263847-08-1Relevant articles and documents
Paired Utility of Aza-Amino Acyl Proline and Indolizidinone Amino Acid Residues for Peptide Mimicry: Conception of Prostaglandin F2α Receptor Allosteric Modulators That Delay Preterm Birth
Mir, Fatemeh M.,Atmuri, N. D. Prasad,Bourguet, Carine B.,Fores, Jennifer Rodon,Hou, Xin,Chemtob, Sylvain,Lubell, William D.
, p. 4500 - 4525 (2019/05/17)
Peptide mimicry employing a combination of aza-amino acyl proline and indolizidinone residues has been used to develop allosteric modulators of the prostaglandin F2α receptor. The systematic study of the N-terminal phenylacetyl moiety and the conformation and side chain functions of the central turn dipeptide residue has demonstrated the sensitive relationships between modulator activity and topology. Examination of aza-Gly-Pro and aza-Phe-Pro analogs 2a and 2b in a murine preterm labor model featuring treatment with lipopolysaccharide demonstrated their capacity to extend significantly (>20 h) the average time of delivery offering new prototypes for delaying premature birth.
A inhibiting DPP-IV compounds and intermediates
-
, (2016/10/20)
Provided are compounds as presented in formulas IA or IB or pharmaceutically acceptable salts thereof, the preparation method therefor, and uses thereof. Also provided are the intermediates of the compounds and the preparation method therefor. The compounds of the present invention can effectively inhibit DPP-IV activity. Compared to the commercial available medicine, Januvia, compound 1 exhibits strong inhibition against DPP4, but has lower activity inhibition against other DPP family members (DPP2, DPP8, and DPP9). Hence the compound of the present invention can not only effectively inhibit DPP4 from exhibiting medicinal activity, but also lower the activity inhibition against other members of the DPP family, reduce toxic side effect, and have better medicinal safety.
Synthesis and electrocatalytic water oxidation by electrode-bound helical peptide chromophore-catalyst assemblies
Ryan, Derek M.,Coggins, Michael K.,Concepcion, Javier J.,Ashford, Dennis L.,Fang, Zhen,Alibabaei, Leila,Ma, Da,Meyer, Thomas J.,Waters, Marcey L.
, p. 8120 - 8128 (2014/08/18)
Artificial photosynthesis based on dye-sensitized photoelectrosynthesis cells requires the assembly of a chromophore and catalyst in close proximity on the surface of a transparent, high band gap oxide semiconductor for integrated light absorption and catalysis. While there are a number of approaches to assemble mixtures of chromophores and catalysts on a surface for use in artificial photosynthesis based on dye-sensitized photoelectrosynthesis cells, the synthesis of discrete surface-bound chromophore-catalyst conjugates is a challenging task with few examples to date. Herein, a versatile synthetic approach and electrochemical characterization of a series of oligoproline-based light-harvesting chromophore-water-oxidation catalyst assemblies is described. This approach combines solid-phase peptide synthesis for systematic variation of the backbone, copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) as an orthogonal approach to install the chromophore, and assembly of the water-oxidation catalyst in the final step. Importantly, the catalyst was found to be incompatible with the conditions both for amide bond formation and for the CuAAC reaction. The modular nature of the synthesis with late-stage assembly of the catalyst allows for systematic variation in the spatial arrangement of light-harvesting chromophore and water-oxidation catalyst and the role of intrastrand distance on chromophore-catalyst assembly properties. Controlled potential electrolysis experiments verified that the surface-bound assemblies function as water-oxidation electrocatalysts, and electrochemical kinetics data demonstrate that the assemblies exhibit greater than 10-fold rate enhancements compared to the homogeneous catalyst alone.
Discovery of small-molecule interleukin-2 inhibitors from a DNA-encoded chemical library
Leimbacher, Markus,Zhang, Yixin,Mannocci, Luca,Stravs, Michael,Geppert, Tim,Scheuermann, Jcrg,Schneider, Gisbert,Neri, Dario
supporting information; experimental part, p. 7729 - 7737 (2012/09/07)
Libraries of chemical compounds individually coupled to encoding DNA tags (DNA-encoded chemical libraries) hold promise to facilitate exceptionally efficient ligand discovery. We constructed a high-quality DNAencoded chemical library comprising 30 000 drug-like compounds; this was screened in 170 different affinity capture experiments. High-throughput sequencing allowed the evaluation of 120 million DNA codes for a systematic analysis of selection strategies and statistically robust identification of binding molecules. Selections performed against the tumor-associated antigen carbonic anhydrase IX (CA IX) and the pro-inflammatory cytokine interleukin-2 (IL-2) yielded potent inhibitors with exquisite target specificity. The binding mode of the revealed pharmacophore against IL-2 was confirmed by molecular docking. Our findings suggest that DNA-encoded chemical libraries allow the facile identification of drug-like ligands principally to any protein of choice, including molecules capable of disrupting high-affinity protein-protein interactions.
Functionalizable oligoprolines as molecular scaffolds
Nagel, Yvonne A.,Kuemin, Michael,Wennemers, Helma
, p. 264 - 267 (2011/12/21)
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.
Solid-phase synthesis of an apoptosis-inducing tetrapeptide mimicking the Smac protein
Le Quement, Sebastian T.,Ishoey, Mette,Petersen, Mette T.,Simonsen, Pernille M.,Holck, Nanna S.,Nielsen, Thomas E.
, p. 7049 - 7053 (2012/01/13)
An approach for the solid-phase synthesis of apoptosis-inducing Smac peptidomimetics is presented. Using a Rink linker strategy, tetrapeptides mimicking the N-4-terminal residue of the Smac protein [(N-Me)AVPF sequence] were synthesized on PEGA resin in excellent purities and yields. Following two synthetic routes, a known tetrapeptide, incorporating a substituted proline, previously shown to exhibit excellent biological activity in vitro as well as low toxicity, was synthesized effectively on a solid support.
Solid-phase synthesis of smac peptidomimetics incorporating triazoloprolines and biarylalanines
Le Quement, Sebastian T.,Ishoey, Mette,Petersen, Mette T.,Thastrup, Jacob,Hagel, Grith,Nielsen, Thomas E.
, p. 667 - 675 (2012/03/22)
Apoptotic induction mechanisms are of crucial importance for the general homeostasis of multicellular organisms. In cancer the apoptotic pathways are downregulated, which, at least partly, is due to an abundance of inhibitors of apoptosis proteins (IAPs) that block the apoptotic cascade by deactivating proteolytic caspases. The Smac protein has an antagonistic effect on IAPs, thus providing structural clues for the synthesis of new pro-apoptotic compounds. Herein, we report a solid-phase approach for the synthesis of Smac-derived tetrapeptide libraries. On the basis of a common (N-Me)AVPF sequence, peptides incorporating triazoloprolines and biarylalanines were synthesized by means of Cu(I)-catalyzed azide-alkyne cycloaddition and Pd-catalyzed Suzuki cross-coupling reactions. Solid-phase procedures were optimized to high efficiency, thus accessing all products in excellent crude purities and yields (both typically above 90%). The peptides were subjected to biological evaluation in a live/dead cellular assay which revealed that structural decorations on the AVPF sequence indeed are highly important for cytotoxicity toward HeLa cells.
Total synthesis and antifungal evaluation of cyclic aminohexapeptides
Klein, Larry L.,Li, Leping,Chen, Hui-Ju,Curty, Cynthia B.,Degoey, David A.,Grampovnik, David J.,Leone, Christina L.,Thomas, Sheela A.,Yeung, Clinton M.,Funk, Kenneth W.,Kishore, Vimal,Lundell, Edwin O.,Wodka, Dariusz,Meulbroek, Jon A.,Alder, Jeffrey D.,Nilius, Angela M.,Lartey, Paul A.,Plattner, Jacob J.
, p. 1677 - 1696 (2007/10/03)
The need for new therapies to treat systemic fungal infections continues to rise. Naturally occurring hexapeptide echinocandin B (1) has shown potent antifungal activity via its inhibition of the synthesis of β-1,3 glucan, a key fungal cell wall component. Although this series of agents has been limited thus far based on their physicochemical characteristics, we have found that the synthesis of analogues bearing an aminoproline residue in the 'northwest' position imparts greatly improved water solubility (>5 mg/mL). The synthesis and structure-activity relationships (SAR) based on whole cell and upon in vivo activity of the series of compounds are reported. Copyright (C) 2000 Elsevier Science Ltd.
