Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2014 Sep 24;114(18):9154-218.
doi: 10.1021/cr5002035. Epub 2014 Aug 21.

Synthesis of nucleoside phosphate and phosphonate prodrugs

Ugo Pradere  1 , Ethel C Garnier-Amblard, Steven J Coats, Franck Amblard, Raymond F Schinazi
Affiliations
Review

Synthesis of nucleoside phosphate and phosphonate prodrugs

Ugo Pradere et al. Chem Rev. .
No abstract available

PubMed Disclaimer

Figures

Figure 1
Figure 1
Mechanism of action of nucleoside monophosphate prodrugs.
Figure 2
Figure 2
Examples of clinical nucleoside prodrugs with anti-HIV, -HBV, or -HCV activities.
Figure 3
Figure 3
Prodrug approaches detailed in this Review.
Figure 4
Figure 4
Examples of carbonyloxymethyl nucleotide prodrugs approved by the FDA or in clinical trials.
Figure 5
Figure 5
Activation of carbonate-type prodrugs (including POC, R = i-Pr).
Figure 6
Figure 6
Activation of ester-type prodrugs (including POM, R = t-Bu).
Figure 7
Figure 7
Methods to access carbonyloxymethyl phosphate nucleosides prodrugs.
Figure 8
Figure 8
Methods to access carbonyloxymethyl phosphonates nucleosides prodrugs.
Scheme 1
Scheme 1. Synthesis of 5-FdU Bis(POM)-monophosphate Prodrug
Scheme 2
Scheme 2. Preparation of Reagents 7 and 8
Scheme 3
Scheme 3. Synthesis of 2′-Deoxy-4′-thioadenosine Bis(POM)-monophosphate Prodrug
Scheme 4
Scheme 4. Synthesis of 8-Bromo-2′-deoxyadenosine Bis(POM)-phosphate Prodrug
Scheme 5
Scheme 5. Conversion of a Monophosphate into Its Corresponding Bis(POM)-monophosphate Nucleoside
Scheme 6
Scheme 6. Preactivation of the Phosphate Moiety as a Tributylstannyl Salt
Scheme 7
Scheme 7. Use of Bis(POM)-phosphorochloridate
Scheme 8
Scheme 8. Synthesis of 5-FdU POM-Phosphate Monoester
Scheme 9
Scheme 9. Synthesis of N2,O2′-Dibutyryl Adenosine-3′,5′-cyclic Monophosphate
Scheme 10
Scheme 10. Synthesis of 2′-C-Methyl Ribonucleosides Cyclic Monophosphates
Scheme 11
Scheme 11. Difference of Reactivity between PMEA versus HPMP-5-azaC Derivatives
Scheme 12
Scheme 12. Synthesis of LB80380
Scheme 13
Scheme 13. Synthesis of Several PMEA and PMPA Bis(alkyloxymethyl) Carbonate Prodrugs
Scheme 14
Scheme 14. Synthesis of Bis(POC)-prodrug 46
Scheme 15
Scheme 15. Synthesis of GS9148
Scheme 16
Scheme 16. N6-Protection Prior to Bis(POM)-phosphonate Nucleoside Formation
Scheme 17
Scheme 17. N6- and Hydroxy Group Protection Prior to Bis(POM)- and Bis(POC)-phosphonates Formation
Scheme 18
Scheme 18. Synthesis of 5-Substituted Uracil Butenyl Acyclic Bis(POM)-phosphonate Nucleoside 62
Scheme 19
Scheme 19. Synthesis of Bis(POM)- and Bis(POC)-allylphosphonates Nucleoside Prodrugs
Scheme 20
Scheme 20. Synthesis of Butenyl Acyclic Purine Bis(POM)-phosphonate Nucleoside Prodrugs
Scheme 21
Scheme 21. Synthesis of 5′-Methylene Phosphonate Furanonucleoside Bis(POM)-prodrugs
Scheme 22
Scheme 22. Synthesis of PMEA POM-Phosphonate Monoester Prodrug
Scheme 23
Scheme 23. Synthesis of PMEA-Carbonyloxymethyl Monoester Prodrug
Scheme 24
Scheme 24. Synthesis of (HPMPC-DAP) POM-Monoester Prodrug 84
Scheme 25
Scheme 25. Synthesis of cHPMP-5-azaC POM-Monoester Prodrug
Scheme 26
Scheme 26. Synthesis of PMEA Mixed Glyoxamide POM-Diester Prodrug
Scheme 27
Scheme 27. Synthesis of Adefovir Bis(l-amino acid) Oxymethyl Phosphonate Prodrugs
Figure 9
Figure 9
Activation of (SATE)- or (DTE)-nucleoside prodrugs.
Figure 10
Figure 10
Access to bis(DTE)-phosphotriesters and bis(DTE)-phosphonodiesters.
Figure 11
Figure 11
Access to bis(SATE)-phosphotriesters and bis(SATE)-phosphonodiesters.
Scheme 28
Scheme 28. Synthesis of Bis(DTE)-monosphosphate Prodrugs
Scheme 29
Scheme 29. Synthesis of Bis(t-Bu-SATE)-Monophosphate Prodrug 96
Scheme 30
Scheme 30. Synthesis of Bis(MeSATE)-ddUMP Using H-Phosphonate Chemistry
Scheme 31
Scheme 31. Traditional (SATE)-Prodrugs Strategies
Scheme 32
Scheme 32. Protection of Base Competitive Sites
Scheme 33
Scheme 33. Mixtures with Sugar Competitive Sites
Scheme 34
Scheme 34. 2′,3′-Isopropylidene Group To Mask Competitive Sites
Scheme 35
Scheme 35. 2′-C-Methyl Adenosine Bis(SATE)-phosphonate Prodrugs
Scheme 36
Scheme 36. Synthesis of Bis(SATE)- or Bis(DTE)-PMEA Prodrugs
Scheme 37
Scheme 37. Preparation of Bis(SATE)-Prodrug 133
Scheme 38
Scheme 38. Synthesis of (SATE)-cMP Prodrugs
Scheme 39
Scheme 39. 3′,5′-Cyclic (SATE)-Phosphonodiester Nucleoside Synthesis
Figure 12
Figure 12
Activation of aryl(SATE)-prodrugs.
Figure 13
Figure 13
Methods of preparation of aryl(SATE)-nucleoside prodrugs.
Scheme 40
Scheme 40. AZT Phenyl(SATE)-phosphotriesters Prodrugs
Scheme 41
Scheme 41. Synthesis of (SATE)-Phosphotriesters Bearing Modified l-Tyrosinyl Residues
Figure 14
Figure 14
Activation pathway of (SATE)-phosphoramidate diester prodrugs.
Scheme 42
Scheme 42. Synthesis of AZT (SATE)-Phosphoramidate Diesters Prodrugs
Scheme 43
Scheme 43. Synthesis of IDX184
Figure 15
Figure 15
Activation of (SATE)-glucosyl phosphorothiolate prodrugs.
Scheme 44
Scheme 44. Synthesis of (SATE)-Glucosyl Phosphorothiolate Derivatives
Scheme 45
Scheme 45. Preparation of (t-Bu)SATE Prodrug 156
Figure 16
Figure 16
Decomposition pathway of iso(SATE)-nucleoside prodrugs.
Scheme 46
Scheme 46. One-Pot Procedure Involving (Pyrrolidino)phosphoramidites
Scheme 47
Scheme 47. Hydrolysis Pathways of the CycloSal-d4TMP Triesters
Figure 17
Figure 17
Different synthetic methods to access cycloSal-diol precursors.
Figure 18
Figure 18
Synthesis of cycloSal prodrugs via P(III) or P(V) chemistry.
Scheme 48
Scheme 48. P(III) Chemistry To Access cycloSal Phosphate Prodrugs
Scheme 49
Scheme 49. P(V) Chemistry To Access cycloSal Phosphate Prodrugs
Scheme 50
Scheme 50. Phosphorochloridate Chemistry To Access CycloSal Phosphate Prodrugs
Scheme 51
Scheme 51. Phosphoramidate Chemistry To Access cycloSal Phosphate Cytosine Prodrugs
Scheme 52
Scheme 52. Chlorophosphane Chemistry To Access cycloSal Phosphate Adenosine Prodrug Derivatives
Scheme 53
Scheme 53. Pd-Catalyzed Reactions with cycloSal Prodrugs
Scheme 54
Scheme 54. Deprotection of a Levulinylate Group on cycloSal-BVdUMP Triesters
Scheme 55
Scheme 55. Preparation of Several 5-[125I]Iodo-uridine cycloSal MP Prodrugs
Scheme 56
Scheme 56. Synthesis of Diastereomerically Pure Monophosphate Prodrug 190
Scheme 57
Scheme 57. Chiral Auxiliaries for 3- and 5-Substituted CycloSal-Derivatives
Figure 19
Figure 19
Meier’s bis(cycloSal)-pronucleotides.
Scheme 58
Scheme 58. Synthesis of Chlorophosphite 200
Scheme 59
Scheme 59. Synthesis of Bis-cycloSal Pronucleotides
Scheme 60
Scheme 60. Bis-cycloSal Pronucleotides
Scheme 61
Scheme 61. MMTr Protection/Deprotection To Access cycloSal-PMEAs
Scheme 62
Scheme 62. Synthesis of cycloAmb-PMEAs Phosphoramidates
Figure 20
Figure 20
Mechanism of action for “lock-in” cycloSal pronucleotides.
Scheme 63
Scheme 63. Elaborated Acyloxy Systems
Figure 21
Figure 21
“Lock-in” cycloSal-pronucleotides bearing geminal dicarboxylate or acetoxyvinyl groups.
Scheme 64
Scheme 64. Synthesis of “Lock-In” cycloSal-Pronucleotides Bearing Geminal Dicarboxylate Groups
Figure 22
Figure 22
HepDirect prodrugs in clinical trial.
Figure 23
Figure 23
Mechanism of activation for HepDirect nucleoside prodrugs.
Figure 24
Figure 24
Methods to access HepDirect phosphate or phosphonate nucleoside prodrugs.
Figure 25
Figure 25
Chirality in HepDirect prodrugs.
Scheme 65
Scheme 65. Preparation of Enantiomerically Pure (R)- and (S)-1-Aryl-propane-1,3-diols Using (−)-Menthone
Scheme 66
Scheme 66. Preparation of Enantiomerically Pure (R)- and (S)-1-Aryl-propane-1,3-diols Using N,N-Dimethyl-phenylalanine
Scheme 67
Scheme 67. Synthesis of the HepDirect Prodrug of Lamivudine
Scheme 68
Scheme 68. Formation of trans-HepDirect Phosphate Prodrug 232
Scheme 69
Scheme 69. Preparation of Enantiomerically Pure trans p-Nitrophenylphosphates
Scheme 70
Scheme 70. Formation of cis-Isomers
Scheme 71
Scheme 71. Synthesis of 3′-Amino-3′-deoxyguanosine Monophosphate HepDirect Prodrug
Scheme 72
Scheme 72. Synthesis of ara-C-HepDirect Prodrug 244
Scheme 73
Scheme 73. Adefovir HepDirect Phosphonate Prodrugs via Peptidic Coupling Conditions
Scheme 74
Scheme 74. Adefovir HepDirect Phosphonate Prodrugs via a Bis-chlorophosphonate
Figure 26
Figure 26
Mechanism of activation for 3′,5′-cyclic phosphate nucleoside prodrugs.
Scheme 75
Scheme 75. Synthesis of PSI-3529386 Using P(III) Chemistry
Yields not provided.
Scheme 76
Scheme 76. Stereoselective Synthesis of PSI-352938
Figure 27
Figure 27
Alkoxyalkyl monoester prodrugs in clinical trial.
Figure 28
Figure 28
Metabolism drives the pathway of HDP/ODE prodrugs.
Figure 29
Figure 29
Modifications of LCP structures.
Figure 30
Figure 30
Methods to synthesize nucleosides alkoxyalkyl phosphate prodrugs, PG = 2-chlorophenyl cyanoethyl, AA = alkoxy alkyl.
Figure 31
Figure 31
Methods to synthesize nucleosides alkoxyalkyl phosphonate prodrugs, AA = alkoxy alkyl.
Scheme 77
Scheme 77. Syntheses of Alkoxyalkyl Phosphate Derivatives
Scheme 78
Scheme 78. AZT Alkoxyalkyl Phosphate Prodrug, AA = Alkoxy Alkyl
Scheme 79
Scheme 79. AZT Alkoxyalkyl Monophosphate Prodrugs
Scheme 80
Scheme 80. Synthesis of ODG-Acyclovir Monophosphate Prodrug, MSNT = 1-Mesitylenesulfonyl-3-nitro-1,2,4-triazole
Scheme 81
Scheme 81. Synthesis of ODG-AZT Monophosphate Prodrug
Scheme 82
Scheme 82. Synthesis of HDP-Acyclovir Phosphate Prodrug
Scheme 83
Scheme 83. Preparation of HDP and ODE Dioxolane Prodrugs
Scheme 84
Scheme 84. Synthesis of Alkoxyalkyl Phosphate Monoester Prodrug of 5-Fluoro-2′-deoxyuridine
Scheme 85
Scheme 85. Synthesis of 3′-Deoxyadenosine Phospholipid Conjugates, NPE = 2-(4-Nitrophenyl)ethoxycarbonyl
Scheme 86
Scheme 86. Synthesis of Alkoxyalkyl Cidofovir HDP Prodrug
Scheme 87
Scheme 87. Synthesis of 5-Aza-HPMPC
Scheme 88
Scheme 88. Synthesis of HPMPDAP Alkoxyalkyl Prodrugs
Scheme 89
Scheme 89. Synthesis of OLE-HPMPC Prodrug
Scheme 90
Scheme 90. Preparation of HDP-PMEG Prodrug
Scheme 91
Scheme 91. Synthesis of Phosphonopropoxymethyl Guanine Alkoxyalkyl Prodrugs
Scheme 92
Scheme 92. Preparation of Alkoxyalkyl cis-5-Phosphono-pent-2-en-1-yl Nucleoside Prodrug 299
Scheme 93
Scheme 93. Synthesis of HPMP-Adenine Prodrug 303
Scheme 94
Scheme 94. Preparations of HDP-Tosylate 309
Scheme 95
Scheme 95. Preparation of Bis(phosphonomethoxy)-acyclic Nucleoside 311
Scheme 96
Scheme 96. Synthesis of 5-Fluorocytosine HPMP Derivatives 315 and 316
Scheme 97
Scheme 97. Synthesis of 2,6-Diaminopurine HPMP Derivative Requires Only Hydroxyl Protective Group
Scheme 98
Scheme 98. Synthesis of HDP-PMPDAP Alkoxyalkyl Prodrugs and Its 2-Amino-6-cyclopropyl Analog
Scheme 99
Scheme 99. Synthesis of HDP-PMEDAP Prodrug
Scheme 100
Scheme 100. Preparation of ODE-(S)-MPMP Guanosine Compound 327
Scheme 101
Scheme 101. Synthesis of HDP-PMEG Prodrug
Scheme 102
Scheme 102. Preparation of HDP-PEE by Hydrolysis of Bis(HDP)-MP Derivatives
Scheme 103
Scheme 103. Hydrolysis of Bis(HDP)-MP Derivatives To Prepare HDP-(S)-HPMPG
Scheme 104
Scheme 104. Synthesis of Alkoxyalkyl Phosphoramidate DOT Prodrug 339
Figure 32
Figure 32
ProTides nucleoside in clinical trials or FDA-approved.
Figure 33
Figure 33
Mode of action of aryloxyphosphoramidates/phosphonamidates.
Figure 34
Figure 34
Methods to access phosphoramidates nucleoside prodrugs.
Figure 35
Figure 35
Methods to access phosphonamidates nucleoside prodrugs (AA = amino acid).
Figure 36
Figure 36
Mechanism to generate phosphoramidates nucleoside prodrugs.
Figure 37
Figure 37
NMI method.
Figure 38
Figure 38
t-BuMgCl method.
Scheme 105
Scheme 105. Comparable Efficiency between the NMI and t-BuMgCl Methodologies
Scheme 106
Scheme 106. NMI versus t-BuMgCl Methodology
Scheme 107
Scheme 107. Competitive O6-Phosphorylation, Separation of Mixtures
Scheme 108
Scheme 108. Competitive O6-Phosphorylation, Hydrolysis to Desired Prodrug 375
Scheme 109
Scheme 109. Competitive N4-Phosphorylation, Benzoyl Protection
Scheme 110
Scheme 110. N2-Protection as a Formamidine Group
Scheme 111
Scheme 111. Competitive N4-Phosphorylation, Formamidine Protection
Scheme 112
Scheme 112. Competitive OH Groups, Protection with a Cyclopentylidene Moiety
Scheme 113
Scheme 113. Competitive OH Groups, Protection with an Isopropylidene Moiety
Scheme 114
Scheme 114. Competitive OH Groups, Cbz-Protection
Scheme 115
Scheme 115. NMI, Used as Coupling Agent for the Cbz-Protection of the Purine Nucleoside
Scheme 116
Scheme 116. Competitive OH Groups, Lev-Protection
Scheme 117
Scheme 117. Competitive OH Groups, Lev-Protection
Scheme 118
Scheme 118. Synthesis of 7-Substituted 7-Deaza-adenine Nucleoside Prodrug
Scheme 119
Scheme 119. Optimized Reaction Conditions for the Synthesis of NB1011, without the Use of Protective Groups
Scheme 120
Scheme 120. Preparation of Key Diaryl Phosphite Species
Scheme 121
Scheme 121. Phosphoramidates via Diaryl Phosphites
Scheme 122
Scheme 122. Three-Component Arbuzov Reaction
Scheme 123
Scheme 123. Protection of Competitive Sites – Use of MMTr for the Nucleobase and Levulinate for the Sugar
Scheme 124
Scheme 124. Protection of Competitive Sites – Levulinate Sugar Potection
Scheme 125
Scheme 125. Protection of Competitive Sites – Isopropylidene Group
Scheme 126
Scheme 126. Other Approach Using P(V) Chemistry
Scheme 127
Scheme 127. Use of Cyclic Phosphorochloridate
Scheme 128
Scheme 128. Synthesis of D4T Phosphoramidate Prodrug 437
Scheme 129
Scheme 129. Use of a Chiral Auxiliary
Scheme 130
Scheme 130. Crystallization of Phosphoramidate Reagent
Scheme 131
Scheme 131. Synthesis of PSI-7977 (Sofosbuvir)
Scheme 132
Scheme 132. Post Modifications – Alkylation Reactions
Scheme 133
Scheme 133. Hydrogenation of l-Cd4A to l-ddA phosphoramidite
Scheme 134
Scheme 134. Post Modifications – Hydrogenation Reactions
Scheme 135
Scheme 135. Post Modifications – Palladium-Catalyzed Cross-Coupling Reactions
Scheme 136
Scheme 136. Synthesis of PMPA-Aryloxy Phosphonamidate Prodrug
Scheme 137
Scheme 137. Syntheses of Both GS-7171 and GS-7340
Scheme 138
Scheme 138. Synthesis of GS-9131
Scheme 139
Scheme 139. 2′-C-Me-Cytidine-3′-5′-cyclic Phosphoramidate
Scheme 140
Scheme 140. 2′-C-Me-FdU 3′-5′-Cyclic Phosphoramidate
Figure 39
Figure 39
Decomposition pathway for amino acid amidate monoester nucleosides prodrugs.
Figure 40
Figure 40
Histidine phosphoramidate nucleoside monoester acting as a triphosphate mimic.
Figure 41
Figure 41
Amino acid phosphoramidate mono ester nucleoside formation.
Figure 42
Figure 42
Amino acid phosphonate mono ester nucleoside formation.
Scheme 141
Scheme 141. First Synthesis of Amino Acid Nucleoside Phosphoramidate Monoester
Scheme 142
Scheme 142. Ara-C Monoester Phosphoramidates
Scheme 143
Scheme 143. Amino Acid Phosphoramidate Monoester of Acyclovir
Scheme 144
Scheme 144. EDC for Milder Coupling Conditions
Scheme 145
Scheme 145. 5-FdU Prodrugs
Scheme 146
Scheme 146. Preparation of Amino Acid 2′-Deoxy Adenosine Phosphoramidate Mono Esters
Scheme 147
Scheme 147. Synthesis of Phosphoramidate Mono Acids 484 and 486
Scheme 148
Scheme 148. Amino Acid Nucleoside Phosphoramidate Monoesters, Generated Using H-Phosphonate Intermediates
Scheme 149
Scheme 149. Preparation of Alkyl Amine Derivatives from H-Phosphonate Nucleosides
Scheme 150
Scheme 150. Preparation of Amino Acid ddA Phosphoramidate Monoester Prodrugs
Scheme 151
Scheme 151. Fluorenylmethyl Protecting Group To Ease the Purification of Highly Polar Nucleoside Phosphate Monoesters
Scheme 152
Scheme 152. Benzyl Protecting Group To Ease the Purification of Highly Polar Nucleoside Phosphate Monoesters
Scheme 153
Scheme 153. Use of Phosphoramidites To Generate Phosphoramidate Prodrugs
Scheme 154
Scheme 154. Synthesis of Amino Acid Nucleoside Phosphoramidate Monoester from Nucleosides Di- and Triphosphates
Scheme 155
Scheme 155. Amino Acid Nucleoside Phosphoramidate Monoesters from T, U, A, and G Triphosphates
Scheme 156
Scheme 156. Hydrolysis of Phosphorothioamidates
Scheme 157
Scheme 157. Synthesis of Nucleoside Phosphoramidates Monoester Libraries on Solid Phase
Scheme 158
Scheme 158. Synthesis of Cidofovir Phosphonamidate Monoester Prodrug
Scheme 159
Scheme 159. Phosphonamidate of Adefovir
Figure 43
Figure 43
Decomposition pathway of Borch’s methylaryl haloalkylamidates prodrugs.
Figure 44
Figure 44
P(III) versus P(V) chemistry.
Scheme 160
Scheme 160. FdU Borch’s Phosphoramidate
Scheme 161
Scheme 161. N-Dihydroxypropyl Phosphoramidates
Scheme 162
Scheme 162. Allyloxycarbonyl Group as Transient Protective Group
Figure 45
Figure 45
Mechanism of action of O- and C-phosphorodiamidate nucleoside prodrugs.
Figure 46
Figure 46
Methods to access O-phosphorodiamidate nucleoside prodrugs.
Figure 47
Figure 47
Methods to access C-phosphorodiamidate nucleoside prodrugs.
Scheme 163
Scheme 163. AZT O-Phosphorodiamidates Synthesis
Scheme 164
Scheme 164. 2’-Methyl-6-alkoxyguanosine Phosphorodiamidate Prodrug
AA = amino acid.
Scheme 165
Scheme 165. Nonsymetrical O-Phosphorodiamidates
Scheme 166
Scheme 166. O-Phosphorodiamidates Nucleoside Prodrugs from Phosphate Nucleosides
Scheme 167
Scheme 167. Synthesis of [(Phosphonomethoxy)ethoxy]adenine Prodrug 538
Scheme 168
Scheme 168. Synthesis of PMEA Bis(amino acid) Nucleoside Phosphorodiamidates with Protective Groups
Scheme 169
Scheme 169. GS-9148 Bis(amino acid) Prodrug
Scheme 170
Scheme 170. Nucleoside Phosphonamidate Prodrugs Directly from the Bis(alkyl) Nucleoside Phosphonates
Figure 48
Figure 48
BLG = biolabile group.
Figure 49
Figure 49
Mechanism of action for nucleoside diphosphate glycerides.
Scheme 171
Scheme 171. AZT DP-Prodrug
Scheme 172
Scheme 172. Synthesis of Oxyalkyl and Thioalkyl Ether Glycerides Ara-C-DP Prodrugs
Figure 50
Figure 50
Expected and observed mechanisms of acyl phosphate nucleoside prodrugs.
Scheme 173
Scheme 173. Synthesis of d4T Octanoyl, Lauroyl, Myristoyl, and Palmitoyl Acyl Nucleoside Diphosphates and Triphosphates
Scheme 174
Scheme 174. ADP or ATP Prodrugs
Figure 51
Figure 51
Cholesterol carbonate prodrug of ATP 563.
Figure 52
Figure 52
Mechanism of action of ether phosphates.
Scheme 175
Scheme 175. Preparation of Ara-C Steroids Diphosphate Derivatives
Scheme 176
Scheme 176. Preparation of ara-C Alkylphosphono Phosphate Derivatives
Scheme 177
Scheme 177. Synthesis of PMEA and HPMPC Phosphonophosphate HDP and ODE Prodrugs
Figure 53
Figure 53
Use of a para-acyloxybenzyl group to synthesize diphosphate prodrugs.
Scheme 178
Scheme 178. AZT and d4T Bis(para-scyloxybenzyl)-phosphoramidites DP Prodrugs
See this image and copyright information in PMC

References

    1. Van Rompay A. R.; Johansson M.; Karlsson A. Pharmacol. Ther. 2000, 87, 189. - PubMed
    1. Lin C.-C.; Yeh L.-T.; Vitarella D.; Hong Z.; Erion M. D. Antiviral Chem. Chemother. 2004, 15, 307. - PubMed
    2. Erion M. D.; van Poelje P. D.; MacKenna D. A.; Colby T. J.; Montag A. C.; Fujitaki J. M.; Linemeyer D. L.; Bullough D. A. J. Pharmacol. Exp. Ther. 2005, 312, 554. - PubMed
    3. Erion M. D.; Bullough D. A.; Lin C.-C.; Hong Z. Curr. Opin. Invest. Drugs 2006, 7, 109. - PubMed
    4. Reddy K. R.; Matelich M. C.; Ugarkar B. G.; Gomez-Galeno J. E.; DaRe J.; Ollis K.; Sun Z.; Craigo W.; Colby T. J.; Fujitaki J. M.; Boyer S. B.; van Poelje P. D.; Erion M. D. J. Med. Chem. 2008, 51, 666. - PubMed
    1. Eisenberg E. J.; He G. X.; Lee W. A. Nucleosides, Nucleotides Nucleic Acids 2001, 20, 1091. - PubMed
    1. Naesens L.; Bischofberger N.; Augustijns P.; Annaert P.; Van den Mooter G.; Arimilli M. N.; Kim C. U.; De Clercq E. Antimicrob. Agents Chemother. 1998, 42, 1568. - PMC - PubMed
    2. Robbins B. L.; Srinivas R. V.; Kim C.; Bischofberger N.; Fridland A. Antimicrob. Agents Chemother. 1998, 42, 612. - PMC - PubMed
    3. Schooley R. T.; Ruane P.; Myers R. A.; Beall G.; Lampiris H.; Berger D.; Chen S.-S.; Miller M. D.; Isaacson E.; Cheng A. K. AIDS 2002, 16, 1257. - PubMed
    4. De Clercq E. Clin. Microbiol. Rev. 2003, 16, 569. - PMC - PubMed
    1. Sofia M. J.; Bao D.; Chang W.; Du J.; Nagarathnam D.; Rachakonda S.; Reddy P. G.; Ross B. S.; Wang P.; Zhang H. R.; Bansal S.; Espiritu C.; Keilman M.; Lam A. M.; Steuer H. M.; Niu C.; Otto M. J.; Furman P. A. J. Med. Chem. 2010, 53, 7202. - PubMed

Publication types

MeSH terms