- Construction of Challenging Proline-Proline Junctions via Diselenide-Selenoester Ligation Chemistry
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Polyproline sequences are highly abundant in prokaryotic and eukaryotic proteins, where they serve as key components of secondary structure. To date, construction of the proline-proline motif has not been possible owing to steric congestion at the ligatio
- Sayers, Jessica,Karpati, Phillip M. T.,Mitchell, Nicholas J.,Goldys, Anna M.,Kwong, Stephen M.,Firth, Neville,Chan, Bun,Payne, Richard J.
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Read Online
- Synthesis of Ribo-Azanucleosides by Anodic Oxidation: Reactivity Control of Intermediate for Efficient Access to Pharmacophores
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Azanucleosides, the sugar-modified nucleoside analogues, have various biological activities, while their efficient synthetic strategy is still under development. Herein, a novel method for the synthesis of pharmaceutically relevant azanucleosides, β-anomers of ribo-azanucleosides, by means of site-specific anodic C?H activation by using a nitroalkane–lithium perchlorate medium is reported. A mechanistic study of the electrochemical reaction and the armed/disarmed concept from traditional glycochemistry revealed that the 2′-substituent has a significant effect on the reactivity of prolinol derivative, and suitable carboxylic acid additives can control the reactivity of the intermediate species, an iminium cation equivalent. Finally, this method was demonstrated to be applicable for the synthesis of β-anomers of ribo-azanucleosides with all four nucleobases in a stereoselective manner.
- Okamoto, Kazuhiro,Shoji, Takao,Tsutsui, Mizuki,Shida, Naoki,Chiba, Kazuhiro
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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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Read Online
- 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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Read Online
- Design and synthesis of fluorinated peptides for analysis of fluorous effects on the interconversion of polyproline helices
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The unique interaction between fluorine atoms has been exploited to alter protein structures and to develop synthetic and analytical applications. To expand such fluorous interaction for novel applications, polyproline peptides represent an excellent molecular nanoscaffold for controlling the presentation of perfluoroalkyl groups on their unique secondary structure. We develop approaches to synthesis fluorinated peptides to systematically investigate how the number, location and types of the fluorous groups on polyproline affect the conformation by monitoring the transition between the two major polyproline structures PPI and PPII. This work provides valuable information on how fluorous interaction affects the peptide structure and also benefits the design of functional fluorous molecules.
- Li, Meng-Che,Liu, Ying-Jie,Hsu, Kuang-Cheng,Lin, Tse-Hsueh,Lin, Chih-Wei,Horng, Jia-Cherng,Wang, Sheng-Kai
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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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- VISUAL DETECTION OF PBD INDUCED DNA CROSSLINKS
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The present invention relates to the field of oncology, laboratory tools and methods, and especially anti-tumor DNA crosslinking agents. Most patients with advanced solid tumors develop resistance to chemotherapy due to the ability of cancer cells to repair or tolerate sustained DNA damages. The inventors showed that the compounds according to the present invention allow the detection and visualization of alkylated DNA damages induced by PBDs without altering their DNA crosslinking ability. This enables the study of the effect and properties of PBDs. In particular, the present invention relates new derivates of PBD molecules and their synthesis. The present invention also relates to a method for visualizing DNA crosslinking; to a method for assessing the resistance of a tumor to a crosslinking agent and to a method for identifying a molecule or treatment for improving the efficiency of a crosslinking agent.
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Page/Page column 47; 48
(2021/04/23)
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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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- Synthesis process of N-BOC-cis-4-hydroxyproline methyl ester
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The invention discloses a synthesis process of N-BOC-cis-4-hydroxyproline methyl ester. The synthesis process comprises the following steps: (1) adding raw materials including dichloromethane, 4-hydroxy-L-proline and DMAP into a 2 L reaction flask, stirring, slowly dropwise adding BOC anhydride into the reaction liquid, after dropwise adding, sampling, carrying out TLC, completely reacting the rawmaterials, adding water into the reaction liquid after treatment, stirring at a temperature of 20-30 DEG C, separating the liquid, drying an organic phase by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a white solid product; and (2) taking the obtained product, adding tetrahydrofuran and DCC into a 5 L reaction flask, stirring at 20-30 DEG C to react for 1 hour, dropwise adding methanol into the reaction solution, keeping the temperature after dropwise adding, sampling, carrying out TLC until the reaction is complete, filtering the reaction solution, collecting the filtrate, concentrating under reduced pressure until no liquid flows out to obtain a white solid crude product, heating, collecting the filtrate, collecting a filter cake, and drying the filter cake to obtain a white solid. According to the invention, the product is prepared with high quality and high yield.
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Paragraph 0021-0023
(2021/01/20)
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- Design, Synthesis, and Biochemical Evaluation of Alpha-Amanitin Derivatives Containing Analogs of the trans-Hydroxyproline Residue for Potential Use in Antibody-Drug Conjugates
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Alpha-amanitin, an extremely toxic bicyclic octapeptide extracted from the death-cap mushroom, Amanita phalloides, is a highly selective allosteric inhibitor of RNA polymerase II. Following on growing interest in using this toxin as a payload in antibody-drug conjugates, herein we report the synthesis and biochemical evaluation of several new derivatives of this toxin to probe the role of the trans-hydroxyproline (Hyp), which is known to be critical for toxicity. This structure activity relationship (SAR) study represents the first of its kind to use various Hyp-analogs to alter the conformational and H-bonding properties of Hyp in amanitin.
- Braun, Alexandra,Gallo, Francesca,Hambira, Chido M.,Hechler, Torsten,Kato, Brandon,Müller, Christoph,Matinkhoo, Kaveh,Pahl, Andreas,Perrin, David M.,Wei, Charlie,Wong, Antonio A. W. L.
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p. 10282 - 10292
(2021/06/25)
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- NOVEL CONNECTED BODY AND USE THEREOF IN SPECIFIC CONJUGATION BETWEEN BIOMOLECULE AND DRUG
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PROBLEM TO BE SOLVED: To provide: a method for producing a connected body; a method for using the connected body in the production of a uniform conjugate; and a method for applying the conjugate in the treatment of cancer, infectious diseases, and autoimmune diseases. SOLUTION: A novel connected body is provided that includes a 2,3-di-substituted succinic acid group or a 2-mono-substituted or 2,3-di-substituted fumaric acid or maleic acid (trans (E)- or cis (Z)-butenedioic acid) group for conjugating 2 or more compounds/cytotoxic agents per connected body with a cell-binding molecule by specifically bridge-linking to a pair of thiol on the cell-binding molecule. The connected body is exemplified by the following general formula. SELECTED DRAWING: None COPYRIGHT: (C)2021,JPOandINPIT
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Paragraph 0209-0210
(2021/05/14)
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- Synthesis and evaluation of “Ama-Flash”, a photocaged amatoxin prodrug for light-activated RNA Pol II inhibition and cell death
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Amanitin is used extensively as a research tool to inhibit RNA Pol II thereby implicating its role in mRNA transcription. Recently, amanitin has gained traction as a toxic payload for targeted therapy. Here we report the first-ever photocaged amanitin analog, that is non-toxic and can be pre-loaded into cells. Light provides a means to inhibit RNA Pol II and provoke cell death on-demand.
- Matinkhoo, Kaveh,Pryyma, Alla,Wong, Antonio A. W. L.,Perrin, David M.
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supporting information
p. 9558 - 9561
(2021/09/28)
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- Altering the sex pheromone cyclo(L-pro-l-pro) of the diatom seminavis robusta towards a chemical probe
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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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- THERAPEUTIC METHODS
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The invention provides methods and compositions for delivering a nucleic acid to a cell or the cytosol of the target cell. The method includes contacting the cell with, 1) a membrane-destabilizing polymer; and 2) a nucleic acid conjugate. The nucleic acid conjugate includes a targeting ligand bound to an optional linker and a nucleic acid.
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Page/Page column 135
(2020/05/28)
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- CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES
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A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.
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Page/Page column 143-144
(2020/01/31)
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- CONJUGATION LINKERS CONTAINING 2,3-DIAMINOSUCCINYL GROUP
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Provided is a conjugate of a cytotoxic drug/molecule to a cell-binding molecule with a bis-linker (adual-linker) containing a 2, 3-diaminosuccinyl group. It also relates to preparation of the conjugate of a cytotoxic drug/molecule to a cell-binding molecule with the bis-linker, particularly when the drug having functional groups of amino, hydroxyl, diamino, amino-hydroxyl, dihydroxyl, carboxyl, hydrazine, aldehyde and thiol for conjugation with the bis-linker in a specific manner, as well as the therapeutic use of the conjugates.
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Page/Page column 289
(2020/05/19)
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- SMAC MIMETICS USED AS IAP INHIBITORS AND USE THEREOF
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Disclosed are a class of SMAC mimetics used as IAP inhibitors, and in particular disclosed are compounds as shown in formula (I), isomers thereof, and pharmaceutically acceptable salts thereof. The IAP inhibitors are drugs for treating cancers, in particu
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Sheet 0182; 0183
(2020/12/10)
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- Substituted Quinazoline and Pyridopyrimidine Derivatives Useful as Anticancer Agents
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Compounds of the general formula: processes for the preparation of these compounds, compositions containing these compounds, and the uses of these compounds.
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Paragraph 0465; 0466
(2019/08/22)
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- METHODS FOR TREATING HEPATITIS B INFECTIONS
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Certain embodiments of the invention provide a method for identifying a patient that has a higher likelihood of responding to an HBV antigen inhibitor, such a method comprising detecting a hepatitis B virus (HBV) infected patient's genotype at one or more of the IL28B/A associated SNPs described herein, wherein the relevant genotype(s) described herein are indicative of a patient that has a higher likelihood of responding to an HBV antigen inhibitor as compared to an HBV infected patient having different genotypes at these locations.
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Page/Page column 203
(2019/04/09)
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- As Aurora kinase inhibitors of the substituted quinazoline derivatives
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The invention relates to a substituted quinazoline derivative as an aurora kinase inhibitor, which is shown as structural formula (I) or (Ia), tautomers, hydrates, solvates or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the tautomers, hydrates, solvates and pharmaceutically acceptable salts as drug active ingredients, and application of the compounds and the pharmaceutical compositions in preparation of medicines for protection, treatment, curing or alleviation of proliferative diseases of patients.
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Paragraph 0291; 0297-0299
(2019/04/04)
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- As Aurora kinase inhibitor derivatives
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The present invention relates to a substituted pyrazole derivative used for inhibiting Aurora kinase and represented by formula (I) or formula (Ia), or stereo isomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs thereof, a medicinal composition containing the above compounds as active ingredients, and a use of the compounds and the medicinal composition in preparation of medicines for protecting, processing, treating or mitigating proliferative diseases of patients.
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Paragraph 0612; 0617; 0618
(2019/06/27)
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- Pyrrolidine ring puckering and prolyl amide bond configurations of 2-methyl-allo-hydroxyproline-based dipeptides
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An expeditious method for the synthesis of homo and heterochiral dipeptides containing l-alanine and d/l 2-methyl allo-hydroxyl prolines was developed using direct aminolysis of bicyclic lactones derived from d/l alanine. The impact of C-2 methylation and its spatial orientation on the pyrrolidine ring puckering and prolyl amide bond configuration was ascertained by solution NMR studies. The present studies reveal that C-2 methylation causes the prolyl amide bond to exist exclusively in the trans geometry in both homo- and heterochiral dipeptides. However, the spatial orientation of the C-2 methyl group and its i + 2 position in appropriately capped model dipeptides may nucleate into a turn like structure.
- Tiwari, Vinay Shankar,Singh, Gajendra,Gurudayal,Ampapathi, Ravi Sankar,Haq, Wahajul
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supporting information
p. 4460 - 4464
(2019/05/17)
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- Synthesis method of teneligliptin key intermediate
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The invention discloses a synthesis method of a teneligliptin key intermediate, and relates to the technical field of synthesis, in particular to a synthesis method of a teneligliptin key intermediate(2S)-4-oxo-2-(3-thiazolidinylcarbonyl)-1-pyrrolidinecarboxylic acid tert-butyl ester. According to the synthesis method, L-hydroxyproline is subjected to an esterification reaction to obtain a compound 1; the compound 1 is protected by t-butyloxycarboryl to obtain a compound 2; the compound 2 is subjected to an oxidation reaction to obtain a compound 3; the compound 3 and thiazolidine are subjected to an ammonia ester exchange reaction to obtain a compound 4. According to the method, a synthesis route suitable for industrial production is designed aiming at the teneligliptin key intermediate,the complexity of the operation is lowered, expensive dehydration reagents are also avoided, the yield is high, the cost is low, and the synthesis method is suitable for industrial application and popularization.
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Paragraph 0026-0029
(2019/10/15)
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- The Distinct Conformational Landscapes of 4S-Substituted Prolines That Promote an endo Ring Pucker
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4-Substitution on proline directly impacts protein main chain conformational preferences. The structural effects of N-acyl substitution and of 4-substitution were examined by NMR spectroscopy and X-ray crystallography on minimal molecules with a proline 4
- Costantini, Nicholas V.,Ganguly, Himal K.,Martin, Maxwell I.,Wenzell, Nicole A.,Yap, Glenn P. A.,Zondlo, Neal J.
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supporting information
p. 11356 - 11364
(2019/08/16)
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- SPIRO-LACTAM AND BIS-SPIRO-LACTAM NMDA RECEPTOR MODULATORS AND USES THEREOF
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Disclosed are compounds having potency in the modulation of NMDA receptor activity. Such compounds can be used in the treatment of conditions such as depression and related disorders. Orally delivered formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
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Page/Page column 63-64
(2018/03/28)
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- PROLINE-BASED NEUROPEPTIDE FF RECEPTOR MODULATORS
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Neuropeptide FF receptor modulators based on a proline scaffold are provided which offer NPFF receptor potencies in the nanomolar range and antagonistic selectivity for the NPFF 1 receptor. Methods, compounds and compositions for modulating the function o
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Paragraph 000213
(2018/09/18)
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- CONJUGATION LINKERS, CELL BINDING MOLECULE-DRUG CONJUGATES CONTAINING THE LIKERS, METHODS OF MAKING AND USES SUCH CONJUGATES WITH THE LINKERS
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The present invention relates to linkers having a group of propiolyl, substituted acryl (acryloyl), or disubstituted propanoyl, and using such linkers for the conjugation of compounds, in particular, cytotoxic agents to a cell-binding molecule.
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Page/Page column 181
(2018/05/27)
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- TARGETED COMPOSITIONS
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The invention provides certain nucleic acids (e.g., double stranded siRNA molecules), as well as conjugates that comprise a targeting moiety, a double stranded siRNA, and optional linking groups. Certain embodiments also provide synthetic methods useful for preparing the conjugates. The conjugates are useful to target therapeutic double stranded siRNA to the liver and to treat liver diseases including hepatitis (e.g. hepatitis B and hepatitis D).
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Page/Page column 123
(2018/11/10)
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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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supporting information
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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supporting information
p. 358 - 369
(2018/05/22)
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- N-methyl-D-aspartate receptor modulators and methods of making and using same
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Disclosed are compounds having enhanced potency in the modulation of NMDA receptor activity. Such compounds are contemplated for use in the treatment of diseases and disorders, such as learning, cognitive activities, and analgesia, particularly in alleviating and/or reducing neuropathic pain. Orally available formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
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Page/Page column 60; 62
(2018/06/25)
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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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- Synthesis and antibacterial activity of 6(R)- and 6(S)-fluoropenibruguieramine As: Fluorine as a probe for testing the powerfulness of memory of chirality (MOC)
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The synthesis of 6(R)- and 6(S)- fluoropenibruguieramine As has been achieved, employing the elegant strategy developed by Kim and co-workers. Single diastereomers were formed via the key intramolecular aldol reaction, and both of the products were unambiguously confirmed by X-ray diffraction crystallography. This reaction shows that the fluorine amide effect could not compete with the memory of chirality (MOC) effect, thus further demonstrating the powerfulness of MOC effect in asymmetric synthesis. The biological testing carried out in this work indicates that the principal of antibacterial activity of the natural extract is probably not penibruguieramine A.
- Liu, Ting,Yan, Nan,Zhao, Hui,Wang, Zhen-Xing,Hu, Xiang-Guo
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- ARYL, HETEROARY, AND HETEROCYCLIC PHARMACEUTICAL COMPOUNDS FOR TREATMENT OF MEDICAL DISORDERS
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Complement Factor D inhibitors, pharmaceutical compositions, and uses thereof, as well as processes for their manufacture are provided. The compounds provided include Formula I, Formula II, Formula III, Formula IV, and Formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition. The inhibitors described herein target Factor D and inhibit or regulate the complement cascade.
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Page/Page column 645; 646
(2018/09/21)
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- Methods for Treating Cognitive Disorders Using Inhibitors of Histone Deacetylase
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This disclosure relates to compounds for the inhibition of histone deacetylase and treatment of a cognitive disorder or deficit. More particularly, the disclosure provides for compounds of formula (I) wherein Q, J, L and Z are as defined in the specification.
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Paragraph 0569
(2017/01/23)
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- Cross-Linked Collagen Triple Helices by Oxime Ligation
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Covalent cross-links are crucial for the folding and stability of triple-helical collagen, the most abundant protein in nature. Cross-linking is also an attractive strategy for the development of synthetic collagen-based biocompatible materials. Nature uses interchain disulfide bridges to stabilize collagen trimers. However, their implementation into synthetic collagen is difficult and requires the replacement of the canonical amino acids (4R)-hydroxyproline and proline by cysteine or homocysteine, which reduces the preorganization and thereby stability of collagen triple helices. We therefore explored alternative covalent cross-links that allow for connecting triple-helical collagen via proline residues. Here, we present collagen model peptides that are cross-linked by oxime bonds between 4-aminooxyproline (Aop) and 4-oxoacetamidoproline placed in coplanar Xaa and Yaa positions of neighboring strands. The covalently connected strands folded into hyperstable collagen triple helices (Tm 80 °C). The design of the cross-links was guided by an analysis of the conformational properties of Aop, studies on the stability and functionalization of Aop-containing collagen triple helices, and molecular dynamics simulations. The studies also show that the aminooxy group exerts a stereoelectronic effect comparable to fluorine and introduce oxime ligation as a tool for the functionalization of synthetic collagen.
- Hentzen, Nina B.,Smeenk, Linde E. J.,Witek, Jagna,Riniker, Sereina,Wennemers, Helma
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supporting information
p. 12815 - 12820
(2017/09/25)
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- TARGETED NUCLEIC ACID CONJUGATE COMPOSITIONS
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The invention provides conjugates that comprise a targeting moiety, a nucleic acid, and optional linking groups as well as synthetic intermediates and synthetic methods useful for preparing the conjugates. The conjugates are useful to target therapeutic nucleic acids to the liver and to treat liver diseases including hepatitis (e.g. hepatitis B and hepatitis D).
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Page/Page column 96; 97
(2017/11/10)
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- Improved binding affinities of pyrrolidine derivatives as Mcl-1 inhibitors by modifying amino acid side chains
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As an important member of anti-apoptotic Bcl-2 protein, myeloid cell leukemia sequence 1 (Mcl-1) protein is an attractive target for cancer therapy. In this study, a new series of pyrrolidine derivatives as Mcl-1 inhibitors were developed by mainly modifying the amino acid side chain of compound 1. Among them, compound 18 (Ki= 0.077 μM) exhibited better potent inhibitory activities towards Mcl-1 protein compared to positive control Gossypol (Ki= 0.18 μM). In addition, compound 40 possessed good antiproliferative activities against PC-3 cells (Ki= 8.45 μM), which was the same as positive control Gossypol (Ki= 7.54 μM).
- Wan, Yichao,Liu, Tingting,Li, Xiaoxian,Chen, Chen,Fang, Hao
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p. 138 - 152
(2016/12/22)
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- Amino 6-membered ring derivative and pharmaceutical applications thereof including the use for manufacturing dipeptidyl peptidase-4(IDPP-IV) inhibitor
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The present invention relates to an amino 6-membered ring derivative and pharmaceutical applications thereof, which specifically relates to the amino 6-membered ring derivative represented by the general formula (I) or stereoisomers thereof, pharmaceutically acceptable salts thereof, a prodrug, a pharmaceutical composition comprising the derivative, and the pharmaceutical use for manufacturing dipeptidyl peptidase-4(IDPP-IV) inhibitor, wherein the definition of each substituent in the general formula (I) is the same as described in the specification.
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Page/Page column 44; 45
(2017/07/31)
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- Total Synthesis and Stereochemical Revision of the 2-Formylpyrrole Alkaloid Hemerocallisamine i
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The first total synthesis of the 2-formylpyrrole alkaloid hemerocallisamine I is reported. The convergent synthesis features a key Maillard-Type condensation of a complex amine derived from cis-4-hydroxy-l-proline with a dihydropyranone, to directly furnish the 2-formylpyrrole ring system. The absolute configuration of hemerocallisamine I has been revised on the basis of optical rotation data obtained for the synthesized compound.
- Wood, James M.,Furkert, Daniel P.,Brimble, Margaret A.
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p. 1926 - 1929
(2017/06/28)
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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 158; 159; 160
(2017/03/08)
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- 7-OXO-6-(SULFOOXY)-1,6-DIAZABICYCLO[3.2.1]OCTANE-2-CARBOXAMIDE CONTAINING COMPOUNDS AND THEIR USE IN TREATING BACTERIAL INFECTIONS
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Compounds of Formula (I), their preparation, and use in preventing or treating a bacterial infection are disclosed. (I)
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Page/Page column 27; 28
(2017/07/06)
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- POLYMYXIN ANALOGS USEFUL AS ANTIBIOTIC POTENTIATORS
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The disclosure provides compounds of the formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of either of the foregoing. The variables A, R1, and R2 are defined in the disclosure. The disclosure further includes pharmaceutical compositions comprising a compound of formula I together with at least one pharmaceutically acceptable carrier. The disclosure also includes a method of sensitizing bacteria to an antibacterial agent, comprising administering to a patient infected with the bacteria, simultaneously or sequentially, a therapeutically effective amount of the antibacterial agent and a compound of formula (I).
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Paragraph 0184
(2017/12/09)
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- 4R- and 4S-iodophenyl hydroxyproline, 4R-pentynoyl hydroxyproline, and S-propargyl-4-thiolphenylalanine: Conformationally biased and tunable amino acids for bioorthogonal reactions
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Bioorthogonal reactions allow the introduction of new functionalities into peptides, proteins, and other biological molecules. The most readily accessible amino acids for bioorthogonal reactions have modest conformational preferences or bases for molecular interactions. Herein we describe the synthesis of 4 novel amino acids containing functional groups for bioorthogonal reactions. (2S,4R)- and (2S,4S)-iodophenyl ethers of hydroxyproline are capable of modification via rapid, specific Suzuki and Sonogashira reactions in water. The synthesis of these amino acids, as Boc-, Fmoc- and free amino acids, was achieved through succinct sequences. These amino acids exhibit well-defined conformational preferences, with the 4S-iodophenyl hydroxyproline crystallographically exhibiting β-turn (φ, ψ ~ -80°, 0°) or relatively extended (φ, ψ ~ -80°, +170°) conformations, while the 4R-diastereomer prefers a more compact conformation (φ ~ -60°). The aryloxyproline diastereomers present the aryl groups in a highly divergent manner, suggesting their stereospecific use in molecular design, medicinal chemistry, and catalysis. Thus, the 4R- and 4S-iodophenyl hydroxyprolines can be differentially applied in distinct structural contexts. The pentynoate ester of 4R-hydroxyproline introduces an alkyne functional group within an amino acid that prefers compact conformations. The propargyl thioether of 4-thiolphenylalanine was synthesized via copper-mediated cross-coupling reaction of thioacetic acid with protected 4-iodophenylalanine, followed by thiolysis and alkylation. This amino acid combines an alkyne functional group with an aromatic amino acid and the ability to tune aromatic and side chain properties via sulfur oxidation. These amino acids provide novel loci for peptide functionalization, with greater control of conformation possible than with other amino acids containing these functional groups.
- Forbes, Christina R.,Pandey, Anil K.,Ganguly, Himal K.,Yap, Glenn P. A.,Zondlo, Neal J.
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supporting information
p. 2327 - 2346
(2016/03/01)
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- MAMMALIAN AND BACTERIAL NITRIC OXIDE SYNTHASE INHIBITORS
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Compounds and related methods for inhibition of mammalian and bacterial nitric oxide synthase.
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Paragraph 0126
(2016/06/01)
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- SPECIFIC CONJUGATION LINKERS, SPECIFIC IMMUNOCONJUGATES THEREOF, METHODS OF MAKING AND USES SUCH CONJUGATES THEREOF
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The present invention relates to novel linkers containing a 2,3-disubstituted succinic group, or 2-monosubstituted, or 2,3-disubstituted fumaric or maleic (trans (E)- or cis (Z)- butenedioic), or acetylenedicarboxyl group for conjugation of a cytotoxic agent, and/or one or more different functional molecules per linker to a cell-binding molecule, through bridge linking pairs of thiols on the cell-binding molecule specifically. The invention also relates to methods of making such linkers, and of using such linkers in making homogeneous conjugates, as well as of application of the conjugates in treatment of cancers, infections and autoimmune disorders.
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Page/Page column 124
(2016/05/24)
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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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- 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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- Organocatalytic Enantioselective Continuous-Flow Cyclopropanation
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A set of six solid-supported diarylprolinol catalysts (varying on the anchoring strategy and the type of polymeric support) has been prepared and applied to the enantioselective cyclopropanation reaction. The selected candidate allows implementation of a long flow experiment (48 h) and generates a library of 12 cyclopropanes by sequential flow experiments. The mildness and utility of the method have enabled a telescoped process in which the outstream is directly used in a Wittig flow reaction.
- Llanes, Patricia,Rodríguez-Escrich, Carles,Sayalero, Sonia,Pericàs, Miquel A.
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supporting information
p. 6292 - 6295
(2016/12/23)
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- COMBINATION OF CHIMERIC ANTIGEN RECEPTOR THERAPY AND AMINO PYRIMIDINE DERIVATIVES
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The invention provides compositions and methods for treating diseases associated with expression of CD19, e.g., by administering a recombinant T cell comprising the CD19 CAR as described herein, in combination with a BTK inhibitor, e.g., an amino pyrimidi
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Page/Page column 273
(2017/04/29)
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- γ-(S)-Trifluoromethyl proline: Evaluation as a structural substitute of proline for solid state 19F-NMR peptide studies
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γ-(4S)-Trifluoromethyl proline was synthesised according to a modified literature protocol with improved yield on a multigram scale. Conformational properties of the amide bond formed by the amino acid were characterised using N-acetyl methyl ester model. The amide populations (s-trans vs. s-cis) and thermodynamic parameters of the isomerization were found to be similar to the corresponding values for intact proline. Therefore, the γ-trifluoromethyl proline was suggested as a structurally low-disturbing proline substitution in peptides for their structural studies by 19F-NMR. Indeed, the exchange of native proline for γ-trifluoromethyl proline in the peptide antibiotic gramicidin S was shown to preserve the overall amphipathic peptide structure. The utility of the amino acid as a selective 19F-NMR label was demonstrated by observing the re-alignment of the labelled gramicidin S in oriented lipid bilayers. This journal is
- Kubyshkin, Vladimir,Afonin, Sergii,Kara, Sezgin,Budisa, Nediljko,Mykhailiuk, Pavel K.,Ulrich, Anne S.
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p. 3171 - 3181
(2015/03/18)
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- Design, synthesis and preliminary biological studies of pyrrolidine derivatives as Mcl-1 inhibitors
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Anti-apoptotic proteins, such as B-cell lymphoma (Bcl-2) protein, myeloid cell leukemia sequence 1 (Mcl-1) protein, are potential targets for cancer treatment. In the studies, a series of pyrrolidine derivatives were developed as potent Mcl-1 inhibitors. The preliminary biological studies suggested that most of target compounds exhibit good abilities for targeting Mcl-1 protein. Among them, compound 21 (Ki = 0.53 μM) exhibited equal inhibitory activities towards Mcl-1 protein compared to positive control gossypol (Ki = 0.39 μM). This compound also possessed good antiproliferative activities against MDA-MB-231 and PC-3 cancer cells.
- Wan, Yichao,Wang, Junhua,Sun, Feng'E,Chen, Minglu,Hou, Xuben,Fang, Hao
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p. 7685 - 7693
(2015/12/20)
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