Exploring endoperoxides as a new entry for the synthesis of branched azasugars

A new class of nitrogen-containing endoperoxides were synthesised by a photochemical [4 + 2]-cycloaddition between a diene and singlet oxygen. The endoperoxides were dihydroxylated and protected to provide a series of endoperoxide building blocks for organic synthesis, with potential use as precursors for the synthesis of branched azasugars. Preliminary exploration of the chemistry of these building blocks provided access to a variety of derivatives including tetrahydrofurans, epoxides and protected amino-tetraols

Exploring endoperoxides as a new entry for the synthesis of branched azasugars

Abstract A new class of nitrogen-containing endoperoxides were synthesised by a photochemical [4 + 2]-cycloaddition between a diene and singlet oxygen. The endoperoxides were dihydroxylated and protected to provide a series of endoperoxide building blocks for organic synthesis, with potential use as precursors for the synthesis of branched azasugars. Preliminary exploration of the chemistry of these building blocks provided access to a variety of derivatives including tetrahydrofurans, epoxides and protected aminotetraols. 64

(2S,4'R,5'R)-(E)-tert-Butyl 2-acetyl-2-(2-oxo-5-phenyl-1,3- dioxolan-4-ylmethyl)-5-phenylpent-4-enoate

The title compound, C₂₇H₃₀O₆, was prepared by monodihydroxylation of the bis-olefin (E,E)-tert-butyl 2-acetyl-2-cinnamyl-5-phenylpent-4-enoate using standard Sharpless asymmetric dihydroxylation conditions, followed by treatment with 1,1'-carbonyl diimidazole. In the crystal structure, the phenyl rings form an intramolecular edge-to-face C-H… π contact with an interplanar angle of 56.4° and a H…centroid distance of 3.03 Å.David J. Fox ; Daniel Sejer Pedersen and Stuart Warre

Identification of the first surrogate agonists for the G protein-coupled receptor GPR132

This is the accepted manuscript. The final version is available at http://pubs.rsc.org/en/Content/ArticleLanding/2015/RA/c5ra04804d#!divAbstract.GPR132 is an orphan Class A G protein-coupled receptor. It has been proposed to be activated by protons\ud and to regulate apoptosis, atherosclerosis and inflammation, but these results are still preliminary. In the\ud current work, we now designed and screened a focused compound library using a ?-arrestin recruitment\ud assay, and thereby identified the first disclosed surrogate GPR132 agonist 1 with a potency of 3.4 ?M.\ud This constitutes the first available pharmacological tool for the in vitro characterization of the orphan\ud receptor GPR132. The testing of 32 analogs furthermore identified a number of compounds with lower\ud activity - of which six were agonists and two were antagonists - that were used to construct preliminary\ud structure-activity relationships. Docking followed by molecular dynamics simulation of compound 1 in a\ud structural model of GPR132 displayed the putative interactions for the key ligand functionalities.M.A.S. was supported by a research scholarship from the\ud Drug Research Academy and Novo Nordisk A/S. D.E.G.\ud and H.B.-O. gratefully acknowledge financial support by\ud the Carlsberg Foundation. D.E.G. and D.S.P. gratefully\ud acknowledges financial support by the Lundbeck\ud Foundation. Nils Nyberg is acknowledged for help with\ud NMR spectroscopy. NMR equipment used in this work\ud was purchased via a grant from The Lundbeck\ud Foundation (R77-A6742)

Chemogenomic discovery of allosteric antagonists at the GPRC6A receptor

SummaryGPRC6A is a Family C G protein-coupled receptor recently discovered and deorphanized by our group. This study integrates chemogenomic ligand inference, homology modeling, compound synthesis, and pharmacological mechanism-of-action studies to disclose two noticeable results of methodological and pharmacological character: (1) chemogenomic lead identification through the first, to our knowledge, ligand inference between two different GPCR families, Families A and C; and (2) the discovery of the most selective GPRC6A allosteric antagonists discovered to date. The unprecedented inference of pharmacological activity across GPCR families provides proof-of-concept for in silico approaches against Family C targets based on Family A templates, greatly expanding the prospects of successful drug design and discovery. The antagonists were tested against a panel of seven Family A and C G protein-coupled receptors containing the chemogenomic binding sequence motif where some of the identified GPRC6A antagonists showed some activity. However, three compounds with at least ∼3-fold selectivity for GPRC6A were discovered, which present a significant step forward compared with the previously published GPRC6A antagonists, calindol and NPS 2143, which both display ∼30-fold selectivity for the calcium-sensing receptor compared to GPRC6A. The antagonists constitute novel research tools toward investigating the signaling mechanism of the GPRC6A receptor at the cellular level and serve as initial ligands for further optimization of potency and selectivity enabling future ex vivo/in vivo pharmacological studies

Diphenylphosphinoyl chloride as a chlorinating agent - The selective double activation of 1,2-diols

© The Royal Society of Chemistry 2006Treatment of 1,2-diols with diphenylphosphinoyl chloride in pyridine produces beta-chloroethyl phosphinates which react with complete control of stereochemistry to give epoxides and azido-alcohols, useful intermediates in cyclopropane synthesis.David J. Fox, Daniel Sejer Pedersen, Asger B. Petersen and Stuart Warre

The orphan G protein-coupled receptor GPR139 is activated by the peptides:Adrenocorticotropic hormone (ACTH), α-, and β-melanocyte stimulating hormone (α-MSH, and β-MSH), and the conserved core motif HFRW

GPR139 is an orphan G protein-coupled receptor that is expressed primarily in the brain. Not much is known regarding the function of GPR139. Recently we have shown that GPR139 is activated by the amino acids l-tryptophan and l-phenylalanine (EC(50) values of 220 μM and 320 μM, respectively), as well as di-peptides comprised of aromatic amino acids. This led us to hypothesize that GPR139 may be activated by peptides. Sequence alignment of the binding cavities of all class A GPCRs, revealed that the binding pocket of the melanocortin 4 receptor is similar to that of GPR139. Based on the chemogenomics principle “similar targets bind similar ligands”, we tested three known endogenous melanocortin 4 receptor agonists; adrenocorticotropic hormone (ACTH) and α- and β-melanocyte stimulating hormone (α-MSH and β-MSH) on CHO-k1 cells stably expressing the human GPR139 in a Fluo-4 Ca(2+)-assay. All three peptides, as well as their conserved core motif HFRW, were found to activate GPR139 in the low micromolar range. Moreover, we found that peptides consisting of nine or ten N-terminal residues of α-MSH activate GPR139 in the submicromolar range. α-MSH(1-9) was found to correspond to the product of a predicted cleavage site in the pre-pro-protein pro-opiomelanocortin (POMC). Our results demonstrate that GPR139 is a peptide receptor, activated by ACTH, α-MSH, β-MSH, the conserved core motif HFRW as well as a potential endogenous peptide α-MSH(1-9). Further studies are needed to determine the functional relevance of GPR139 mediated signaling by these peptides