A convenient and general approach to the synthesis of properly protected d-nucleoside-3′-hydrogenphosphonates via phosphite intermediates

Marugg, J. E.; Tromp, M.; Kuyl‐Yeheskiely, E.; Marel, Gijsbert A. van der; Boom, J. H. Van

doi:10.1016/s0040-4039(00)84611-0

Cited by 127 publications

(59 citation statements)

References 11 publications

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“…The phosphorodiamidite 347 could also be used for the preparation of 355 despite a much slower acidolysis rate. 499 Deoxyribonucleoside phosphoramidites carrying the 2-(2-pyridyl)ethy1500 and the 2-(4-pyridyl)ethyl group 501 have also been generated/n situ and used in solid-phase DNA synthesis upon activation with 1H-tetrazole or 5-(p-nitrophenyl)-lH-tetrazole. The removal of the 2-(2-pyridyl)ethyl or the 2-(4-pyridyl)ethyl group was accomplished by treatment with phenyl ¢hloroformate followed by concentrated ammonium hydroxide 501 or by treatment with methyl iodide without any apparent alkylation of the nucleobases.~ Allyl groups were shown by Hayakawa et a/.~3 to be useful protecting groups for intemucleotidic phosphodiester linkages.…”

mentioning

confidence: 99%

Advances in the Synthesis of Oligonucleotides by the Phosphoramidite Approach

Beaucage¹,

Iyer²

1992

Tetrahedron

688

390

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mentioning

confidence: 99%

Advances in the Synthesis of Oligonucleotides by the Phosphoramidite Approach

Beaucage¹,

Iyer²

1992

Tetrahedron

688

390

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“…These were products of the deacylation-reacylation of DPPF which formed during the absorption from the intestine after oral administration. In contrast to previously synthesized nucleoside diphosphate glycerides, which are not expected to be absorbed via the absorption pathway for phospholipids (Marugg et et., 1986;Lindh and Stawinski, 1987;Shuto et sl., 1988;Hostetler et sl., 1990;Piantadosi et el., 1991;Sakai et al, 1993), they hypothesized that there was enhanced delivery to the lymphatic system by DPPF since PAPF and PLPF have the same backbone structure as is found in natural phospholipids. These compounds can therefore be delivered to desired regions by the lymphatic route following oral administration by association with chylomicrons in gut epithelial cells.…”

Section: Introductionmentioning

confidence: 66%

“…A number of phospholipid derivatives of anti-cancer and antiviral compounds have been synthesized and tested for biological activity (Marugg et al, 1986;Lindh and Stawinski, 1987;Shuto et al, 1988;Hostetler et al, 1990, Kucera et al, 1990van Wijik et el., 1992;Sakai et el., 1993). Results of a recent study by Sakai et al (1993) seemed to be promising and prompted us to explore the targeting of anti-HIV nucleosides towards the lymphatic system using a similar approach.…”

Section: Introductionmentioning

confidence: 99%

Lymphatic Targeting of anti-HIV Nucleosides: Distribution of 3′-azido-3′-deoxythymidine (AZT) and 3′-azido-2′,3′-dideoxyuridine (AZdU) after Administration of Dipalmitoylphosphatidyl Prodrugs to Mice

Manouilov

Fedorov

Boudinot

et al. 1995

Antivir Chem Chemother

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SummaryHuman immunodeficiency virus appears to be proliferating within the lymphatic system throughout the period of clinical latency. Targeting of anti-HIV compounds to the lymphatic tissue may therefore provide therapeutic benefits. The purpose of this investigation was to determine the distribution of 3'-azido-3'-deoxythymidine (AZT) and 3'-azido-2',3'-dideoxyuridine (AZdU) in lymph nodes in a mouse model after administration of the lipophilic prodrugs dipalmitoylphosphatidyl-azidodeoxythymidine (DPP-AZT) and dipalmitoylphosphatidyl-azidodideoxyuridine (DPPAZdU). Mice received 50 mg kg-1 of parent nucleoside and 164 mg kg-1 of DPP-AZT (equivalent to 50 mg kg-1 AZT) intravenously or orally and 180mg kg-1 DPPAZdU (equivalent to 50 mg kg-1 AZdU) orally. Serum, neck, axillary and mesenteric lymph nodes were collected at selected times and AZT and AZdU concentrations were determined by HPLC. The disposition of AZT and AZdU in serum and lymph nodes was significantly altered after intravenous and oral administration of DPP-AZT and oral administration of DPP-AZdU when compared to that after administration of parent nucleoside. Lower peak concentrations of AZT and AZdU were observed in serum and lymph nodes after administration of the phospholipid prodrugs. However, DPP-AZT and DPP-AZdU produced consistently higher concentrations of AZT and AZdU, respectively, Received 11 January, 1995; accepted 21 February, 1995 © 1995 Blackwell Science Ltd 2-3 h after prodrug administration. Half-life values for both nucleosides in serum and lymph nodes were significantly greater after prodrug administration.Greater AUC values for nucleosides were noted in neck (AZT and AZdU) and mesenteric (AZT) lymph nodes after administration of prodrugs compared with values obtained for parent drugs. Furthermore, relative lymph node exposure to AZT and AZdU in the lymph nodes was greater after administration of prodrug than after administration of parent compound. Thus, DPP-AZT and DPP-AZdU show potential as useful prodrugs for the delivery of AZT and AZdU to the lymphatic system.

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“…Salicyl phosphorochloridite was originally used in the synthesis of the H-phosphonate. 16) The H-phosphonate is obtained when water reacts with 2, and trace amounts of water in the reaction mixture can react Note * To whom correspondence should be addressed. e-mail: s.nagata@po.nippon-shinyaku.co.jp…”

Section: Resultsmentioning

confidence: 99%

Improved Method for the Solid-Phase Synthesis of Oligoribonucleotide 5′-Triphosphates

Nagata

Takagaki

Wada

2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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We have developed an improved solid-phase method for the synthesis of 5′-triphosphates (5′-TPs) of oligoribonucleotides. The method is based on the use of salicyl phosphorochloridite as the phosphitylating reagent and the improvement is characterized by the use of the highly reactive pyrophosphorylating reagent tris(tetra-n-butylammonium) hydrogen pyrophosphate instead of the conventional tri-n-butylammonium salt for the nucleophilic substitution reaction to form the cyclic ester intermediate. The improved method can be used to generate oligoribonucleotide 5′-TPs efficiently and reproducibly.Key words 5′-triphosphate; oligoribonucleotide; solid phase; RNA; triphosphorylation 5′-Triphosphates (5′-TPs) of nucleosides and nucleic acids play an important role in biochemical reactions and have many research and medical applications. Thus, nucleoside 5′-TPs have long been known to be substrates for enzymatic DNA and RNA synthesis. A more recent discovery is the fact that the immune response triggered by the binding of 5′-TPs of RNA oligomers to retinoic acid-induced protein I (RIG-I) works together in synergy with gene silencing mediated by small interfering RNAs to promote apoptosis in tumor cells. 1)As for applications, 5′-TPs of DNA and RNA oligomers are used as substrates for ligation in vitro, while modified nucleoside triphosphates are used as antiviral medicines and diagnostic reagents. The demand for 5′-TPs of DNA and RNA is increasing and will most likely be met by chemical synthetic rather than enzymatic methods because of advantages resulting from the ability to introduce chemically modified nucleosides at any point in the sequence as well as the practicality of scaling up the synthesis. Chemical methods for the synthesis of 5′-TPs of RNA in particular have the additional advantage that they allow the production of highly pure RNA.A number of chemical syntheses of 5′-TPs of DNA and RNA have been reported. 2-9) Among these, a liquid-phase synthesis of 5′-TPs by reaction of the oligonucleotide with 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one (salicyl phosphorochloridite) developed by Ludwig and Eckstein 10) is well known.11) However, there are few reports of the solid-phase synthesis of DNA and RNA 5′-TPs. 4,9,11) A solid-phase adaptation of the salicyl phosphorochloridite method of Ludwig and Eckstein 10) has been developed by Schmidt et al.,12) who used it to synthesize the 5′-TP of a 25-mer RNA.For triphosphorylation experiments in the present study, we synthesized a 25-mer RNA oligomer by the 2-cyanoethoxymethyl (CEM) method of RNA synthesis developed in our laboratory. [13][14][15] In this method, the CEM group is used as the 2′-hydroxyl protecting group. Because the CEM group is small, it offers minimal steric hindrance and so allows an increased yield at each coupling step. As a result, and also because of the ease of removal of the CEM group under mild conditions after synthesis, RNA can be synthesized more simply and easily by the CEM method than by methods involving conventional 2′-hydroxyl protect...

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A convenient and general approach to the synthesis of properly protected d-nucleoside-3′-hydrogenphosphonates via phosphite intermediates

Cited by 127 publications

References 11 publications

Advances in the Synthesis of Oligonucleotides by the Phosphoramidite Approach

Advances in the Synthesis of Oligonucleotides by the Phosphoramidite Approach

Lymphatic Targeting of anti-HIV Nucleosides: Distribution of 3′-azido-3′-deoxythymidine (AZT) and 3′-azido-2′,3′-dideoxyuridine (AZdU) after Administration of Dipalmitoylphosphatidyl Prodrugs to Mice

Improved Method for the Solid-Phase Synthesis of Oligoribonucleotide 5′-Triphosphates

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