- Photolabile Coumarinylmethyl Esters of Cyclic Nucleotides, Methods for their Preparation and Their Use
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The invention relates to new photolabile coumarinylmethyl esters of cyclic nucleotides of general formula I wherein R1 represents hydrogen, bromine or p-chlorophenylthio R4 represents 7-carboxymethoxy, 6,7-, 5,7- or 7,8-bis-(carboxymethoxy), 7-C1-C3-alkoxycarbonylmethoxy, 6,7-bis(C1-C3-alkoxycarbonylmethoxy), 5,7-bis(C1-C3-alkoxy-carbonylmethoxy), or 7,8-bis(C1-C3-alkoxycarbonylmethoxy), R2 represents —NH2 and R3 is hydrogen (adenine residue), or R2 represents —OH and R3 represents NH2 (guanine residue) The inventive compounds are biologically inactive and exhibit high solubility in aqueous buffer solutions, high efficiency in photocleavage and rapid kinetics of liberation, together with high resistance to solvolysis.
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Page/Page column 6; Figure 1
(2008/06/13)
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- Coumarinylmethyl esters for ultrafast release of high concentrations of cyclic nucleotides upon one- and two-photon photolysis
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(Chemical Equation Presented) Shedding light: Efficient activation of cyclic nucleoside monophosphates (cNMPs) can be achieved upon one- and two-photon flash photolysis of novel photolabile coumarinylmethyl esters of cAMP and cGMP (A = adenosine, G = guanosine) as well as their 8-bromosubstituted derivatives. The phototriggers show high solubility in water and permit space- and time-resolved investigations of the molecular mechanisms of cyclic nucleotide dependent processes.
- Hagen, Volker,Dekowski, Brigitte,Nache, Vasilica,Schmidt, Reinhard,Geissler, Daniel,Lorenz, Dorothea,Eichhorst, Jenny,Keller, Sandra,Kaneko, Hiroshi,Benndorf, Klaus,Wiesner, Burkhard
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p. 7887 - 7891
(2007/10/03)
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- Highly efficient and ultrafast phototriggers for cAMP and cGMP by using long-wavelength uv/vis-activation
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Caged cyclic nucleotides exhibiting remarkable advantageous properties have been developed through the use of novel photolabile coumarinylmethyl protecting groups (see scheme). They serve as excellent intracellular sources of cAMP and cGMP and allow the study of spatial- and time-dependent aspects of cyclic nucleotide signaling.
- Hagen, Volker,Bendig, Juergen,Frings, Stephan,Eckardt, Torsten,Helm, Siegrun,Reuter, Dirk,Kaupp, U. Benjamin
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p. 1046 - 1048
(2007/10/03)
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- Deactivation behavior and excited-state properties of (coumarin-4- yl)methyl derivatives. 1. Photocleavage of (7-methoxycoumarin-4-yl)methyl- caged acids with fluorescence enhancement
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The photochemistry of the (7-methoxycoumarin-4-yl)methyl (MCM) carboxylates 3a-d, the mesylate 4, and the phosphates 5a-e has been examined under near physiological conditions in acetonitrile or methanol/aqueous HEPES buffer solution, respectively. Analysis of photoproducts as well as measurements of photochemical quantum yields, fluorescence quantum yields, and lifetimes for the excited singlet state verified the similar photochemical and photophysical behavior of all the esters studied here. 4- (Hydroxymethyl)-7-methoxycoumarin (2) and the corresponding free acids were obtained as major products upon irradiation. The rates of deactivation of the excited MCM derivatives 3a-5e were found to be dependent on the leaving group ability of the anion concerned as well as on the solvent polarity. The polarity dependence and the exclusive formation of 18O-labeled 2 during irradiation of 5a in 18O-labeled water indicate that photocleavage of the excited singlet state of the MCM caged compounds 3a-5e proceeds via a photo S(N)1 mechanism (solvent-assisted photoheterolysis).
- Schade, Bjoern,Hagen, Volker,Schmidt, Reinhard,Herbrich, Ralph,Krause, Eberhard,Eckardt, Torsten,Bendig, Juergen
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p. 9109 - 9117
(2007/10/03)
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- Secretion of cyclic GMP by cultured epithelial and fibroblast cell lines in response to nitric oxide
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LLC-PK1 epithelial cells and RFL-6 fibroblasts secreted both cyclic AMP (cAMP) and cyclic GMP (cGMP) when costimulated with forskolin and 3- morpholinosydnonimine (a chemical nitric oxide generator). Intracellular cAMP levels as high as 1100 and 12,000 pmol/106 cells were achieved for the two cell types, respectively. These levels were high enough to reach approximately 50% saturation of the cAMP transporter and inhibited transport of cGMP to an equal extent, suggesting that the two cyclic nucleotides compete for a common transport system. The rates of secretion of cGMP and cAMP from LLC-PK1 cells increased in proportion to their rates of synthesis as concentrations of stimulant were varied, but increased only 25% relative to intracellular concentrations in response to inhibition of phosphodiesterases by 3-isobutylmethylxanthine. It is proposed that secretion of cyclic nucleotides is not simply proportional to the total intracellular pool in these cells, but rather is coupled to synthesis. In support of this model, oxyhemoglobin was used to trap nitric oxide and block activity of guanylate cyclase in cells treated with 3-morpholinosydnonimine. As a result, secretion of cGMP ceased within 1 min, whereas intracellular levels decreased slowly over 60 min. Probenecid [p(dipropylsulfamoyl)benzoic acid] is a nonselective antagonist of anion transport that inhibited secretion of cAMP in both cell types but, unexpectedly, blocked synthesis of cGMP, and this was reflected in direct inhibition of soluble guanylate cyclase in cell lysates. Two heat-stable, high molecular weight factors that confer sensitivity to probenecid were identified, and these factors increased the sensitivity of guanylate cyclase to nitric acid by an order of magnitude.
- Patel,Wypij,Rose,Rimele,Wiseman
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