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The mechanisms of enzymatic and chemical hydrolysis of RNA have been the subject of intense interest for many years. Early demonstration of a dramatically enhanced hydrolytic reactivity of RNA compared to DNA established a crucial mechanistic role for the 2'-hydroxyl group. [1] Hitherto, it has been accepted that the major role of the 2'-hydroxyl group is nucleophilic catalysis and the 2',3'-cyclic phosphate intermediate is well established. The comparatively recent discovery of RNA catalysis (ribozymes) [2] has stimulated renewed interest in the potential role(s) of the 2'-hydroxyl group in an increasingly diverse range of reactions. Thus, the report by Roussev et al. [3] of the electrophilic catalysis of displacement reactions at a neighboring phosphoryl center by the cis vicinal hydroxyl group, if it is correct, offers a potentially novel mechanism that could be of significance to ribozymes. The importance of this claim prompted the present investigation.Roussev and colleagues compared the reactions of 5'protected ribonucleosides and 5'-protected-2'-deoxyribonucleosides with an excess of phosphorus oxychloride and pyridine in CH 2 Cl 2 followed by treatment with an excess of an alcohol. [3] In the case of the ribonucleosides the two-stage sequence led to a mixture of the corresponding 2'-and 3'phosphate triesters (Scheme 1) while in the case of the 2'deoxyribonucleosides the 3'-phosphate triester was produced. Importantly the substrates with a free 2'-hydroxyl group showed much greater reactivity in the second stage, which is the alcoholysis of the intermediate chlorophosphates. This was rationalized in terms of the cis vicinal hydroxyl group hydrogen bonding to the PO group of the ribonucleoside phosphorodichloridate 2 or 3, thereby assisting the subsequent nucleophilic displacements of chlorine by electrophilic catalysis. Crucial to this rationalization was the identification of the intermediate as a mixture of the regioisomeric phosphorodichloridates 2 and 3. This assignment was based on the 31 P NMR spectrum of the reaction mixture. The relevant signals in the case of 5'-O-trityl uridine were reported O TrO HO OH Ura O TrO O OH Ura P O Cl Cl O TrO HO O Ura P O Cl Cl O TrO O OH Ura P O MeO OMe O TrO HO O Ura P O OMe OMe1 + 2 4 3 a) b) + 5 Scheme 1. Reaction scheme proposed by Roussev et al. [3] for the two step synthesis of the 5'-protected ribonucleoside phosphate triesters. Reagents: a) POCl 3 and pyridine in CH 2 Cl 2 ; b) MeOH. as d 22.40 (d, 3 J P,H 12 Hz) and d 20.03 (d, 3 J P,H 10 Hz).The cyclic phosphorochloridate structure 6 a/b was assigned to a minor resonance (6 ± 7 %) at d P 20.01 (t, 3 J P,H 9.2 and 8.4 Hz), and this signal apparently did not increase with time (1 h). Reaction of the 5'-O-trityl-2'-deoxyuridine under the same conditions gave the phosphorodichloridate 7 with a 31 P chemical shift of d 6.7 (d, 3 J P,H 11 Hz). Treatment of the intermediates with an excess of methanol led to the nucleoside dimethylphosphate triesters 4/5 (d P 1.11 and 0.92) and 8 (d P 0.65), respectively. Two aspe...
The mechanisms of enzymatic and chemical hydrolysis of RNA have been the subject of intense interest for many years. Early demonstration of a dramatically enhanced hydrolytic reactivity of RNA compared to DNA established a crucial mechanistic role for the 2'-hydroxyl group. [1] Hitherto, it has been accepted that the major role of the 2'-hydroxyl group is nucleophilic catalysis and the 2',3'-cyclic phosphate intermediate is well established. The comparatively recent discovery of RNA catalysis (ribozymes) [2] has stimulated renewed interest in the potential role(s) of the 2'-hydroxyl group in an increasingly diverse range of reactions. Thus, the report by Roussev et al. [3] of the electrophilic catalysis of displacement reactions at a neighboring phosphoryl center by the cis vicinal hydroxyl group, if it is correct, offers a potentially novel mechanism that could be of significance to ribozymes. The importance of this claim prompted the present investigation.Roussev and colleagues compared the reactions of 5'protected ribonucleosides and 5'-protected-2'-deoxyribonucleosides with an excess of phosphorus oxychloride and pyridine in CH 2 Cl 2 followed by treatment with an excess of an alcohol. [3] In the case of the ribonucleosides the two-stage sequence led to a mixture of the corresponding 2'-and 3'phosphate triesters (Scheme 1) while in the case of the 2'deoxyribonucleosides the 3'-phosphate triester was produced. Importantly the substrates with a free 2'-hydroxyl group showed much greater reactivity in the second stage, which is the alcoholysis of the intermediate chlorophosphates. This was rationalized in terms of the cis vicinal hydroxyl group hydrogen bonding to the PO group of the ribonucleoside phosphorodichloridate 2 or 3, thereby assisting the subsequent nucleophilic displacements of chlorine by electrophilic catalysis. Crucial to this rationalization was the identification of the intermediate as a mixture of the regioisomeric phosphorodichloridates 2 and 3. This assignment was based on the 31 P NMR spectrum of the reaction mixture. The relevant signals in the case of 5'-O-trityl uridine were reported O TrO HO OH Ura O TrO O OH Ura P O Cl Cl O TrO HO O Ura P O Cl Cl O TrO O OH Ura P O MeO OMe O TrO HO O Ura P O OMe OMe1 + 2 4 3 a) b) + 5 Scheme 1. Reaction scheme proposed by Roussev et al. [3] for the two step synthesis of the 5'-protected ribonucleoside phosphate triesters. Reagents: a) POCl 3 and pyridine in CH 2 Cl 2 ; b) MeOH. as d 22.40 (d, 3 J P,H 12 Hz) and d 20.03 (d, 3 J P,H 10 Hz).The cyclic phosphorochloridate structure 6 a/b was assigned to a minor resonance (6 ± 7 %) at d P 20.01 (t, 3 J P,H 9.2 and 8.4 Hz), and this signal apparently did not increase with time (1 h). Reaction of the 5'-O-trityl-2'-deoxyuridine under the same conditions gave the phosphorodichloridate 7 with a 31 P chemical shift of d 6.7 (d, 3 J P,H 11 Hz). Treatment of the intermediates with an excess of methanol led to the nucleoside dimethylphosphate triesters 4/5 (d P 1.11 and 0.92) and 8 (d P 0.65), respectively. Two aspe...
The vicinal hydroxyl group accelerates the second stage of the sequence leading to 2′‐ and 3′‐dialkyl nucleotide triesters 3 and 4 because it enables formation of the reactive 2′,3′‐cyclic phosphorochloridate intermediate 2 a/b (mixture of diastereoisomers); it is not because of electrophilic catalysis (hydrogen bonding) in acyclic phosphorodichloridates as recently proposed.
BackgroundNonsteroidal anti‐inflammatory drugs (NSAIDs) are used for pain relief following tonsillectomy in children. However, as they inhibit platelet aggregation and prolong bleeding time, they could cause increased perioperative bleeding. The overall risk remains unclear. This review was originally published in 2004 and was updated in 2010.ObjectivesThe primary objective of this review was to assess the effects of NSAIDs on bleeding with paediatric tonsillectomy. Our secondary outcome was to establish whether NSAIDs affect the incidence of other postoperative complications when compared to other forms of analgesia.Search methodsWe searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 6); MEDLINE (inception until May 2010); EMBASE (inception until May 2010); Current Problems (produced by the UK Medicines Control Agency), MedWatch (produced by the US Food and Drug Administration) and the Australian Adverse Drug Reactions Bulletins (to May 2010). The original search was performed in August 2004. We also contacted manufacturers and researchers in the field.Selection criteriaWe included randomized controlled trials assessing NSAIDs in children, up to and including 16 years of age, undergoing elective tonsillectomy or adenotonsillectomy.Data collection and analysisTwo authors independently assessed trial quality and extracted the data. We contacted study authors for additional information, where necessary.Main resultsWe included 15 trials that involved 1046 children in this updated review. This included one trial that was added as a result of updating our search and another trial that we had incorrectly excluded from our previous review. All included trials compared NSAIDs with other analgesics or placebo and looked at bleeding requiring surgical intervention. NSAIDs did not significantly alter the number of perioperative bleeding events requiring surgical intervention: Peto odds ratio (OR) 1.32 (95% confidence interval (CI) 0.47 to 3.70). Eight trials involving 532 children looked at bleeding not requiring surgical intervention. NSAIDs did not significantly alter the number of perioperative bleeding events not requiring surgical intervention: Peto OR 1.00 (95% CI 0.39 to 2.53). Twelve trials involving 928 children looked at postoperative nausea and vomiting. There was less nausea and vomiting when NSAIDs were used as part of the analgesic regime than when NSAIDs were not used: OR 0.49 (95% CI 0.29 to 0.83).Authors' conclusionsNSAIDs did not cause any increase in bleeding that required a return to theatre. There was significantly less nausea and vomiting when NSAIDs were used compared to alternative analgesics.Plain Language SummaryNonsteroidal anti‐inflammatory drugs (NSAIDs) do not significantly increase bleeding in children having their tonsils out, and there is less nausea and vomiting when NSAIDs are used.Nonsteroidal anti‐inflammatory drugs (NSAIDs) are used for pain relief following tonsillectomy in children. Bleeding is a recognised complication of this procedure but NSAIDs can interfere with blood clotting so there has been concern that these drugs will increase the risk of bleeding. If bleeding is severe this may result in the child being re‐admitted to hospital, having a blood transfusion or returning to theatre. It was therefore important to establish whether these drugs are safe to use in children having their tonsils out. The review focused on clinically significant bleeding that results in the child requiring additional treatment rather than measured blood loss.We also wanted to establish whether NSAIDs affect the incidence of other postoperative complications when compared to other forms of analgesia.The review found that NSAIDs did not significantly increase bleeding. There were insufficient data to compare the risk of bleeding with each individual type of NSAID. However, we were able to compare ketorolac, which has been perceived as having a greater risk of bleeding, with the other NSAIDs and found no increased risk of bleeding. There was less nausea and vomiting when NSAIDs were used as part of the analgesic regime than when NSAIDs were not used.The main limitation of our review is that bleeding following tonsillectomy is an uncommon event (occurring in 3% to 5% of children). We found all the data that are currently available (15 trials studying approximately 1000 children) but a very large number of participants are required to provide an adequate number of events to give a significant result. It is possible that the numbers of participants are too small to establish whether NSAIDs increase bleeding. However, currently there is no evidence to support withholding NSAIDs for paediatric tonsillectomy.
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