P. Turhanen, K. Demadis, P. Kafarski
Apr 30, 2021
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0
Influential Citations
8
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Journal
Frontiers in Chemistry
Abstract
Phosphonates are surrogates of natural phosphates, but they possess direct C-P bonds and one or more phosphonic acid moieties (R-PO3H2). These compounds are also generally used as a bioisosteres of carboxylates and serve as analogs of carboxylic acids, amino acids and peptides. Phosphon(in)ate groups are also actively mimicking the transition state during hydrolysis of amides and esters, thus being effective transition-state inhibitors. The interest in these compounds has grown immensely because of: their bioactive properties (as drugs, pro-drugs), their use as the tools for the design of enzyme inhibitors, their potential as bone-targeting drugs, their novel antibacterial and anticancer activity, their use in medical imaging and diagnostics and their phosphoantigen properties. There are several compounds containing phosphonate groups that are already in use as antiviral drugs. For example, bisphosphonates, which are active drugs against osteoporosis, demonstrate rich chemistry and biology. Applications of phosphonates cover a plethora of research fields, beyond the realm of medicinal chemistry. Examples of phosphonate compounds currently in medicinal use are given in Figure 1. In the current research topic three review articles were published covering: antiviral and anticancer pro-nucleotides, phosphonate and bisphosphonate inhibitors of farnesyl pyrophosphate synthases, and biologically active nucleoside phosphonates. Kraszewski et al. presented a short account of their work on the synthesis and biological activity of electrically neutral and charged anti-HIV and anticancer pronucleotides, presented in the framework of contemporary research in this area. Phosphonates and bisphosphonates have proven their pharmacological utility as inhibitors of enzymes that metabolize phosphate and pyrophosphate substrates. Nitrogen-containing bisphosphonates represent the best-known examples. Widely used to treat bone-resorption disorders, these drugs mostly work by inhibiting the enzyme farnesyl pyrophosphate synthase. Playing a key role in the isoprenoid biosynthetic pathway, this enzyme is also a potential anticancer target. A comprehensive overview was presented on research efforts to identify new inhibitors of farnesyl pyrophosphate synthase for various therapeutic applications. While the majority of these efforts have been directed against the human enzyme, some have been targeted on its homologs from other organisms, such as protozoan parasites and insects. The main focus is on the structures of the target enzymes and how the structural information has guided the drug discovery efforts (Park et al.). The use of the phosphonate motif featuring a C-P 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 aims to guide readers through the fundamentals of nucleoside phosphonate Edited and reviewed by: Michael Kassiou, The University of Sydney, Australia