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WO1998043992A1 - Analogues de l'adenosine-diphosphate-ribose cyclique - Google Patents

Analogues de l'adenosine-diphosphate-ribose cyclique Download PDF

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Publication number
WO1998043992A1
WO1998043992A1 PCT/GB1998/000921 GB9800921W WO9843992A1 WO 1998043992 A1 WO1998043992 A1 WO 1998043992A1 GB 9800921 W GB9800921 W GB 9800921W WO 9843992 A1 WO9843992 A1 WO 9843992A1
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WIPO (PCT)
Prior art keywords
cadpr
bromo
deaza
induced
compound
Prior art date
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Ceased
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PCT/GB1998/000921
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English (en)
Inventor
Antony Galione
Barry Potter
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Bath
Oxford University Innovation Ltd
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University of Bath
Oxford University Innovation Ltd
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Publication date
Application filed by University of Bath, Oxford University Innovation Ltd filed Critical University of Bath
Priority to AU68439/98A priority Critical patent/AU6843998A/en
Publication of WO1998043992A1 publication Critical patent/WO1998043992A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

Definitions

  • Cyclic adenosine.diphosphate ribose is a ubiquitous Ca 2+ mobilizing metabolite of ⁇ -NAD + (1 , 2). It is reported to mediate Ca 2+ release via ryanodine sensitive channels in many cell types, in both animal and plant kingdoms (1 , 3-6). Endogenous levels of cADPR have been detected and reported to be equally widespread (7). This finding has led to the postulation that cADPR may be the endogenous/physiological regulator of ryanodine receptors (5, 8-10).
  • cADPR metabolising enzymes are also present which can modulate its levels (11).
  • the synthetic activity of ADP-ribosyl cyclase and catabolic activity of cADPR hydrolase are often co-localised on the same polypeptide. In these cases, the hydrolase activity often exceeds that of cyclase (1).
  • Aplysia ADP-ribosyl cyclase which is isolated and purified from soluble ovotestis extracts of the sea hare. Aplysia californica.
  • the first series of pharmacologically useful cADPR analogues to be synthesised were the 8-substituted analogues (13). These differ from cADPR by a substitution at the 8 position of the adenine ring. This single modification abolishes the agonistic activity of these compounds and instead produces specific competitive antagonists of cADPR-sensitive Ca 2+ release (13).
  • 8-NH 2 -cADPR has been used successfully to demonstrate the involvement of cADPR - mediated Ca 2+ signalling in sea urchin eggs during fertilisation (14) and NO and cGMP-induced Ca 2+ release (15), in Purkinje neurons (16), in hippocampal synaptic plasticity, in permeabilized Jurkat T cells (6), in intestinal smooth muscle during cholecystokinin-induced contractions (5), in PC12 cells (17) and in excitation contraction coupling in cardiac myocytes ( 8).
  • the 8- substituted analogues are prone to hydrolysis by endogenous enzymes (13).
  • ABBREVIATIONS cADPR cyclic adenosine 5'-diphosphate ribose
  • IP 3 myo-inositol-( 1 ,4,5)-trisphosphate; cAMP cyclic adenosine 3', 5'-monophosphate; cGMP cyclic guanosine 3', ⁇ '-monophosphate;
  • the invention provides compounds having the formula (1)
  • Y is halo, C1 - C20 hydrocarbon, NR 2 , OR, SR, nitro or carboxyl,
  • R is H or C1 - C20 hydrocarbon and R groups can be the same or different, and one or each Z represents H or one Z is a cageing group.
  • X 7 is CH and X 3 is N.
  • the preparation of such a compound is described below. Preparation of compounds where X 7 is not CH, or where X 3 is not N can readily be achieved by known chemistry using a different starting compound 6 (see the reaction scheme below).
  • Y is preferably halo, particularly bromo. This is the compound whose preparation is described in detail below. Alternatively Y may be amino. Alternatively Y may be iodo, either a natural or a radioisotope such as 125 l. Radiolabelled compound may be useful in an assay, eg. a competitive binding assay, to screen for other compounds with more potent binding characteristics for a cADPR receptor. Compounds where Y is other than bromo may readily be prepared inter alia using known chemistry with a different n-succinimide derivative in reaction (i).
  • R is H or C1 - C20 hydrocarbon e.g. alkyl, aryl, aralkyl, alkaryl, alkenyl or alkynyl and which may be substituted or unsubstituted.
  • R is H or C1 - C4 alkyl.
  • Either both groups Z represent hydrogen atoms (or negative charges) as in a conventional diphosphate system.
  • one group Z may be a "cageing" group e.g. 1-(o-nitrophenyl)ethyl, whereby the compound of the invention is a caged analogue adapted to be converted into an active compound in situ e.g. by light irradiation.
  • the chemistry of such caged analogues is well known, see Aarhaus R et al, J. Biol. Chem., 1995, 270, 7745; McCray J A and Trentham D R, Ann. Rev. Biophys., Biophys. Chem, 1989, 18, 239-270 and such compounds can be prepared by standard methods.
  • the two sugar rings have been shown as ribose for simplicity, it is envisaged that other groups may be present as in known nucleotide chemistry.
  • the 5'- oxygen atom may be replaced by S, CHF, CF 2 , SO, NR or CH 2 .
  • the 2'- and 3'-hydroxyl groups may be replaced by H, F, NH 2 , N 3 or O-hydrocarbyl.
  • Such compounds may be made by known chemical methods analogous to those described below.
  • 7-deaza-8-bromo-cADPR The synthesis of 7-deaza-8-bromo-cADPR. Briefly, 7-deaza- adenosine (Tubercidin) was brominated and selectively phosphorylated to yield 7-deaza-8-bromo-adenosine ⁇ '-monophosphate (7-deaza-8-bromo- AMP). This was then coupled to nicotinamide mononucleotide (NMN) to form 7-deaza-8-bromo- ⁇ -NAD + as has previously been described for 7- deaza- ⁇ -NAD + (20).
  • NPN nicotinamide mononucleotide
  • the material was purified by ion exchange chromatography and the fractions containing the product, which eluted between 90 and 120mM TEAB, were combined, the solvent removed in vacuo and excess TEAB removed by coevaporation with MeOH to yield the title compound in 27.7% yield.
  • Lytechinus pictus sea urchins were from Marinus Inc. Long Beach, CA. USA. Fluo-3 and Fura 2 was purchased from Cambridge Bioscience (Molecular Probes). All other chemicals were from Sigma inc. (London). Cyclic ADP-ribose, 8-bromo-cADPR and 7 deaza-cADPR were synthesised as previously described (12, 20).
  • Figure 1 A shows the chemical structure of 7-deaza-8-bromo-cADPR as compared with that of cADPR and two previously reported analogues 8-bromo-cADPR, a specific cADPR antagonist (10) and 7-deaza cADPR, a hydrolysis resistant, partial agonist (20). Whereas the latter two compounds have a single modification made at either the 7 or 8 position of the adenosine ring, 7-deaza-8-bromo- cADPR possesses both these modifications. The effect of each modification on the Ca 2+ mobilizing (agonistic) ability was first tested using sea urchin egg homogenates (2.5%).
  • Figure 1 B shows the Ca 2+ releasing action of 2 ⁇ M applications of 7-deaza-8-bromo-cADPR and related cyclic nucleotides.
  • 7-deaza-8- bromo-cADPR did not induce Ca 2+ release from sea urchin egg microsomes, even at concentrations up to 20 ⁇ M (a supra-maximal agonist concentration).
  • 7-deaza-8-bromocADPR resembles the antagonist 8-bromo-cADPR.
  • 7-deaza-8-bromo-cADPR like 8-bromo-cADPR, was also an antagonist of cADPR-sensitive Ca 2+ release was investigated next.
  • FIG. 2 shows that this was indeed the case.
  • Sea urchin egg homogenates pre-treated with either 8-bromo-cADPR or 7-deaza-8-bromo- cADPR were markedly less responsive to 100 nM cADPR (Figure 2A). These inhibitory actions were dependent on the antagonist concentration ( Figure 2B).
  • 7-deaza-8-bromo-cADPR should have greater hydrophobic character than any previously synthesised.
  • Eggs were co-injected with the 1 P 3 receptor antagonist, heparin (250 ⁇ g/ml) and Ca 2+ sensitive fluorochrome fura-2 (2 ⁇ M).
  • Figure 4A shows that upon sperm addition to control heparinized eggs, a propagating Ca 2+ wave was produced (Figure 4A, open squares).
  • Figure 1 (A) Structural formulae of cADPR 7-deaza-cADPR, 8-bromo- cADPR and 7-deaza-8-bromo-cADPR. Modifications were made to cADPR at the 7 and 8 positions of the adenosine ring. The N 7 nitrogen atom is replaced with a carbon (and associated proton) to form 7-deaza cADPR whilst 8-bromo-cADPR is formed by substituting the hydrogen on the C-8 position with a bromine atom. 7-Deaza-8-bromo-cADPR has both these modifications.
  • FIG. 2 Concentration dependent inhibition of cADPR-induced Ca 2+ release by 8-bromo-cADPR and 7-deaza-8-bromo-cADPR.
  • Lytechinus pictus egg homogenates (2.5 %, v/v) containing the Ca 2+ sensitive dye, fluo-3 (3 ⁇ M) were prepared as described in Materials and Methods.
  • Their sensitivity to cADPR-induced Ca 2+ release was used to test the antagonistic action of 8-bromo-cADPR (A) as compared to that of 7-deaza-8-bromo-cADPR (B).
  • Figure 3 Effect of heat treatment on antagonist activity of 8-bromo- cADPR and 7-deaza-8-bromo-cADPR.
  • FIG. 4 Antagonistic actions of extracellularly applied 7-deaza-8- bromo-cADPR and 8-bromo-cADPR on fertilisation-induced Ca 2+ transients in intact sea urchin eggs.

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  • Chemical & Material Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

L'invention concerne un composé de la formule (1) dans laquelle un des éléments X3 et X7 est CR et l'autre élément est N; Y est halo, hydrocarbure C1-C20, NR¿2?, OR, SR, nitro ou carboxyle; R est H ou hydrocarbure C1-C20, et les groupes R peuvent être identiques ou différents; et un ou chaque élément de Z est H, ou Z est un groupe d'insertion. Le composé 7-deaza-8-bromo-adénosine 5'-diphosphate-ribose cyclique s'est avéré un antagoniste de la cADP-ribose stable et résistant à l'hydrolyse.
PCT/GB1998/000921 1997-03-27 1998-03-26 Analogues de l'adenosine-diphosphate-ribose cyclique Ceased WO1998043992A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU68439/98A AU6843998A (en) 1997-03-27 1998-03-26 Cyclic adenosine diphosphate ribose analogues

Applications Claiming Priority (2)

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GBGB9706424.0A GB9706424D0 (en) 1997-03-27 1997-03-27 Cyclic adenosine diphosphate ribose analogues
GB9706424.0 1997-03-27

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WO1998043992A1 true WO1998043992A1 (fr) 1998-10-08

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GB (1) GB9706424D0 (fr)
WO (1) WO1998043992A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000037089A1 (fr) * 1998-12-18 2000-06-29 University Of Bath Analogues de ribose d'adenosine diphosphate cyclique utilises pour la modulation de l'activite des lymphocytes t

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5486604A (en) * 1993-11-01 1996-01-23 Regents Of The University Of Minnesota Cyclic ADP ribose antagonists

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5486604A (en) * 1993-11-01 1996-01-23 Regents Of The University Of Minnesota Cyclic ADP ribose antagonists

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
E.BUTT ET AL.: "Analysis of the Functional Role of cGMP-Dependent Protein Kinase in Intact Human Platelets Using a Specific Activator 8-para-Chlorophenylthio-cGMP.", BIOCHEM. PHARMACOL., vol. 43, 1992, pages 2591 - 2600, XP002068816 *
T.F.WALSETH ET AL.: "Synthesis and Characterization of Antagonists of Cyclic-ADP-Ribose-Induced Ca2+ Release.", BIOCHIMICA ET BIOPHYSICA ACTA, vol. 1178, no. 3, 1993, pages 235 - 242, XP002068814 *
V.C.BAILEY ET AL.: "7-Deaza Cyclic Adenosine 5'-Diphosphate Ribose : First Example of a Ca2+-Mobilizing Partial Agonist Related to Cyclic Adenosine 5'-Diphosphate Ribose.", CHEMISTRY AND BIOLOGY, vol. 4, 1997, pages 51 - 61, XP002068815 *
V.C.BAILEY ET AL.: "Synthesis of 7-Deaza-8-bromo Cyclic Adenosine 5'-Diphosphate Ribose : the First Hydrolysis Resistant Antagonist at the cADPR Receptor.", CHEMICAL COMMUNICATIONS., no. 7, 7 April 1997 (1997-04-07), ROYAL SOCIETY OF CHEMISTRY GB, pages 695 - 696, XP002068817 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000037089A1 (fr) * 1998-12-18 2000-06-29 University Of Bath Analogues de ribose d'adenosine diphosphate cyclique utilises pour la modulation de l'activite des lymphocytes t

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AU6843998A (en) 1998-10-22
GB9706424D0 (en) 1997-05-14

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