Overview of Biologically Active Nucleoside Phosphonates

Abstract

The use of the phosphonate motif featuring a carbon-phosphorous bond as bioisosteric replacement of the labile P–O bond is widely recognized as an attractive structural concept in different areas of medicinal chemistry, since it addresses the very fundamental principles of enzymatic stability and minimized metabolic activation. This review discusses the most influential successes in drug design with special emphasis on nucleoside phosphonates and their prodrugs as antiviral and cancer treatment agents. A description of structurally related analogs able to interfere with the transmission of other infectious diseases caused by pathogens like bacteria and parasites will then follow. Finally, molecules acting as agonists/antagonists of P2X and P2Y receptors along with nucleotidase inhibitors will also be covered. This review aims to guide readers through the fundamentals of nucleoside phosphonate therapeutics in order to inspire the future design of molecules to target infections that are refractory to currently available therapeutic options.

Acyclic nucleoside phosphonates with adenine nucleobase inhibit Trypanosoma brucei adenine phosphoribosyltransferase in vitro

“…Acyclic nucleoside phosphonates (ANPs) represent a group of compounds whose biological activity is based on their structural resemblance to the natural nucleotides 8 , 9 . Their flexibility enables them to adopt a conformation suitable for the interaction with the active site of the nucleotide binding enzymes.…”

Supported Synthesis of Adenosine Nucleotides and Derivatives on a Benzene‐Centered Tripodal Soluble Support

“…A linear 15 min gradient from 0 % to 100 % B, followed by 5 min isocratic 100 % B, and then a linear 1 min gradient from 100 % to 0 % B was used. 1 H NMR (300 or 400 MHz), 13 C NMR (101, 126 or 151 MHz), and 31 P NMR (162 MHz) spectra were obtained in CDCl 3 (δ H 7.26 ppm, δ C 77.16 ppm) or DMSO-d 6 (δ H 2.50 ppm, δ C 39.52 ppm) or D 2 O (δ H 4.79 ppm). Data are reported as follow: chemical shift (δ, ppm), multiplicity (s = singlet; d = doublet; dd = double doublet; t = triplet; q, quartet; bs = broad signal; and m = multiplet or not resolved signal).…”

“…[35] 93 mg (0.06 mmol, 82 % yield), brown solid. 1 H NMR (400 MHz, CH 3 OD) δ = 8.75 (bs, 1H), 8.61 (bs, 1H), 7.42 (bs, 1H), 6.62 (d, J PH = 644 Hz, 1H), 6.27 (bs, 1H), 6.07 (bs, 1H), 5.43-5.42 (bs, 2H), 5.19-5.18 (bs, 2H), 4.68-4.65 (bs, 1H), 4.09 (bs, 2H), 3.27 (q, J = 7.3 Hz, 2H), 1.67 (s, 3H), 1.46 (s, 3H), 1.25 (t, J = 7.3 Hz, 3H); 31 P NMR (162 MHz, CH 3 OD) δ = 5.9 (s); HRMS (ESI) m/z: [M + H] + calcd. for C 54 H 61 N 21 O 21 P 3 + 1432.3558, found 1432.3556.…”

“…31 mg (0.053 mmol, 58 % yield), white solid. 1 Supported bisphosphonates 13 a and 13 b. A solution of methylene bis(phosphonic dichloride) (804 mg, 3.22 mmol, 30 equiv) in trimethyl phosphate (1.6 mL) was added to a suspension of 4 (200 mg, 0.16 mmol, 1 equiv) in trimethylphosphate (1.6 mL) at 0 °C.…”

Fission Impossible: Stabilized miRNA-Based Analogs in Neurodegenerative Disease

“…Non-ribose backbone modifications including phosphorodiamidate morpholino oligonucleotides (PMOs) and peptide nucleic acids (PNAs) have shown promise as steric blocking antisense agents, and when conjugated with cell-penetrating peptides or molecules that facilitate delivery into mammalian cell systems via intravenous or intraperitoneal injection allow the rapid penetration of a wide range of cellular membranes and biophysical barriers including the blood-brain barrier (Lima et al, 2018 ; Nguyen et al, 2021 ; Walgrave et al, 2021 ). The use and details of these novel stability-augmenting chemistries for sncRNAs and miRNAs have been extensively discussed and reviewed over the last decade in a series of comprehensive studies and detailed reports some of which are listed here (Lennox and Behlke, 2011 ; De Clercq, 2013 ; Baigude and Rana, 2014 ; Evers et al, 2015 ; Elbarbary et al, 2017 ; Lima et al, 2018 ; Mai et al, 2019 ; Silva et al, 2020 ; Grabowska-Pyrzewicz et al, 2021 ; Groaz and De Jonghe, 2021 ; Seley-Radtke et al, 2021 ).…”