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Review

. 2014 Sep 24;114(18):9154-218.

doi: 10.1021/cr5002035. Epub 2014 Aug 21.

Synthesis of nucleoside phosphate and phosphonate prodrugs

Ugo Pradere¹, Ethel C Garnier-Amblard, Steven J Coats, Franck Amblard, Raymond F Schinazi

Affiliations

Affiliation

¹ Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center , Atlanta, Georgia 30322, United States.

PMID: 25144792
PMCID: PMC4173794
DOI: 10.1021/cr5002035

Review

Synthesis of nucleoside phosphate and phosphonate prodrugs

Ugo Pradere et al. Chem Rev. 2014.

. 2014 Sep 24;114(18):9154-218.

doi: 10.1021/cr5002035. Epub 2014 Aug 21.

Authors

Ugo Pradere¹, Ethel C Garnier-Amblard, Steven J Coats, Franck Amblard, Raymond F Schinazi

Affiliation

¹ Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center , Atlanta, Georgia 30322, United States.

PMID: 25144792
PMCID: PMC4173794
DOI: 10.1021/cr5002035

No abstract available

PubMed Disclaimer

Figures

Figure 1
Mechanism of action of nucleoside monophosphate prodrugs.

Figure 2
Examples of clinical nucleoside prodrugs with anti-HIV, -HBV, or -HCV activities.

Figure 3
Prodrug approaches detailed in this Review.

Figure 4
Examples of carbonyloxymethyl nucleotide prodrugs approved by the FDA or in clinical trials.

Figure 5
Activation of carbonate-type prodrugs (including POC, R = i-Pr).

Figure 6
Activation of ester-type prodrugs (including POM, R = t-Bu).

Figure 7
Methods to access carbonyloxymethyl phosphate nucleosides prodrugs.

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,O^2′-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
Activation of (SATE)- or (DTE)-nucleoside prodrugs.

Figure 10
Access to bis(DTE)-phosphotriesters and bis(DTE)-phosphonodiesters.

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
Activation of aryl(SATE)-prodrugs.

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
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
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
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
Different synthetic methods to access cycloSal-diol precursors.

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
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
Mechanism of action for “lock-in” cycloSal pronucleotides.

Scheme 63 — Scheme 63. Elaborated Acyloxy Systems

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
HepDirect prodrugs in clinical trial.

Figure 23
Mechanism of activation for HepDirect nucleoside prodrugs.

Figure 24
Methods to access HepDirect phosphate or phosphonate nucleoside prodrugs.

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
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
Alkoxyalkyl monoester prodrugs in clinical trial.

Figure 28
Metabolism drives the pathway of HDP/ODE prodrugs.

Figure 29
Modifications of LCP structures.

Figure 30
Methods to synthesize nucleosides alkoxyalkyl phosphate prodrugs, PG = 2-chlorophenyl cyanoethyl, AA = alkoxy alkyl.

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
ProTides nucleoside in clinical trials or FDA-approved.

Figure 33
Mode of action of aryloxyphosphoramidates/phosphonamidates.

Figure 34
Methods to access phosphoramidates nucleoside prodrugs.

Figure 35
Methods to access phosphonamidates nucleoside prodrugs (AA = amino acid).

Figure 36
Mechanism to generate phosphoramidates nucleoside prodrugs.

Figure 37
NMI method.

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
Decomposition pathway for amino acid amidate monoester nucleosides prodrugs.

Figure 40
Histidine phosphoramidate nucleoside monoester acting as a triphosphate mimic.

Figure 41
Amino acid phosphoramidate mono ester nucleoside formation.

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
Decomposition pathway of Borch’s methylaryl haloalkylamidates prodrugs.

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
Mechanism of action of O- and C-phosphorodiamidate nucleoside prodrugs.

Figure 46
Methods to access O-phosphorodiamidate nucleoside prodrugs.

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
BLG = biolabile group.

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
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
Cholesterol carbonate prodrug of ATP 563.

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
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

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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

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