The clinical potential of the acyclic (and cyclic) nucleoside phosphonates. The magic of the phosphonate bond

Abstract

The use of the acyclic nucleoside phosphonates, starting with (S)-HPMPA as the prototype, yielded three clinically approved antiviral drugs, cidofovir for the treatment of CMV retinitis in AIDS patients, adefovir dipivoxil for the treatment of chronic hepatitis B and tenofovir disoproxil fumarate for the treatment of HIV infections (AIDS) and HBV infections. This era has now grown to many more acyclic (and cyclic) nucleoside phosphonates (such as the "open ring" DAPy and Fd4A phosphonates) and alkoxyalkyl and phosphonoamidate prodrugs thereof, as well as new clinical applications, including new drug combination regimens for the treatment of AIDS, the chemoprophylaxis of HIV infections, and the anticancer potential against some malignant disorders.

Antiviral Drug Development – Success and Failure: A Personal Perspective with a Japanese Connection

“…In addition to its use in the therapy of HIV and HBV, tenofovir disoproxil fumarate has also gone in the direction of the prevention (both topically, as microbicide, and systemically as Viread ® or Truvada ® ) of HIV infections [82]. The usefulness of adefovir and tenofovir in the treatment of HBV infections was pioneered by the original work of Yokota et al [83][84][85] in the early 1990s.…”

Simple and rapid synthesis of some nucleoside derivatives: structural and spectral characterization

“…1 H-NMR (400 MHz) spectra were recorded for solutions in CDCl3 using TMS as internal standard with a Bruker DPX-400 spectrometer. Evaporations were carried out under reduced pressure using VV-1 type vacuum rotary evaporator (Germany) with a bath temperature below 40 o C. Melting points were determined on an electro-thermal melting point apparatus (England) and are uncorrected.…”

“…Nucleosides and their analogues are of enormous importance. They are an established class of clinically useful medicinal agents possessing antiviral and anticancer activity; [1][2][3][4] at the same time they are one class of compounds worthy of further investigation as antibacterial agents since some derivatives have shown moderate to good activity against specific bacterial strains. 5 The chemical modification of naturally occurring nucleoside and nucleotide structures is an important field in nucleic acid and medicinal chemistry.…”

Evaluation of Novel Acyclic Nucleoside Phosphonates against Human and Animal Gammaherpesviruses Revealed an Altered Metabolism of Cyclic Prodrugs upon Epstein-Barr Virus Reactivation in P3HR-1 Cells

“…These nucleotide analogs contain a phosphonate group that is linked to the acyclic nucleoside moiety through a stable POC bond, which cannot be cleaved by cellular esterases (13). ANPs need to be phosphorylated by cellular kinases to their diphosphate forms to become biologically active, and their selectivity is based on inhibition of reverse transcriptase and/or viral DNA polymerase (14).…”

“…In addition, cyclic prodrugs of ANPs have been developed, such as cyclic HPMPC, which was reported to exhibit similar an-tiviral activity as HPMPC but reduced nephrotoxicity (15). These novel ANPs have been shown to exert antiherpesvirus activity and yield great potential for the treatment of various DNA virus and retrovirus infections (13,16,17). However, their potencies against gammaherpesviruses have not yet been investigated.…”