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Kiuru E.,University of Turku | Ahmed Z.,University of Turku | Lonnberg H.,University of Turku | Beigelman L.,AliosBiopharma | Ora M.,University of Turku
Journal of Organic Chemistry | Year: 2013

Five different 2,2-disubstituted 4-acylthio-3-oxobutyl groups have been introduced as esterase-labile phosphodiester protecting groups that additionally are thermolabile. The phosphotriesters 1-3 were prepared to determine the rate of the enzymatic and nonenzymatic removal of such groups at 37 C and pH 7.5 by HPLC-ESI-MS. Additionally, 1H NMR spectroscopic monitoring was used for structural characterization of the intermediates and products. When treated with hog liver esterase, these groups were removed by enzymatic deacylation followed by rapid chemical cyclization to 4,4-disubstituted dihydrothiophen- 3(2H)-one. The rate of the enzymatic deprotection could be tuned by the nature of the 4-acylthio substituent, the benzoyl group and acetyl groups being removed 50 and 5 times as fast as the pivaloyl group. No alkylation of glutathione could be observed upon the enzymatic deprotection. The half-life for the nonenzymatic deprotection varied from 0.57 to 35 h depending on the electronegativity of the 2-substituents and the size of the acylthio group. The acyl group evidently migrates from the sulfur atom to C3-gem-diol obtained by hydration of the keto group and the exposed mercapto group attacks on C1 resulting in departure of the protecting group as 4,4-disubstituted 3-acyloxy-4,5-dihydrothiophene with concomitant release of the desired phosphodiester. © 2012 American Chemical Society. Source


Kiuru E.,University of Turku | Ora M.,University of Turku | Beigelman L.,AliosBiopharma | Blatt L.,AliosBiopharma | Lonnberg H.,University of Turku
Chemistry and Biodiversity | Year: 2011

As a first step towards a viable prodrug strategy for short oligoribonucleotides, such as 2-5A and its congeners, adenylyl-2′, 5′-adenosines bearing a 3-(acetyloxy)-2,2-bis(ethoxycarbonyl)propyl group at the phosphate moiety, and an (acetyloxy)methyl- or a (pivaloyloxy)methyl- protected 3′-OH group of the 2′-linked nucleoside have been prepared. The enzyme-triggered removal of these protecting groups by hog liver carboxyesterase at pH 7.5 and 37° has been studied. The (acetyloxy)methyl group turned out to be too labile for the 3′-O-protection, being removed faster than the phosphate-protecting group, which results in 2′,5′- to 3′,5′-isomerization of the internucleosidic phosphoester linkage. In addition, the starting material was unexpectedly converted to the 5′-O-acetylated derivative. (Pivaloyloxy)methyl group appears more appropriate for the purpose. The fully deprotected 2′,5′-ApA was accumulated as a main product, although, even in this case, the isomerization of the starting material takes place. © 2011 Verlag Helvetica Chimica Acta AG, Zürich. Source


Kiuru E.,University of Turku | Ora M.,University of Turku | Beigelman L.,AliosBiopharma | Blatt L.,AliosBiopharma | Lonnberg H.,University of Turku
Chemistry and Biodiversity | Year: 2012

Fully protected pA2′p5′A2′p5′A trimers 1a and 1b have been prepared as prodrug candidates for a short 2′-5′ oligoadenylate, 2-5A, and its 3′-O-Me analog, respectively. The kinetics of hog liver carboxyesterase (HLE)-triggered deprotection in HEPES buffer (pH 7.5) at 37° has been studied. The deprotection of 1a turned out to be very slow, and 2-5A never appeared in a fully deprotected form. By contrast, a considerable proportion of 1b was converted to the desired 2-5A trimer, although partial removal of the 3′-O-[(acetyloxy)methyl] group prior to exposure of the adjacent phosphodiester linkage resulted in 2′, 5′→3′,5′ phosphate migration and release of adenosine as side reactions. © 2012 Verlag Helvetica Chimica Acta AG. Source


Leisvuori A.,University of Turku | Ahmed Z.,University of Turku | Ora M.,University of Turku | Blatt L.,AliosBiopharma | And 2 more authors.
Arkivoc | Year: 2012

Bis(2′-C-methyladenosin-5′-yl) (11), bis(2′-C- methylguanosin-5′-yl) (13), bis(2′-C-methyluridin-5′-yl) (15 ) and 2′-C-methylguanosin-5′-yl 2′-C-methyluridin-5′-yl (16) phosphodiesters have been prepared as pro-drug candidates for the respective 2′-C-methylribonucleoside 5′-monophosphates, expectedly exhibiting antiviral activity against Hepatitis C virus. Additionally, the bis(2′-C-methyladenosine) diester has been converted to 3-acetyloxymethoxy-2,2-bis(ethoxycarbonyl)propyl (19) or pivaloyloxymethyl (20 ) triester. The underlying idea is that the 5′,5′-phosphodiester is first released by intracellular carboxyesterases and subsequently cleaved to nucleoside and nucleoside 5′-monophosphate by phosphodiesterases. ©ARKAT-USA, Inc. Source


Leisvuori A.,University of Turku | Ahmed Z.,University of Turku | Ora M.,University of Turku | Beigelman L.,AliosBiopharma | And 2 more authors.
Helvetica Chimica Acta | Year: 2012

2'-C-Methylnucleosides are known to exhibit antiviral activity against Hepatitis C virus. Since the inhibitory activity depends on their intracellular conversion to 5'-triphosphates, dosing as appropriately protected 5'-phosphates or 5'-phosphorothioates appears attractive. For this purpose, four potential pro-drugs of 2'-C-methylguanosine, i.e., 3',5'-cyclic phosphorothioate of 2'-C-methylguanosine and 2'-C,O 6-dimethylguanosine, 1 and 2, respectively, the S-[(pivaloyloxy)methyl] ester of 2'-C,O 6- dimethylguanosine 3',5'-cyclic phosphorothioate and the O-methyl ester of 2'-C,O 6-dimethylguanosine 3',5'-cyclic phosphate, 3 and 4, respectively, have been prepared. © 2012 Verlag Helvetica Chimica Acta AG, Zürich. Source

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