- Electron-deficient benzotriazoles for the selective N-acetylation of nucleosides
-
The use of an acetylated benzotriazole for the selective protection of the amino groups of cytidine and 2′-deoxycytidine is reported. The use of the acetyl group is of considerable interest industrially in this role, and a single-step protection strategy advantageous in bulk production. 1-Acetyl-4-nitrobenzotriazole was found to readily acetylate the amine of cytidine preferentially over the exposed alcohol functionalities. With adaptation of the protocol, 2′-deoxycytidine was protected using the same reagent. A similar approach was attempted for the benzoylation of adenosine but was found to be unsuitable.
- Reid, Andrew K.,McHugh, Callum J.,Richie, Graham,Graham, Duncan
-
-
Read Online
- Chlorothioketene, the ultimate reactive intermediate formed by cysteine,conjugate β-lyase-mediated cleavage of the trichloroethene metabolite S-(1,2-dichlorovinyl)-L-cysteine, forms cytosine adducts in organic solvents, but not in aqueous solution
-
Chlorothioketene has been suggested as a reactive intermediate formed by the cysteine conjugate β-lyase-mediated cleavage of S-(1,2-dichlorovinyl)- L-cysteine, a minor metabolite of trichloroethene. Halothioketenes are highly reactive, and their intermediate formation may be confirmed by reactions such as cycloadditions and thioacylations of nucleophiles. A precursor of chlorothioketene, S-(1,2-dichlorovinyl)thioacetate, is readily accessible by the reaction of dichloroethyne with thioacetic acid. In presence of base, S- (1,2-dichlorovinyl)thioacetate is cleaved to chlorothioketene. Chlorothioketene is not stable at room temperature and was characterized after transformation to stable products by reaction with compounds such as cyclopentadiene, N,N-diethylamine, and ethanol. In organic solvents, the cleavage of S-(1,2-dichlorovinyl)thioacetate in the presence of cytosine results in N4-acetylcytosine, N4-(chlorothioacetyl)cytosine; and small amounts of 3-(N4-thioacetyl)cytosine. No reaction products were seen with guanosine, adenosine, and thymidine under identical conditions. When cytosine was reacted with S-(1,2-dichlorovinyl)thioacetate in aqueous solutions, only N4-acetylcytosine was formed. N4-(Chlorothioacetyl)cytosine and 3-(N4- thioacetyl)cytosine were not detected even when using a very sensitive method, derivatization with pentafluorobenzyl bromide and electron capture mass spectrometry with a detection limit of 50 fmol/μL of injection volume. Aqueous solutions of DNA cleave S-(1,2-dichlorovinyl)thioacetate to give N4- acetyldeoxycytidine in DNA, but chlorothioketene adducts of deoxynucleosides were also not detected in these experiments. These results confirm the electrophilic reactivity of chlorothioketene toward nucleophilic groups of DNA constituents in inert solvents but also demonstrate that the formation of DNA adducts under physiological conditions likely is not efficient. Therefore, DNA adducts may not represent useful biomarkers of exposure and biochemical effects for trichloroethene.
- Voelkel, Wolfgang,Dekant, Wolfgang
-
p. 1082 - 1088
(2007/10/03)
-
- CAC H-phosphonate and its use in the synthesis of oligonucleotides
-
Disclosed herein are N4 protected deoxycytidines for use in the synthesis of oligonucleotides, the protecting groups being represented by the formula: --CO--(CH2)0-9 --CH3. Preferred embodiments are N4 acetyl deoxycytidines and include N4 acetyl deoxycytidine phosphoramidites and N4 acetyl deoxycytidine H-phosphonates. When used to prepare oligonucleotides the protected deoxycytidine compounds provide high quality oligonucleotide products with little side product from cleavage and deprotection reactions carried out with alkyl amine compounds.
- -
-
-
- Ultrafast cleavage and deprotection of oligonucleotides synthesis and use of C(Ac) derivatives
-
We have investigated the use of alkylamines as fast cleavage and deprotection reagents for the solid phase synthesis of oligonucleotides and found methylamine/ammonium hydroxide (or methylamine) as an efficient reagent. The transamination side product formed with the commonly used dC(b2) has been eliminated by the use of dC(Ac) phosphoramidite. This system has successfully been used in the synthesis of oligonucleotides and oligonucleoside phosphorothioates. DMT dC(Ac) hydrogen phosphonate and DMT ribo C(Ac)-2'-OMe phosphoramidite also have been prepared and used in the synthesis of oligonucleotides.
- Reddy,Hanna, Naeem B.,Farooqui, Firdous
-
p. 1589 - 1598
(2007/10/03)
-
- Processes for synthesizing nucleotides and modified nucleotides using N
-
Disclosed herein are protecting groups for exocyclic amino groups of the base cytosine for use in the synthesis of oligonucleotides and oligonucleoside phosphorothioates, the protecting groups being represented by the formula: --CO--(CH2)0-9 --CH3. In a particularly preferred embodiment, the base cytosine is protected with acetyl (--CO--CH3), and the oligonucleotide or oligonucleoside phosphorothioate incorporating the protected cytosine is subjected to a cleavage/deprotection reagent comprising methylamine and ammonia.
- -
-
-
- Differential reactivity of carbohydrate hydroxyls in glycosylations. II. The likely role of intramolecular hydrogen bonding on glycosylation reactions. Galactosylation of nucleoside 5'-hydroxyls for the syntheses of novel potential anticancer agents
-
Contrary to expectations, many primary hydroxy groups are completely unreactive in glycosylation reactions, or give the desired glycosides in very low yields accompanied by products of many side reactions. Hydrogens of such primary hydroxyls are shown to be intramolecularly hydrogen bonded. Intermediates formed by nucleophilic attack by these hydroxyls on activated glycosylating agents may resist hydrogen abstraction. This resistance to proton loss is postulated to be the origin of the observed unreactivity. It is shown that successful glycosylations take place under acidic conditions under which such hydrogen bonds cease to exist. Accordingly, direct galactosylations of the normally unreactive 5'-hydroxyls of nucleosides were accomplished for the first time with a galactose trichloroacetimidate donor in chloroform under silver triflate promotion. It is noted that such galactosylated anticancer nucleosides may have improved biological specificity. Contrary to expectations, many primary hydroxy groups are completely unreactive in glycosylation reactions, or give the desired glycosides in very low yields accompanied by products of many side reactions. Hydrogens of such primary hydroxyls are shown to be intramolecularly hydrogen bonded. Intermediates formed by nucleophilic attack by these hydroxyls on activated glycosylating agents may resist hydrogen abstraction. This resistance to proton loss is postulated to be the origin of the observed unreactivity. It is shown that successful glycosylations take place under acidic conditions under which such hydrogen bonds cease to exist. Accordingly, direct galactosylations of the normally unreactive 5′-hydroxyls of nucleosides were accomplished for the first time with a galactose trichloroacetimidate donor in chloroform under silver triflate promotion. It is noted that such galactosylated anticancer nucleosides may have improved biological specificity.
- Whitfield,Douglas,Tang,Csizmadia,Pang,Moolten,Krepinsky
-
p. 2225 - 2238
(2007/10/02)
-
- N-ACYL PROTECTING GROUPS FOR DEOXYNUCLEOTSIDES A QUANTITATIVE AND COMPARATIVE STUDY
-
A detailed study in search for suitable N-acyldeoxy-nucleosides which could serve as building blocks for the stepwise synthesis of deoxyoligonucleotides was undertaken.Several acyl groups namely 4-t-butylphenylacetyl, 4-t-butylphenoxyacetyl, 4-chlorobenzoyl, 3,4-dichlorobenzoyl, 2-methyl-benzoyl, 2,4-dimethylbenzoyl, nicotinoyl, 4-t-butylbenzoyl and 4-phenylazobenzoyl have been used for the protection of the exocyclic amino groups of deoxynucleosides.Interesting data concerning the stability of N-acyl groups towards a potent deacylating system (0.2N NaOH/MeOH) are presented.
- Koester, Hubert,Kulikowski, Konrad,Liese, Thomas,Heikens, Wiebke,Kohli, Vipin
-
p. 363 - 369
(2007/10/02)
-
