- Macrocyclisation of small peptides enabled by oxetane incorporation
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Cyclic peptides are an important source of new drugs but are challenging to produce synthetically. We show that head-to-tail peptide macrocyclisations are greatly improved, as measured by isolated yields, reaction rates and product distribution, by substi
- Roesner, Stefan,Saunders, George J.,Wilkening, Ina,Jayawant, Eleanor,Geden, Joanna V.,Kerby, Paul,Dixon, Ann M.,Notman, Rebecca,Shipman, Michael
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Read Online
- BROAD SPECTRUM ANTI-CANCER COMPOUNDS
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Described herein, inter alia, are compounds for treating cancer and methods of use. This disclosure features chemical entities (e.g., small hairpin RNAs (shRNAs), micro RNA (miRNAs), small interfering RNA (siRNAs), small molecule inhibitors, antisense nucleic acids, peptides, viruses, CRISPR-sgRNAs, or combinations thereof) that inhibit one or more of m6A writers (e.g., methyltransferase like 3 (Mettl3 or MT-A70) or methyltransferase like-14 (Mettl14)), m6Am writers (e.g., phosphorylated CTD interacting factor I (PCIF 1), or Mettl3/14), m6A erasers (e.g., fat-mass and obesity-associated protein (FTO) or ALKB homolog 5 (ALKBH5)), m6Am erasers (e.g., FTO), m6A readers (e.g., YTH domain-containing family proteins (YTHs)), YTF domain family member 1 (YTHDF 1), YTF domain family member 2 (YTHDF 2), YTF domain family member 3 (YTHDF 3), or tyrosine-protein phosphatase non-receptor type 2 (PTPN2).
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Page/Page column 285
(2021/04/23)
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- Development of oxetane modified building blocks for peptide synthesis
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The synthesis and use of oxetane modified dipeptide building blocks in solution and solid-phase peptide synthesis (SPPS) is reported. The preparation of building blocks containing non-glycine residues at the N-terminus in a stereochemically controlled man
- Beadle, Jonathan D.,Clarkson, Guy J.,Raubo, Piotr,Roesner, Stefan,Shipman, Michael,Tam, Leo K. B.,Wilkening, Ina
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supporting information
p. 5400 - 5405
(2020/08/03)
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- Method for taking DAST reagent as removing reagent to synthetize conjugated nitroolefin substituted series derivative
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The invention discloses a preparation method of taking a DAST reagent as a removing reagent to synthesize a conjugated nitroolefin substituted series derivative. The preparation method comprises the following steps that a carbonyl compound (compound II) i
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Paragraph 0060; 0061; 0064; 0065
(2018/12/13)
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- Enzymatically-stable oxetane-based dipeptide hydrogels
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Low molecular weight gelators that are not easily degraded by enzymes have a range of potential applications. Here, we report new Fmoc-protected dipeptides in which the amide carbonyl group has been replaced by an oxetane ring. Remarkably one of these peptidomimetics, but not the corresponding dipeptide, is an effective gelator, forming hydrogels at a concentration of 3 mg mL-1. On assembly, there is a lack of beta-sheet structure, implying that there is no requirement for this motif in such a gel. Furthermore, the modified dipeptide is also stable to proteolysis compared to the parent dipeptide.
- McDougall, Laura,Draper, Emily R.,Beadle, Jonathan D.,Shipman, Michael,Raubo, Piotr,Jamieson, Andrew G.,Adams, Dave J.
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supporting information
p. 1793 - 1796
(2018/02/21)
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- Synthesis of 6-Azaspiro[4.3]alkanes: Innovative Scaffolds for Drug Discovery
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New scaffolds for drug discovery, 6-azaspiro[4.3]alkanes, have been synthesized in two steps from four-membered-ring ketones: cyclobutanone, thienone, N-Boc-azetidinone (Boc = tert-butoxycarbonyl), etc. The key transformation was the reaction between electron-deficient exocyclic alkenes and an in-situ generated N-benzylazomethine ylide.
- Chalyk, Bohdan A.,Isakov, Andrei A.,Butko, Maryna V.,Hrebeniuk, Kateryna V.,Savych, Olena V.,Kucher, Olexandr V.,Gavrilenko, Konstantin S.,Druzhenko, Tetiana V.,Yarmolchuk, Vladimir S.,Zozulya, Sergey,Mykhailiuk, Pavel K.
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p. 4530 - 4542
(2017/08/30)
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- Solid-Phase Synthesis of Oxetane Modified Peptides
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Solid-phase peptide synthesis (SPPS) is used to create peptidomimetics in which one of the backbone amide C=O bonds is replaced by a four-membered oxetane ring. The oxetane containing dipeptide building blocks are made in three steps in solution, then integrated into peptide chains by conventional Fmoc SPPS. This methodology is used to make a range of peptides in high purity including backbone modified derivatives of the nonapeptide bradykinin and Met- and Leu-enkephalin.
- Beadle, Jonathan D.,Knuhtsen, Astrid,Hoose, Alex,Raubo, Piotr,Jamieson, Andrew G.,Shipman, Michael
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supporting information
p. 3303 - 3306
(2017/06/23)
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- Synthesis of Oxetane- and Azetidine-Containing Spirocycles Related to the 2,5-Diketopiperazine Framework
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A simple two-step sequence is used to efficiently make novel spirocyclic analogues of the diketopiperazine nucleus. Conjugate addition of chiral α-amino esters to nitroalkenes, generated from oxetan-3-one or N-Boc-azetidin-3-one, followed by nitro group r
- Beadle, Jonathan D.,Powell, Nicola H.,Raubo, Piotr,Clarkson, Guy J.,Shipman, Michael
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supporting information
p. 169 - 172
(2015/12/26)
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- HEPATITIS B CORE PROTEIN ALLOSTERIC MODULATORS
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ABSTRACT The present disclosure provides, in part, compounds having allosteric effector properties against Hepatitis B virus Cp. Also provided herein are methods of treating viral infections, such as hepatitis B, comprising administering to a patient in need thereof a disclosed compound.
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Paragraph 000279
(2015/10/05)
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- NEW POSITIVE ALLOSTERIC MODULATORS OF NICOTINIC ACETYLCHOLINE RECEPTOR
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The present invention relates to indole derivatives useful in therapy, to compositions comprising said compounds, and to methods of treating diseases comprising administration of said com- pounds. The compounds referred to are positive allosteric modulators (PAMs) of the nicotinic acetylcholine α7 receptor.
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Page/Page column 45-46
(2014/04/17)
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- Synthesis and structure of oxetane containing tripeptide motifs
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A new class of peptidomimetic is reported in which one of the amide CO bonds of the peptide backbone is replaced by an oxetane ring. They are synthesised by conjugate addition of various α-amino esters to a 3-(nitromethylene)oxetane, reduction of the nitro group and further coupling with N-Z protected amino acids to grow the peptide chain. Structural insights are provided by X-ray diffraction and molecular dynamics simulations.
- Powell, Nicola H.,Clarkson, Guy J.,Notman, Rebecca,Raubo, Piotr,Martin, Nathaniel G.,Shipman, Michael
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supporting information
p. 8797 - 8800
(2014/07/22)
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- Oxetanes in drug discovery: Structural and synthetic insights
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An oxetane can trigger profound changes in aqueous solubility, lipophilicity, metabolic stability, and conformational preference when replacing commonly employed functionalities such as gem-dimethyl or carbonyl groups. The magnitude of these changes depends on the structural context. Thus, by substitution of a gem-dimethyl group with an oxetane, aqueous solubility may increase by a factor of 4 to more than 4000 while reducing the rate of metabolic degradation in most cases. The incorporation of an oxetane into an aliphatic chain can cause conformational changes favoring synclinal rather than antiplanar arrangements of the chain. Additionally spirocyclic oxetanes (e.g., 2-oxa-6-aza-spiro[3.3]heptane) bear remarkable analogies to commonly used fragments in drug discovery, such as morpholine, and are even able to supplant the latter in its solubilizing ability. A rich chemistry of oxetan-3-one and derived Michael acceptors provide venues for the preparation of a broad variety of novel oxetanes not previously documented, thus providing the foundation for their broad use in chemistry and drug discovery.
- Wuitschik, Georg,Carreira, Erick M.,Wagner, Bj?rn,Fischer, Holger,Parrilla, Isabelle,Schuler, Franz,Rogers-Evans, Mark,Müller, Klaus
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scheme or table
p. 3227 - 3246
(2010/08/19)
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- Oxetanes as promising modules in drug discovery
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(Chemical Equation Presented) Ring the changes: Introduction of an oxetane ring results in remarkably improved physico- and biochemical properties of the underlying scaffold. The oxetane ring confers enhanced solubility, reduces the metabolic degredation, lipophilicity, and amphiphilicity, and modulates the basicity of a nearby amine group.
- Wuitschik, Georg,Rogers-Evans, Mark,Mueller, Klaus,Fischer, Holger,Wagner, Bjoern,Schuler, Franz,Polonchuk, Liudmila,Carreira, Erick M.
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p. 7736 - 7739
(2007/10/03)
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