- Catalysis of Hydrogen-Deuterium Exchange Reactions by 4-Substituted Proline Derivatives
-
The identification and understanding of structure-activity relationships is vital for rational catalyst design. A kinetic study of the hydrogen-deuterium exchange reaction of cyclohexanone in aqueous solution, as catalyzed by proline derivatives, has revealed valuable structure-activity relationships. In phosphate-buffered solution, cis-4-fluoroproline is more active than the trans isomer, a distinction that appears to originate from a destabilizing interaction between the fluorine atom and phosphate anion during general acid-catalyzed dehydration of the carbinolamine intermediate. trans-4-Ammoniumprolines are exceptionally active catalysts owing to favorable Coulombic interactions involving the ammonium group and the alkoxide moiety formed upon 1,2-addition of the proline derivative to the ketone. These results could be used for the optimization of proline catalysts, especially in transformations where the formation of the putative iminium ion is rate-limiting.
- Myers, Eddie L.,Palte, Michael J.,Raines, Ronald T.
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Read Online
- Altering the sex pheromone cyclo(L-pro-l-pro) of the diatom seminavis robusta towards a chemical probe
-
As a major group of algae, diatoms are responsible for a substantial part of the primary production on the planet. Pennate diatoms have a predominantly benthic lifestyle and are the most species-rich diatom group, with members of the raphid clades being motile and generally having heterothallic sexual reproduction. It was recently shown that the model species Seminavis robusta uses multiple sexual cues during mating, including cyclo(L-Pro-L-Pro) as an attraction pheromone. Elaboration of the pheromone-detection system is a key aspect in elucidating pennate diatom life-cycle regulation that could yield novel fundamental insights into diatom speciation. This study reports the synthesis and bio-evaluation of seven novel pheromone analogs containing small structural alterations to the cyclo(L-Pro-L-Pro) pheromone. Toxicity, attraction, and interference assays were applied to assess their potential activity as a pheromone. Most of our analogs show a moderate-to-good bioactivity and low-to-no phytotoxicity. The pheromone activity of azide-and diazirine-containing analogs was unaffected and induced a similar mating behavior as the natural pheromone. These results demonstrate that the introduction of confined structural modifications can be used to develop a chemical probe based on the diazirine-and/or azide-containing analogs to study the pheromone-detection system of S. robusta.
- Bonneure, Eli,De Baets, Amber,De Decker, Sam,Van den Berge, Koen,Clement, Lieven,Vyverman, Wim,Mangelinckx, Sven
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- Multipodal insulin mimetics built on adamantane or proline scaffolds
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Multi-orthogonal molecular scaffolds can be applied as core structures of bioactive compounds. Here, we prepared four tri-orthogonal scaffolds based on adamantane or proline skeletons. The scaffolds were used for the solid-phase synthesis of model insulin mimetics bearing two different peptides on the scaffolds. We found that adamantane-derived compounds bind to the insulin receptor more effectively (Kd value of 0.5 μM) than proline-derived compounds (Kd values of 15–38 μM) bearing the same peptides. Molecular dynamics simulations suggest that spacers between peptides and central scaffolds can provide greater flexibility that can contribute to increased binding affinity. Molecular modeling showed possible binding modes of mimetics to the insulin receptor. Our data show that the structure of the central scaffold and flexibility of attached peptides in this type of compound are important and that different scaffolds should be considered when designing peptide hormone mimetics.
- Hajduch, Jan,Fabre, Benjamin,Klopp, Benjamin,Pohl, Radek,Budě?ínsky, Milo?,?olínová, Veronika,Ka?i?ka, Václav,K?prülüoglu, Cemal,Eyrilmez, Saltuk Mustafa,Lep?ík, Martin,Hobza, Pavel,Mitrová, Katarína,Lubos, Marta,Hernández, María Soledad Garre,Jirá?ek, Ji?í
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- Quinoline-Proline, Triazole Hybrids: Design, Synthesis, Antituberculosis, Molecular Docking, and ADMET Studies
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A series of novel quinoline-proline hybrids (11a-g) and quinoline-proline-1,2,3-triazole hybrids (12-14) were synthesized by click chemistry based on molecular hybridization concept and were characterized by NMR, mass spectrometry, and elemental analysis. All the titled target compounds were tested for antitubercular activity by MABA and LORA methods by in vitro. Interestingly, two compounds (2R,4S)-1-((2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl)-methyl)-4-(4-nitrobenzamido)-N-phenylpyrrolidine-2-carboxamide (11b) and (2R,4S)-1-((2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl)-methyl)-4-(4-fluorobenzamido)-N-phenylpyrrolidine-2-carboxamide (11c) exhibited significant activity against the tested Mycobacterium tuberculosis H37Rv strain. Further, the cytotoxicity (CC50) profile of the titled compounds against the Vero cell was performed and discussed. A molecular docking study of the hit compounds (11b and 11c) was also performed to find their putative binding interaction with the active site of the target proteins. Finally, in silico ADMET properties were also predicted for all the synthesized molecules to evaluate their drug-likeness behavior.
- Ganesan, Moorthiamma Sarathy,Raja, Kamatchi Kanmani,Murugesan, Sankaranarayanan,Karankumar, Banoth,Faheem, Faheem,Thirunavukkarasu, Sappanimuthu,Shetye, Gauri,Ma, Rui,Franzblau, Scott G.,Wan, Baojie,Rajagopal, Gurusamy
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p. 952 - 968
(2021/02/16)
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- TRI-SUBSTITUTED HETEROARYL DERIVATIVES AS SRC HOMOLOGY-2 PHOSPHATASE INHIBITORS
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The present disclosure provides certain tri-substituted heteroaryl derivatives that are Src Homology-2 phosphatase (SHP2) inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of SHP2. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
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Page/Page column 141
(2020/04/25)
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- Compounds for inhibiting HCV (hepatitis C virus), pharmaceutical composition and application of compounds or pharmaceutical composition
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The invention discloses compounds for inhibiting HCV (hepatitis C virus), pharmaceutical composition and an application of the compounds or the pharmaceutical composition. The compounds are compoundsshown in formula (I) or a stereoisomer, geometric isomer, a tautomer, an enantiomer, sulfur oxide, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compounds shown in formula (I); the compounds are effective antiviral drugs, especially can be used for inhibiting the function of NS5A protein encoded by the HCV, thereby effectively inhibiting the HCV.The method for preventing and/or treating drugs or diseases associated with the HCV by the compounds or the composition containing the new compounds has good market development prospects.
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Paragraph 0157; 0158; 0159; 0160; 0161
(2019/02/04)
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- Superior HIV-1 TAR Binders with Conformationally Constrained R52 Arginine Mimics in the Tat(48–57) Peptide
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We report a 100-fold increase in binding affinity of the Tat(48–57) peptide to HIV-1 transcriptional activator-responsive element (TAR) RNA by replacing Arg52, an essential and critical residue for Tat's specific binding, with (2S,4S)-4-guanidinoproline. The resulting αTat1M peptide is a far superior binder than γTat1M, a peptide containing another conformationally constrained arginine mimic, (2S,4S)-4-amino-N-(3-guanidinopropyl)proline, or even the control Tat peptide (CtrlTat) itself. Our observations are supported by circular dichroism (CD), isothermal titration calorimetry (ITC), gel electrophoresis and UV spectroscopy studies. Molecular dynamics simulations suggest increased interactions between the more compact αTat1M and TAR RNA, relative to CtrlTat. The CD signature of the RNA itself remains largely unchanged upon binding of the peptides. The Tat mimetics further have better cell uptake properties than the control Tat peptide, thus increasing their potential application as specific TAR-binding molecules.
- Bhosle, Govind S.,Kharche, Shalmali,Kumar, Santosh,Sengupta, Durba,Maiti, Souvik,Fernandes, Moneesha
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p. 220 - 226
(2018/01/22)
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- Antibacterial and anti-TB tat-peptidomimetics with improved efficacy and half-life
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Non-natural antimicrobial peptides are ideal as next-generation antibiotics because of their ability to circumvent the problems of drug resistance and in vivo instability. We report novel all-α- and α,γ-mixed Tat peptide analogues as potential antibacterial and anti-TB agents. These peptides have broad spectrum antibacterial activities against Gram-positive (MICs 0.61 ± 0.03 to 1.35 ± 0.21 μM with the peptide γTatM4) and Gram-negative (MICs 0.71 ± 0.005 to 1.26 ± 0.02 μM with γTatM4) bacteria and are also effective against active and dormant forms of Mycobacterium tuberculosis, including strains that are resistant to rifampicin and isoniazid. The introduction of the non-natural amino acids of the study in the Tat peptide analogues results in increased resistance to degradation by proteolysis, significantly increasing their half-life. The peptides appear to inhibit bacteria by a membrane disruption mechanism, and have only a low cytotoxic effect on mammalian cells.
- Bhosle, Govind S.,Nawale, Laxman,Yeware, Amar M.,Sarkar, Dhiman,Fernandes, Moneesha
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p. 358 - 369
(2018/05/22)
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- Synthetic Marine Sponge Collagen by Late-Stage Dihydroxylation
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Based on the observation that an increased substrate size is paralleled by an enhanced diastereoselectivity, a late-stage dihydroxylation protocol toward the 21mer CMP (collagen model peptide) Ac-(Pro-Hyp-Gly)3-Pro-Dyp-Gly-(Pro-Hyp-Gly)3-NH2 is presented. C3 and C4 hydroxylation have a converse effect on the triple-helical stability of collagen. Their combined influence on the melting temperature was studied by NMR spectroscopy.
- Priem, Christoph,Geyer, Armin
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supporting information
p. 162 - 165
(2018/01/17)
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- Design and Synthesis of a Series of l-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid
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Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (Ki = 4 μM). In a functional assay, 1b displayed full antagonist activity with IC50 = 6 ± 2 μM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14° was seen compared to the structure with glutamate, consistent with 1b being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C, O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor.
- Krogsgaard-Larsen, Niels,Delgar, Claudia G.,Koch, Karina,Brown, Patricia M. G. E.,M?ller, Charlotte,Han, Liwei,Huynh, Tri H. V.,Hansen, Stinne W.,Nielsen, Birgitte,Bowie, Derek,Pickering, Darryl S.,Kastrup, Jette Sandholm,Frydenvang, Karla,Bunch, Lennart
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p. 441 - 457
(2017/04/26)
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- COMPOSITIONS AND METHODS FOR TREATING AND PREVENTING NEURODEGENERATIVE DISORDERS
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Compounds, pharmaceutical compositions, methods and kits are described for treating or preventing neurodegenerative diseases such as Alzheimer's disease.
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Page/Page column 140; 141
(2017/03/08)
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- CARBOCYCLIC PROLINAMIDE DERIVATIVES
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This invention is directed to novel carbocyclic prolinamide derivatives of Formula (I), and pharmaceutically acceptable salts, solvates, solvates of the salt and prodrugs thereof, useful in the prevention (e.g., delaying the onset of or reducing the risk
- -
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Paragraph 0152; 0153
(2018/04/11)
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- HETEROCYCLIC PROLINAMIDE DERIVATIVES
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This invention is directed to novel heterocyclic prolinamide derivatives of Formula (I), and pharmaceutically acceptable salts, solvates, solvates of the salt and prodrugs thereof, useful in the prevention (e.g., delaying the onset of or reducing the risk of developing) and treatment (e.g., controlling, alleviating, or slowing the progression of) of age-related macular degeneration (AMD) and related diseases of the eye. These diseases include dry-AMD, wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells. The invention disclosed herein is further directed to methods of prevention, slowing the progress of, and treatment of dry-AMD, wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells, comprising: administration of a therapeutically effective amount of compound of the invention. The compounds of the invention are inhibitors of HTRAl. Thus, the compounds of the invention are useful in the prevention and treatment of a wide range of diseases mediated (in whole or in part) by HTRAl. The compounds of the invention are also useful for inhibiting HTRAl protease activity in an eye or locus of an arthritis or related condition.
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Paragraph 0192; 0194
(2018/04/11)
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- ALIPHATIC PROLINAMIDE DERIVATIVES
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This invention is directed to novel aliphatic prolinamide derivatives of Formula I, and pharmaceutically acceptable salts, solvates, solvates of the salt and prodrugs thereof, useful in the prevention (e.g., delaying the onset of or reducing the risk of developing) and treatment (e.g., controlling, alleviating, or slowing the progression of) of age-related macular degeneration (AMD) and related diseases of the eye. These diseases include dry-AMD, wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells. The invention disclosed herein is further directed to methods of prevention, slowing the progress of, and treatment of dry-AMD, wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells, comprising: administration of a therapeutically effective amount of compound of the invention. The compounds of the invention are inhibitors of HTRAl. Thus, the compounds of the invention are useful in the prevention and treatment of a wide range of diseases mediated (in whole or in part) by HTRAl. The compounds of the invention are also useful for inhibiting HTRAl protease activity in an eye or locus of an arthritis or related condition.
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Paragraph 0235; 0236
(2018/04/11)
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- Dideoxy nucleoside triphosphate (ddNTP) analogues: Synthesis and polymerase substrate activities of pyrrolidinyl nucleoside triphosphates (prNTPs)
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The dideoxynucleoside triphosphates (ddNTPs) terminate the bio-polymerization of DNA and become essential chemical component of DNA sequencing technology which is now basic tool for molecular biology research. In this method the radiolabeled or fluorescent dye labeled ddNTP analogues are being used for DNA sequencing by detection of the terminated DNA fragment after single labeled ddNTP incorporation into DNA under PCR conditions. This report describes the syntheses of rationally designed novel amino-functionalized ddNTP analogue such as Pyrrolidine nucleoside triphosphates (prNTPs), and their polymerase activities with DNA polymerase by LC–MS and Gel-electrophoretic techniques. The Mass and PAGE analyses strongly support the incorporation of prNTPs into DNA oligonucleotide with Therminator DNA polymerase as like control substrate ddNTP. As resultant the DNA oligonucleotide are functionalized as amine group by prNTP incorporation with polymerase. Hence prNTPs provide opportunities to prepare demandable conjugated DNA with other biomolecules/dyes/fluorescence molecule without modifying nucleobase structure.
- Gade, Chandrasekhar Reddy,Dixit, Manjusha,Sharma, Nagendra K.
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p. 4016 - 4022
(2016/08/23)
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- Bioactive gold(i) complexes with 4-mercaptoproline derivatives
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Unprecedented gold(i) bioconjugates bearing non-proteinogenic amino acid 4-mercaptoproline species as bioorganic ligands have been prepared. Firstly, the synthesis of Boc-Pro(SH)-OMe (1) has been accomplished by standard procedures. The subsequent reaction of 1 with [AuCl(PR3)] gives complexes Boc-Pro(SAuPR3)-OMe (PR3 = PPh3 (2), PPh2Py (3)). Starting from complex 2 several structural modifications have been performed, in addition to the incorporation of a different phosphine in 3, such as the formation of the acid Boc-Pro(SAuPPh3)-OH (4), the synthesis of a dipeptide derivative by coupling the amino acid glycine tert-butyl ester Boc-Pro(SAuPPh3)-Gly-OtBu (5), or the coordination of another gold phosphine fragment to the sulfur atom as in [Boc-Pro(SAuPPh3)2-OMe]OTf (6). The cytotoxic activity in vitro of these complexes has been evaluated against three different tumor human cell lines, A549 (lung carcinoma), Jurkat (T-cell leukaemia) and MiaPaca2 (pancreatic carcinoma). All the complexes displayed excellent cytotoxic activity with IC50 values in the low μM range and even in the nM range in some cases. Structure-Activity Relationships (SAR) observed from this family of complexes opens the possibility of designing more potent and selective promising gold(i) anticancer agents.
- Gutiérrez, Alejandro,Cativiela, Carlos,Laguna, Antonio,Gimeno, M. Concepción
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p. 13483 - 13490
(2016/09/04)
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- Preparation method for (1S,4S)-2,5-diazabicyclo[2.2.1]heptane or (1S,4S)-2,5-diazabicyclo [2.2.1]octane derivative
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The invention discloses a preparation method for a (1S,4S)-2,5-diazabicyclo[2.2.1]heptane or (1S,4S)-2,5-diazabicyclo [2.2.1]octane derivative. The method comprises the following steps: subjecting a hydroxyl group of five-component or six-component N-heterocycle to sulfonylation by using a sulfonylation reagent; then subjecting sulfonate to a substitution reaction of SN2 by using an azide; simultaneously reducing an azido group and an ester group by using a reduction reaction; and finally, carrying out ring closure so as to obtain the derivative. The synthesis route of the preparation method has higher selectivity compared with the prior art; reaction steps are reduced; cost for raw materials and time cost are saved; product yield is substantially higher than product yield in the prior art; and the preparation method can easily realize purification and enlarged production and reduce discharging of waste.
- -
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Paragraph 0057; 0059; 0060
(2017/06/02)
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- THERAPEUTIC AGENT FOR FGFR INHIBITOR-RESISTANT CANCER
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The problem to be solved by the present invention is to provide an anticancer agent for treating tumors resistant to other antitumor agents that inhibit FGFR, and a method for treating such tumors. The present invention provides an antitumor agent for administration to a tumor patient resistant to an FGFR inhibitor, the antitumor agent comprising a 3,5-disubstituted benzene alkynyl compound represented by Formula (I) below or a salt thereof. The present invention also provides a therapeutic method using the anticancer agent.
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Paragraph 0284; 0380
(2016/06/06)
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- ANTITUMOR DRUG FOR INTERMITTENT ADMINISTRATION OF FGFR INHIBITOR
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The problem to be solved by the present invention is to provide a potent and highly selective novel FGFR inhibitor, and an antitumor agent having reduced side effects, such as increased blood phosphorus levels, while maintaining the antitumor effect of the FGFR inhibitor. The present invention provides an antitumor agent comprising a 3,5-disubstituted benzene alkynyl compound represented by Formula (I) or a salt thereof that is used so that the 3,5-disubstituted benzene alkynyl compound or a salt thereof is administered on an administration schedule of at least twice a week and a dosing interval of at least one day.
- -
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Paragraph 0286; 0383
(2016/08/07)
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- POTENT AND SELECTIVE INHIBITORS OF HEPATITIS C VIRUS
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The present invention is directed to compounds, compositions and methods for treating or preventing hepatitis C virus (HCV) infection in human subjects or other animal hosts. The compounds are as also pharmaceutically acceptable, salts, prodrugs, and othe
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Page/Page column 31
(2015/11/09)
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- SUBSTITUTED 4-PROLINE DERIVATIVES AS IGLUR ANTAGONISTS
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The present invention relates to compounds of Formula (I), combinations and use thereof for disease therapy, or pharmaceutically acceptable salt or solvate thereof, including all tautomers, stereoismers and polymorphs thereof, which are iGluR receptor inhibitors, and hence are useful in the treatment of psychiatric diseases or neurological disorders or a disease or disorder associated with abnormal activities of iGluR receptors.
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Page/Page column 40; 41
(2015/02/02)
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- A Highly Stereoselective and Scalable Synthesis of l -allo-Enduracididine
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A highly stereoselective and scalable synthesis of l-allo-enduracididine from hydroxyproline derivative is described. Pyrrolidine oxidation and reductive ring opening are the key steps in the synthesis. Compared to previously reported approaches, the curr
- Craig, William,Chen, Janet,Richardson, David,Thorpe, Rondel,Yuan, Yu
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supporting information
p. 4620 - 4623
(2015/09/28)
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- AZAQUINAZOLINE INHIBITORS OF ATYPICAL PROTEIN KINASE C
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The present invention provides a compound of formula (I) or a salt thereof, wherein R7, R8, R9, G, and X are as defined herein. A compound of formula (I) and its salts have a PKC inhibitory activity, and may be used to treat proliferative disorders.
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Page/Page column 223-224
(2014/04/17)
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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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- C3′-endo-puckered pyrrolidine containing PNA has favorable geometry for RNA binding: Novel ethano locked PNA (ethano-PNA)
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A novel peptide nucleic acid (PNA) analogue is designed with a constraint in the aminoethyl segment of the aegPNA backbone so that the dihedral angle β is restricted within 60-80, compatible to form PNA:RNA duplexes. The designed monomer is further functionalized with positively charged amino-/guanidino-groups. The appropriately protected monomers were synthesized and incorporated into aegPNA oligomers at predetermined positions and their binding abilities with cDNA and RNA were investigated. A single incorporation of the modified PNA monomer into a 12-mer PNA sequence resulted in stronger binding with complementary RNA over cDNA. No significant changes in the CD signatures of the derived duplexes of modified PNA with complementary RNA were observed.
- Banerjee, Anjan,Kumar, Vaijayanti A.
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p. 4092 - 4101
(2013/07/27)
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- 1,3,4-OXADIAZOLE AND 1,3,4-THIADIAZOLE BETA-LACTAMASE INHIBITORS
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β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed.
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- HEPATITIS C VIRUS INHIBITORS
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The invention provides compounds of formula (I): wherein the variables are defined in the specification, or a pharmaceutically-acceptable salt thereof, that are inhibitors of replication of the hepatitis C virus. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat hepatitis C viral infections, and processes and intermediates useful for preparing such compounds.
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Paragraph 0323
(2013/05/21)
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- MACROCYCLIC COMPOUNDS FOR INHIBITION OF INHIBITORS OF APOPTOSIS
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The invention relates generally to macrocyclic compounds and their therapeutic use. More particularly, the invention relates to macrocyclic compounds that modulate the activity of inhibitors of apoptosis (IAPs) and/or are useful in the treatment of medical conditions, such as cancer.
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Paragraph 00135; 00136
(2013/05/23)
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- SUBSTITUTED CYCLIC COMPOUNDS AND METHODS OF USE
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The present invention provides novel substituted cyclic compounds, pharmaceutical acceptable salts and formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating cellular activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
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Paragraph 0193
(2013/09/26)
-
- Synthesis of proline analogues as potent and selective cathepsin S inhibitors
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Cathepsin S is a potential target of autoimmune disease. A series of proline derived compounds were synthesized and evaluated as cathepsin S inhibitors. We discovered potent cathepsin S inhibitors through structure-activity relationship studies of proline analogues. In particular, compound 19-(S) showed promising in vitro/vivo pharmacological activities and properties as a selective cathepsin S inhibitor.
- Kim, Mira,Jeon, Jiyoung,Song, Jiyeon,Suh, Kwee Hyun,Kim, Young Hoon,Min, Kyung Hoon,Lee, Kwang-Ok
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p. 3140 - 3144
(2013/06/26)
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- 3,5-DISUBSTITUTED ALKYNYLBENZENE COMPOUND AND SALT THEREOF
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The present invention provides a compound represented by Formula (I) (wherein R1, X1, X2, Y, and Z are as defined in the specification), or a salt thereof.
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Paragraph 0193; 0291
(2013/11/19)
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- Synthesis of chiral pyrrolidine isostere inserted into pyrrole polyamide skeleton
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An efficient and general route towards the synthesis of a series of chiral pyrrolidine pyrrole polyamide distamycin analogues starting from (L)-hydroxyproline is described. The binding abilities of these chiral pyrrolidine containing molecules to calf thymus DNA were evaluated by duplex DNA melting temperature analysis. The results revealed that both the chirality at the pyrrolidine ring and the site of incorporation plays an important role for binding at the duplex DNA.
- Lin, Chun-Yu,Yang, Ya-Ting,Ong, Chi Wi
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p. 436 - 442
(2012/07/27)
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- Synthesis of deoxynucleoside triphosphates that include proline, urea, or sulfonamide groups and their polymerase incorporation into DNA
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To expand the chemical array available for DNA sequences in the context of in vitro selection, I present herein the synthesis of five nucleoside triphosphate analogues containing side chains capable of organocatalysis. The synthesis involved the coupling
- Hollenstein, Marcel
-
supporting information
p. 13320 - 13330,11
(2012/12/12)
-
- Synthesis of deoxynucleoside triphosphates that include proline, urea, or sulfonamide groups and their polymerase incorporation into DNA
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To expand the chemical array available for DNA sequences in the context of in vitro selection, I present herein the synthesis of five nucleoside triphosphate analogues containing side chains capable of organocatalysis. The synthesis involved the coupling
- Hollenstein, Marcel
-
supporting information
p. 13320 - 13330
(2013/01/15)
-
- Total synthesis and structure-activity relationships of new echinocandin-like antifungal cyclolipohexapeptides
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A series of new echinocandin-like cyclolipohexapeptides were designed and total synthesized via solution phase [3 + 3]-segment coupling strategy with an attempt to improve antifungal activity. The designed compounds showed potent antifungal activities with broad spectrum. In particular, 11 compounds (i.e. 28a-e, 28g, 28i-j, 29a, 29c and 29e) showed better in vitro antifungal activities against Candida albicans or Aspergillus fumigatus than caspofungin. Moreover, the synthesized compounds provided new SAR information for the echinocandins. The findings in this work suggested that the "left" tripeptide segment of cyclolipohexapeptide scaffold might be a hydrophilic structural motif, whereas the "right" lipopeptide segment was preferred as a hydrophobic core. The amino acid component of the cyclolipohexapeptide scaffold could significantly affect the SAR of the side chains.
- Yao, Jianzhong,Liu, Hongming,Zhou, Ting,Chen, Hai,Miao, Zhenyuan,Sheng, Chunquan,Zhang, Wannian
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scheme or table
p. 196 - 208
(2012/07/28)
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- Functionalizable oligoprolines as molecular scaffolds
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Azidoproline (Azp) containing oligoprolines are conformationally well-defined, helical molecular scaffolds that allow for facile functionalization. Within this article we describe the synthesis of Azp-containing oligoprolines and different strategies to introduce functional moieties. In addition, the influence of factors such as substituents at the γ-position of proline as well as functional groups at the termini on the conformational stability of the molecular scaffolds are briefly presented. Schweizerische Chemische Gesellschaft.
- Nagel, Yvonne A.,Kuemin, Michael,Wennemers, Helma
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scheme or table
p. 264 - 267
(2011/12/21)
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- MELANOCORTIN RECEPTOR AGONISTS
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The present invention relates to a compound having a good agonistic activity to melanocortin receptor, or pharmaceutically acceptable salt or isomer thereof, and an agonistic composition for melanocortin receptor comprising the same as an active ingredient.
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Page/Page column 10
(2010/06/11)
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- MELANOCORTIN RECEPTOR AGONISTS
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The present invention relates to a compound having a good agonistic activity to melanocortin receptor, or pharmaceutically acceptable salt or isomer thereof, and an agonistic composition for melanocortin receptor comprising the same as an active ingredient.
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Page/Page column 22
(2010/06/15)
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- NOVEL PROLINE DERIVATIVES
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The invention relates to a compound of formula (I) wherein A, R1-R6 are as defined in the description and in the claims. The compound of formula (I) can be used as a medicament.
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Page/Page column 39
(2010/11/03)
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- Novel chemotactic For-Met-Leu-Phe-OMe (fMLF-OMe) analogues based on Met residue replacement by 4-amino-proline scaffold: Synthesis and bioactivity
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cis-(2S,4S) 4-Amino-proline (cAmp) and trans-(2S,4R) 4-amino-proline (tAmp) residues, bearing N-For or N-Boc substituents at the two amino groups, have been incorporated into the potent chemotactic agent fMLF-OMe in place of the N-terminal native (S)-methionine to give the analogues 17a-19a and 17b-19b. The new ligands have been examined for their activity (chemotaxis, superoxide anion production and lysozyme release) on human neutrophils as agonists and antagonists. Compounds 19a and 19b, bearing two N-For groups at the proline scaffold, are active and selective chemoattractants. The ligand 18b, containing N-For at the 4-amino group of the N-Boc-tAmp residue, exhibits significant chemotactic antagonism. The influence of the different substitution at the N-terminal position of the new analogues is discussed.
- Torino, Domenica,Mollica, Adriano,Pinnen, Francesco,Feliciani, Federica,Spisani, Susanna,Lucente, Gino
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experimental part
p. 251 - 259
(2011/03/19)
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- MINERALOCORTICOID RECEPTOR ANTAGONISTS AND METHODS OF USE
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The present invention provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof; pharmaceutical compositions comprising a compound of Formula (I) in combination with a suitable carrier, diluent, or excipient; and methods for treating physiological disorders, particularly congestive heart failure, hypertension, diabetic nephropathy, or chronic kidney disease, comprising administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
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Page/Page column 21
(2009/07/10)
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- The synthesis and biological evaluation of a novel series of C7 non-basic substituted fluoroquinolones as antibacterial agents
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A series of non-basic building blocks was synthesized and introduced to the C7 position of the quinolone nucleus 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid to afford the corresponding fluoroquinolones in 46-85% yield. The antibacterial activity of these new fluoroquinolones was evaluated using a standard broth microdilution technique. The sulfur-containing quinolone, 7-(2-thia-5-azabicyclo[2.2.1]heptan-5-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid exhibited a superior antibacterial activity against quinolone-susceptible and multidrug-resistant strains in comparison with the clinically used fluoroquinolones ciprofloxacin and vancomycin, especially to the Streptococcus pneumonia and multidrug-resistant S. pneumonia clinical isolates. Crown Copyright
- Huang, Xiaoguang,Chen, Dongliang,Wu, Ning,Zhang, Aiqin,Jia, Zhenhua,Li, Xingshu
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scheme or table
p. 4130 - 4133
(2010/04/26)
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- PROCESS FOR PRODUCING ESTER OR ALCOHOL
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Provided is a process for producing an ester or alcohol using a fluoroimidinium sulfonate derivative represented by the general formula (9) or a fluoroimidinium carboxylate derivative represented by the general formula (6) and using as a raw material alcohol involving inversion of steric configuration. Further provided are a fluoroimidinium sulfonate derivative represented by the general formula (9), and a process for producing the same.
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Page/Page column 46
(2009/04/23)
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- DUAL-ACTING ANTIHYPERTENSIVE AGENTS
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The invention relates to compounds having the formula: (I) wherein: Ar, r, R3, Z, X, and R5-7 are as defined in the specification, or a pharmaceutically acceptable salt thereof. These compounds have AT1 receptor antagonist activity and neprilysin inhibition activity. The invention also relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.
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Page/Page column 83-84
(2009/04/25)
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- 4-Trifluoromethanesulfonamidyl prolinol tert-butyldiphenylsilyl ether as a highly efficient bifunctional organocatalyst for Michael addition of ketones and aldehydes to nitroolefins
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4-Trifluoromethanesulfonamidyl prolinol tert-butyldiphenylsilyl ether bifunctional organocatalyst 3a is a highly efficient catalyst for the asymmetric Michael addition reactions of ketones and aldehydes to nitrostyrenes, leading to syn-selective adducts with excellent yields (>99%), high diastereoselectivities (up to 99:1 dr) and excellent enantioselectivities (up to 99% ee). Control experiments suggested that the trans-configuration relationship between the bulky group (-CH2OTBDPS) and the sulfonamido group at the 4-position of the pyrrolidine ring was important to achieve high yield and stereoselectivity.
- Wang, Chao,Yu, Chun,Liu, Changlu,Peng, Yungui
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supporting information; experimental part
p. 2363 - 2366
(2009/08/17)
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- Synthesis and crystal structure of cis-4-azido-L-proline methyl ester hydrochloride
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The key precursor for the synthesis of novel influenza neuraminidase inhibitors, cis-4-azido-L-proline methyl ester hydrochloride (C6H 11ClN4O2, Mr = 206.63), was prepared as white needle-shaped crystals and its structure was elucidated by single-crystal X-ray diffraction. In the crystal structure, molecules are linked through intermolecular hydrogen bonds, forming layers perpendicular to the bc plane.
- Gong, Jianzhi,Gong, Yanqing,Xu, Wenfang
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scheme or table
p. 668 - 670
(2010/03/03)
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- Constrained (l-)-S-adenosyl-l-homocysteine (SAH) analogues as DNA methyltransferase inhibitors
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Potent SAH analogues with constrained homocysteine units have been designed and synthesized as inhibitors of human DNMT enzymes. The five membered (2S,4S)-4-mercaptopyrrolidine-2-carboxylic acid, in 1a, was a good replacement for homocysteine, while the corresponding six-member counterpart was less active. Further optimization of 1a, changed the selectivity profile of these inhibitors. A Chloro substituent at the 2-position of 1a, compound 1d, retained potency against DNMT1, while N6 alkylation, compound 7a, conserved DNMT3b2 activity. The concomitant substitutions of 1a at both 2- and N6 positions reduced activity against both enzymes.
- Isakovic, Ljubomir,Saavedra, Oscar M.,Llewellyn, David B.,Claridge, Stephen,Zhan, Lijie,Bernstein, Naomy,Vaisburg, Arkadii,Elowe, Nadine,Petschner, Andrea J.,Rahil, Jubrail,Beaulieu, Norman,Gauthier, France,MacLeod, A. Robert,Delorme, Daniel,Besterman, Jeffrey M.,Wahhab, Amal
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scheme or table
p. 2742 - 2746
(2010/03/03)
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- Design, synthesis, and preliminary evaluation of 4-(6-(3-nitroguanidino)hexanamido)pyrrolidine derivatives as potential iNOS inhibitors
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A series of 4-(6-(3-nitroguanidino)hexanamido)pyrrolidine derivatives were synthesized and evaluated for their abilities to inhibit inducible nitric oxide synthase (iNOS) isoform. All target compounds were prepared in 11 steps from commercially trans-4-hydroxy-l-proline. The preliminary pharmacological test showed that three compounds, 17, 21, and 30, have the good potency (IC50 = 2.36, 2.68, 2.5 μM, respectively) which are compared to the NOS inhibitor NG-nitroarginine(L-NNA) (IC50 = 14.74 μM), and could be used as lead compounds for exploring new iNOS inhibitors in the future.
- Liu, Feng-Zhi,Fang, Hao,Zhu, Hua-Wei,Wang, Qiang,Yang, Yue,Xu, Wen-Fang
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p. 578 - 585
(2008/04/12)
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- MELANOCORTIN RECEPTOR AGONISTS
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The present invention relates to a compound of the following formula 1, pharmaceutically acceptable salt and isomer thereof effective as agonist of melanocortin receptor, and an agonistic composition of melanocortin receptor comprising the same as active ingredient.
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Page/Page column 25
(2008/06/13)
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