio)proline analogs, and that trans-3-(alkylthio)proline analogs had higher affinities than corresponding cis-3-(alkylthio)proline analogs.Within both the cis- and trans-3-(alkylthio)proline series, the order of potency was found to be Me 431>.Comparison of the low-energy structures calculated for several high-affinity Ac-CCK4 analogs reveal a common geometry which we propose to be the CCK-B receptor-bound conformation.This model shows grouping of the hydrophobic side chains of Trp, Met, and Phe at one side of the molecule and the hydrophilic side chain of Asp and the C-terminal carboxamide at the other side.
- Kolodziej, Stephen A.,Nikiforovich, Gregory V.,Skeean, Richard,Lignon, Marie-Francoise,Martinez, Jean,Marshall, Garland R.
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p. 137 - 149
(2007/10/02)
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