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Phosphonated Nucleoside Analogues as Antiviral Agents

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Therapy of Viral Infections

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 15))

Abstract

The present review is focused on the description of synthesis and antiviral activities of both acyclic and carbocyclic nucleoside phosphonates, endowed with an antiviral potential. Despite the outstanding results in antiviral therapy of acyclovir and azidothymidine, a major drawback concerning the use of nucleoside analogues (NA) is the retention of their stability following triphosphorylation within the host cell. The instability of the phosphate forms of NA has been, at least partially, overcome by the introduction of phosphate groups in the molecular structure. This approach gives rise to two main classes of compounds endowed with ascertained or potential antiviral activity, such as acyclic nucleoside phosphonates (ANP) and phosphonated carbocyclic nucleosides (PCN). Regarding ANP, a higher affinity for HIV reverse transcriptase (RT), with respect to NA, and the potent inhibition of HIV and hepatitis B virus (HBV) have been reported for some of them. Regarding PCN, some phosphonated cyclopropyl and cyclopentyl carbanucleosides, characterized by the presence of one or more phosphonic groups and by replacement of the endocyclic oxygen atom with a methylene group, showed to be good inhibitors of HBV and HIV infection. Another class of PCN is represented by phosphonated N,O-nucleosides (PCOAN). PCOAN encompass homo phosphonated-, phosphonated- and truncated phosphonated-N,O-nucleosides. Some PCOAN have been shown to directly inhibit RT activity of both murine and human retroviruses and to block HTLV-1 infection in vitro. The flexibility of the phosphonated NA structure suggests the possibility to develop new analogues endowed with antiviral activity towards a broad range of DNA or RNA viruses.

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Abbreviations

3TC, lamivudine:

(−)-l-3′-thia-2′,3′-dideoxycytidine

ABC, abacavir:

Cyclopentenyl-N6-cyclopropylaminopurine

ACV:

Acyclovir

adefovir:

PMEA

AdF:

(5′S)-5-fluoro-1-isoxazolidin-5-yl-1H-pyrimidine-2,4-dione

ADV:

Adefovir dipivoxil

ANP:

Acyclic nucleoside phosphonates

APC:

Apricitabine

ATL:

Adult T-cell leukemia

AZT, zidovudine:

3′-Azido-3′-deoxythymidine

BMS986001:

Festinavir

CMV:

Cytomegalovirus

d4T, stavudine:

2′,3′-Didehydro-2′,3′-dideoxythymidine

ddC, zalcitabine:

2′3′-Dideoxycytidine

ddI, didanosine:

2′3′-Dideoxynosine

ddNMP:

Dideoxynucleotide monophosphate

EBV:

Epstein–Barr virus

ETC, entecavir:

BMS-200475

Fd4AP:

5-[(6-Amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl] phosphonic acid disodium salt (50)

FPMPA:

2,6-Diaminopurine

[(−) FTC, emtricitabine]:

(−)-L5-fluoro-3′-thia-2′,3′-dideoxycytidine

HBV:

Hepatitis B virus

HCV:

Hepatitis C virus

HDP:

Hexadecyloxypropyl

HAM/TSP:

HTLV-1 associated-myelopathy/tropical spastic paraparesis

HMCV:

Human cytomegalovirus

hOAT1 and hOAT3:

Human renal organic anion transporters types 1 and 3

HPMPC, cidofovir:

(S)-1-(3-Hydroxy-2-phosphonylmethoxypropyl)cytosine

HSV:

Herpes simplex virus

HTLV-1:

Human T-cell leukemia/lymphotropic virus type 1

MRP4:

Multidrug resistance protein 4

NA:

Nucleoside analogues

NNRTI:

Non-nucleoside reverse-transcriptase inhibitors

NRTI:

Nucleoside reverse-transcriptase inhibitors

ODE:

Octadecyloxyethyl

PBMC:

Peripheral blood mononuclear cells

PCN:

Phosphonated carbocyclic nucleosides

PCOAN:

Phosphonated N,O-nucleosides

PMCG:

9-[1-(Phosphonomethoxycyclopropyl) methyl] guanine

PMCG:

9-[1-(Phosphonomethoxycyclopropyl)methyl]guanine 55

PMEO-DAPy:

2,4-Diamino 6-[2-(phosphonomethoxy)ethoxy]pyridine

PMPA:

9-(2R,S)-2-phosphonylmethoxypropyl derivatives of adenine

R7128:

Mericitabine

TDF:

Tenofovir disoproxil fumarate

TPCOAN:

Truncated phosphonated N,O-nucleosides 119

VZV:

Varicella-zoster virus

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Authors and Affiliations

  1. Department of System Medicine, University of Rome “Tor Vergata”, 00133, Rome, Italy

    Beatrice Macchi

  2. Department of Pharmaceutical and Health Sciences, University of Messina, 98168, Messina, Italy

    Giovanni Romeo & Salvatore V. Giofrè

  3. Department of Pharmaceutical Sciences, University of Catania, 95125, Catania, Italy

    Ugo Chiacchio

  4. Department of Experimental Medicine and Surgery, University of Rome “Tor Vergata”, 00133, Rome, Italy

    Caterina Frezza

  5. Department of Biological and Environmental Sciences, University of Messina, 98166, Messina, Italy

    Francesca Marino-Merlo & Antonio Mastino

  6. Institute of Translational Pharmacology, CNR, 00133, Rome, Italy

    Antonio Mastino

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Correspondence to Beatrice Macchi .

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Editors and Affiliations

  1. Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marburg, Germany

    Wibke E. Diederich

  2. -, Bayer Pharma AG, Lead Discovery Berlin - Structural Biology, Berlin, Germany

    Holger Steuber

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Macchi, B. et al. (2013). Phosphonated Nucleoside Analogues as Antiviral Agents. In: Diederich, W., Steuber, H. (eds) Therapy of Viral Infections. Topics in Medicinal Chemistry, vol 15. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7355_2013_28

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