Synthetic Methods for Azaheterocyclic Phosphonates and Their Biological Activity: An Update 2004-2024.

The increasing importance of azaheterocyclic phosphonates in the agrochemical, synthetic, and medicinal field has provoked an intense search in the development of synthetic routes for obtaining novel members of this family of compounds. This updated review covers methodologies established since 2004, focusing on the synthesis of azaheterocyclic phosphonates, of which the phosphonate moiety is directly substituted onto to the azaheterocyclic structure. Emphasizing recent advances, this review classifies newly developed synthetic approaches according to the ring size and providing information on biological activities whenever available. Furthermore, this review summarizes information on various methods for the formation of C-P bonds, examining sustainable approaches such as the Michaelis-Arbuzov reaction, the Michaelis-Becker reaction, the Pudovik reaction, the Hirao coupling, and the Kabachnik-Fields reaction. After analyzing the biological activities and applications of azaheterocyclic phosphonates investigated in recent years, a predominant focus on the evaluation of these compounds as anticancer agents is evident. Furthermore, emerging applications underline the versatility and potential of these compounds, highlighting the need for continued research on synthetic methods to expand this interesting family.

Impact of Single Acyclic Phosphonate Nucleotide (ZNA) Modifications on DNA Duplex Stability.

An acyclic phosphonate-linked nucleic acid backbone (ZNA) demonstrated the capability to support duplex formation and propagate genetic information in vivo, unveiling its potential for evolution into a synthetic genetic system (XNA). To determine the structural impact of such modification, modified Dickerson Drew DNA dodecamers (DDDs) were prepared by solid phase synthesis, each containing either an (R) or (S) isomeric form of a cytosine ZNA nucleotide. While the DDD is known to adopt a stable duplex, both duplex and hairpin forms were simultaneously observed for both modified oligonucleotides by NMR spectroscopy over a broad temperature range (5-65 °C). Diffusion-ordered spectroscopy (DOSY) experiments allowed to separate duplex and hairpin signals based on the different diffusion constants of both conformational states. For the oligomer containing (R)-ZNA, only the duplex form occurred at 5 °C, while it was not possible to determine by NMR a single hairpin conformation at higher temperatures. In the case of the (S)-ZNA nucleoside modified oligomer, both hairpin and duplex forms were observable at 0 °C, while a single hairpin conformation was detected at 37 °C, suggesting a higher destabilizing effect on dsDNA.

Preparation and characterization of bis-phosphonated polycarbohydrates.

A simple, cost-effective, one-pot method was proposed to introduce bis-phosphonic groups onto alginic acid and carboxymethyl cellulose (CMC). New derivatives were characterized by means of nuclear magnetic resonance, X-ray photoelectron, and attenuated total reflectance Fourier transform infrared spectroscopy. These analyses confirmed the successful transformation of carboxylic groups present in alginic acid and CMC into bis-phosphonic groups. Additionally, thermogravimetric analysis coupled with differential scanning calorimetry was employed to investigate the thermal properties of the bis-phosphonic derivatives of alginate and CMC. The results clearly demonstrate the char-forming ability of both studied bis-phosphonated polycarbohydrates, suggesting their potential as intumescent materials.

N-Functionalization of ß-aminophosphonates: cytotoxic effects of the new derivatives.

ß-Aminophosphonates obtained by the Michael addition of primary amines to the double bond of diethyl vinylphosphonate proved to be suitable starting materials (amine components) in the Kabachnik-Fields reaction with formaldehyde and dialkyl phosphites or secondary phosphine oxides to afford N-phosphonylmethyl- and N-phosphinoylmethyl-ß-aminophosphonates. On the other hand, the starting aminophosphonates were modified by N-acylation using acid chlorides. The N-acyl products were found to exist in a dynamic equilibrium of two conformers as suggested by the broad NMR signals. At 26 °C, there may be rotation around the N-C axis of the acylamide function. At the same time, low-temperature NMR measurements at -5 °C revealed the presence of two distinct rotamers that could be characterized by 31P, 13C and 1H NMR data. The modified ß-aminophosphonic derivatives were subjected to a comparative structure-activity analysis on MDA-MB-231, PC-3, A431 and Ebc-1 tumor cell lines, and in a few cases, significant activity was detected.

Design, synthesis, docking, and antiviral evaluation of some novel pyrimidinone-based α-aminophosphonates as potent H1N1 and HCoV-229E inhibitors.

Dialkyl/aryl aminophosphonates, 3a-g and 4a-e were synthesized using the LiClO4 catalyzed Kabachnic Fields-type reaction straightforwardly and efficiently. The synthesized phosphonates structures were characterized using elemental analyses, FT-IR, 1H NMR, 13C NMR, and MS spectroscopy. The new compounds were subjected to in-silico molecular docking simulations to evaluate their potential inhibition against Influenza A Neuraminidase and RNA-dependent RNA polymerase of human coronavirus 229E. Subsequently, the compounds were further tested in vitro using a cytopathic inhibition assay to assess their antiviral activity against both human Influenza (H1N1) and human coronavirus (HCoV-229E). Diphenyl ((2-(5-cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl) hydrazinyl) (furan-2-yl) methyl) phosphonate (3f) and diethyl ((2-(5-cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl) hydrazinyl) (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) methyl) phosphonate (4e) were demonstrated direct inhibition activity against Influenza A Neuraminidase and RNA-dependent RNA polymerase. This was supported by their highly favorable binding energies in-silico, with top-ranked values of -12.5 kcal/mol and -14.2 kcal/mol for compound (3f), and -13.5 kcal/mol and -9.89 kcal/mol for compound (4e). Moreover, they also displayed notable antiviral efficacy in vitro against both viruses. These compounds demonstrated significant antiviral activity, as evidenced by selectivity indices (SI) of 101.7 and 51.8, respectively against H1N1, and 24.5 and 5.1 against HCoV-229E, respectively.

Sulfonamide-incorporated bis(α-aminophosphonates) as promising carbonic anhydrase inhibitors: Design, synthesis, biological evaluation, and X-ray crystallographic studies.

A novel series of sulfonamide-incorporated bis(α-aminophosphonates) acting as effective carbonic anhydrase (CA, EC 4.2.1.1) inhibitors is reported. The synthesized bivalent ligands were tested against five human (h) isoforms, hCA I, hCA II, hCA VII, hCA IX, and hCA XIII. Such derivatives showed high activity and selectivity against the cancer-related, membrane-bound isoform hCA IX, and among them, compound 5h, tetraisopropyl (1,3-phenylenebis{[(4-sulfamoylphenyl)amino]methylene})bis(phosphonate) showed a KI of 15.1 nM, being highly selective against this isoform over all other investigated ones (hCA I/IX = 42; hCA II/IX = 6, hCA VII/IX = 3, hCA XIII/IX = 5). Therefore, compound 5h could be a potential lead for the development of selective anticancer agents. The newly developed sulfonamides were also found effective inhibitors against the cytosolic hCA XIII isoform. Compound 5i displayed the best inhibition against this isoform with a KI of 17.2 nM, equal to that of the well-known inhibitor acetazolamide (AAZ), but significantly more selective over all other tested isoforms (hCA I/XIII = 239; hCA II/XIII = 23, hCA VII/XIII = 2, hCA IX/XIII = 3) compared to AAZ.

Synthesis of Mixed Phosphonate Esters and Amino Acid-Based Phosphonamidates, and Their Screening as Herbicides.

While organophosphorus chemistry is gaining attention in a variety of fields, the synthesis of the phosphorus derivatives of amino acids remains a challenging task. Previously reported methods require the deprotonation of the nucleophile, complex reagents or hydrolysis of the phosphonate ester. In this paper, we demonstrate how to avoid these issues by employing phosphonylaminium salts for the synthesis of novel mixed n-alkylphosphonate diesters or amino acid-derived n-alkylphosphonamidates. We successfully applied this methodology for the synthesis of novel N-acyl homoserine lactone analogues with varying alkyl chains and ester groups in the phosphorus moiety. Finally, we developed a rapid, quantitative and high-throughput bioassay to screen a selection of these compounds for their herbicidal activity. Together, these results will aid future research in phosphorus chemistry, agrochemistry and the synthesis of bioactive targets.

A Comparative Study of New Fluorescent Anthraquinone and Benzanthrone α-Aminophosphonates: Synthesis, Spectroscopy, Toxicology, X-ray Crystallography, and Microscopy of Opisthorchis felineus.

In this research, we explore the synthesis of and characterize α-aminophosphonates derived from anthraquinone and benzanthrone, focusing on their fluorescence properties and potential applications in confocal laser scanning microscopy (CLSM). The synthesized compounds exhibit notable solvatochromic behavior, emitting fluorescence from green to red across various solvents. Spectroscopic analysis, including 1H-, 13C-, and 31P-NMR, FTIR, and mass spectrometry, confirms the chemical structures. The compounds' toxicity is evaluated using etiolated wheat sprouts, revealing varying degrees of impact on growth and oxidative damage. Furthermore, the study introduces these α-aminophosphonates for CLSM imaging of the parasitic flatworm Opisthorchis felineus, demonstrating their potential in visualizing biological specimens. Additionally, an X-ray crystallographic study of an anthraquinone α-aminophosphonate provides valuable structural insights.

Kinetics of glyphosate and aminomethylphosphonic acid sorption onto montmorillonite clays in soil and their translocation to genetically modified corn.

The co-occurrence of glyphosate (GLP) and aminomethylphosphonic acid (AMPA) in contaminated water, soil, sediment and plants is a cause for concern due to potential threats to the ecosystem and human health. A major route of exposure is through contact with contaminated soil and consumption of crops containing GLP and AMPA residues. However, clay-based sorption strategies for mixtures of GLP and AMPA in soil, plants and garden produce have been very limited. In this study, in vitro soil and in vivo genetically modified corn models were used to establish the proof of concept that the inclusion of clay sorbents in contaminated soils will reduce the bioavailability of GLP and AMPA in soils and their adverse effects on plant growth. Effects of chemical concentration (1-10 mg/kg), sorbent dose (0.5%-3% in soil and 0.5%-1% in plants) and duration (up to 28 days) on sorption kinetics were studied. The time course results showed a continuous GLP degradation to AMPA. The inclusion of calcium montmorillonite (CM) and acid processed montmorillonite (APM) clays at all doses significantly and consistently reduced the bioavailability of both chemicals from soils to plant roots and leaves in a dose- and time-dependent manner without detectable dissociation. Plants treated with 0.5% and 1% APM inclusion showed the highest growth rate (p ≤ 0.05) and lowest chemical bioavailability with up to 76% reduction in roots and 57% reduction in leaves. Results indicated that montmorillonite clays could be added as soil supplements to reduce hazardous mixtures of GLP and AMPA in soils and plants.

Phosphonoalamides Reveal the Biosynthetic Origin of Phosphonoalanine Natural Products and a Convergent Pathway for Their Diversification.

Phosphonate natural products, with their potent inhibitory activity, have found widespread use across multiple industries. Their success has inspired development of genome mining approaches that continue to reveal previously unknown bioactive scaffolds and biosynthetic insights. However, a greater understanding of phosphonate metabolism is required to enable prediction of compounds and their bioactivities from sequence information alone. Here, we expand our knowledge of this natural product class by reporting the complete biosynthesis of the phosphonoalamides, antimicrobial tripeptides with a conserved N-terminal l-phosphonoalanine (PnAla) residue produced by Streptomyces. The phosphonoalamides result from the convergence of PnAla biosynthesis and peptide ligation pathways. We elucidate the biochemistry underlying the transamination of phosphonopyruvate to PnAla, a new early branchpoint in phosphonate biosynthesis catalyzed by an aminotransferase with evolved specificity for phosphonate metabolism. Peptide formation is catalyzed by two ATP-grasp ligases, the first of which produces dipeptides, and a second which ligates dipeptides to PnAla to produce phosphonoalamides. Substrate specificity profiling revealed a dramatic expansion of dipeptide and tripeptide products, while finding PnaC to be the most promiscuous dipeptide ligase reported thus far. Our findings highlight previously unknown transformations in natural product biosynthesis, promising enzyme biocatalysts, and unveil insights into the diversity of phosphonopeptide natural products.

A Novel Pathway for Biosynthesis of the Herbicidal Phosphonate Natural Product Phosphonothrixin Is Widespread in Actinobacteria.

Phosphonothrixin is an herbicidal phosphonate natural product with an unusual, branched carbon skeleton. Bioinformatic analyses of the ftx gene cluster, which is responsible for synthesis of the compound, suggest that early steps of the biosynthetic pathway, up to production of the intermediate 2,3-dihydroxypropylphosphonic acid (DHPPA) are identical to those of the unrelated phosphonate natural product valinophos. This conclusion was strongly supported by the observation of biosynthetic intermediates from the shared pathway in spent media from two phosphonothrixin producing strains. Biochemical characterization of ftx-encoded proteins confirmed these early steps, as well as subsequent steps involving the oxidation of DHPPA to 3-hydroxy-2-oxopropylphosphonate and its conversion to phosphonothrixin by the combined action of an unusual heterodimeric, thiamine-pyrophosphate (TPP)-dependent ketotransferase and a TPP-dependent acetolactate synthase. The frequent observation of ftx-like gene clusters within actinobacteria suggests that production of compounds related to phosphonothrixin is common within these bacteria. IMPORTANCE Phosphonic acid natural products, such as phosphonothrixin, have great potential for biomedical and agricultural applications; however, discovery and development of these compounds requires detailed knowledge of the metabolism involved in their biosynthesis. The studies reported here reveal the biochemical pathway phosphonothrixin production, which enhances our ability to design strains that overproduce this potentially useful herbicide. This knowledge also improves our ability to predict the products of related biosynthetic gene clusters and the functions of homologous enzymes.

Variability in the Responses of Hepatitis B Virus D-Subgenotypes to Antiviral Therapy: Designing Pan-D-Subgenotypic Reverse Transcriptase Inhibitors.

Nucleos(t)ide analogues entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are recommended as first-line monotherapies for chronic hepatitis B (CHB). Multiple HBV genotypes/subgenotypes have been described, but their impact on treatment response remains largely elusive. We investigated the effectiveness of ETV/TDF on HBV/D-subgenotypes, D1/D2/D3/D5, studied the structural/functional differences in subgenotype-specific reverse transcriptase (RT) domains of viral polymerase, and identified novel molecules with robust inhibitory activity on various D-subgenotypes. Transfection of Huh7 cells with full-length D1/D2/D3/D5 and in vitro TDF/ETV susceptibility assays demonstrated that D1/D2 had greater susceptibility to TDF/ETV while D3/D5 exhibited poorer response. Additionally, HBV load was substantially reduced in TDF-treated CHB patients carrying D1/D2 but minimally reduced in D3/D5-infected patients. Comparison of RT sequences of D-subgenotypes led to identification of unique subgenotype-specific residues, and molecular modeling/docking/simulation studies depicted differential bindings of TDF/ETV to the active site of their respective RTs. Replacement of signature residues in D3/D5 HBV clones with corresponding amino acids seen in D1/D2 improved their susceptibility to TDF/ETV. Using high throughput virtual screening, we identified N(9)-[3-fluoro-2-(phosphonomethoxy)propyl] (FPMP) derivatives of purine bases, including N6-substituted (S)-FPMP derivative of 2,6-diaminopurine (DAP) (OB-123-VK), as potential binders of RT of different D-subgenotypes. We synthesized (S)-FPMPG prodrugs (FK-381-FEE/FK-381-SEE/FK-382) and tested their effectiveness along with OB-123-VK. Both OB-123-VK and FK-381-FEE exerted similar antiviral activities against all D-subgenotypes, although FK-381-FEE was more potent. Our study highlighted the natural variation in therapeutic response of D1/D2/D3/D5 and emphasized the need for HBV subgenotype determination before treatment. Novel molecules described here could benefit future design/discovery of pan-D-subgenotypic inhibitors. IMPORTANCE Current treatment of chronic hepatitis B relies heavily on nucleotide/nucleoside analogs in particular, tenofovir disoproxil fumarate (TDF) and entecavir (ETV) to keep HBV replication under control and prevent end-stage liver diseases. However, it was unclear whether the therapeutic effects of TDF/ETV differ among patients infected with different HBV genotypes and subgenotypes. HBV genotype D is the most widespread of all HBV genotypes and multiple D-subgenotypes have been described. We here report that different subgenotypes of HBV genotype-D exhibit variable response toward TDF and ETV and this could be attributed to naturally occurring amino acid changes in the reverse transcriptase domain of the subgenotype-specific polymerase. Further, we identified novel molecules and also synthesized prodrugs that are equally effective on different D-subgenotypes and could facilitate management of HBV/D-infected patients irrespective of D-subgenotype.

The functional importance of bacterial oxidative phosphonate pathways.

Organophosphonates (Pns) are a unique class of natural products characterized by a highly stable C-P bond. Pns exhibit a wide array of interesting structures as well as useful bioactivities ranging from antibacterial to herbicidal. More structurally simple Pns are scavenged and catabolized by bacteria as a source of phosphorus. Despite their environmental and industrial importance, the pathways involved in the metabolism of Pns are far from being fully elucidated. Pathways that have been characterized often reveal unusual chemical transformations and new enzyme mechanisms. Among these, oxidative enzymes play an outstanding role during the biosynthesis and degradation of Pns. They are to a high extent responsible for the structural diversity of Pn secondary metabolites and for the break-down of both man-made and biogenic Pns. Here, we review our current understanding of the importance of oxidative enzymes for microbial Pn metabolism, discuss the underlying mechanistic principles, similarities, and differences between pathways. This review illustrates Pn biochemistry to involve a mix of classical redox biochemistry and unique oxidative reactions, including ring formations, rearrangements, and desaturations. Many of these reactions are mediated by specialized iron-dependent oxygenases and oxidases. Such enzymes are the key to both early pathway diversification and late-stage functionalization of complex Pns.

Asymmetric Transfer Hydrogenation as a Key Step in the Synthesis of the Phosphonic Acid Analogs of Aminocarboxylic Acids.

α-Aminophosphonic acids have a remarkably broad bioactivity spectrum. They can function as highly efficient transition state mimics for a variety of hydrolytic and angiotensin-converting enzymes, which makes them interesting target structures for synthetic chemists. In particular, the phosphonic acid analogs to α-aminocarboxylic acids (Pa AAs) are potent enzyme inhibitors, but many of them are only available by chiral or enzymatic resolution; sometimes only one enantiomer is accessible, and several have never been prepared in enantiopure form at all. Today, a variety of methods to access enantiopure α-aminophosphonic acids is known but none of the reported approaches can be generally applied for the synthesis of Pa AAs. Here we show that the phosphonic acid analogs of many (proteinogenic) α-amino acids become accessible by the catalytic, stereoselective asymmetric transfer hydrogenation (ATH) of α-oxo-phosphonates. The highly enantioenriched (enantiomeric excess (ee) ≥ 98 %) α-hydroxyphosphonates obtained are important pharmaceutical building blocks in themselves and could be easily converted to α-aminophosphonic acids in most studied cases. Even stereoselectively deuterated analogs became easily accessible from the same α-oxo-phosphonates using deuterated formic acid (DCO2 H).

Initial Steps of the Acid-Catalyzed Polyoxometalate-Functionalization with Phosphonic Acid Esters.

The organo-functionalization of metal oxides is a key strategy to introduce new functionalities. Often, phosphonates are used to anchor organic moieties to a range of metal oxides. Despite their widespread use, there is a lack of understanding of the parameters which enable selective and efficient formation of organophosphonate-metal oxide hybrids. Here, we report fundamental insights into the mechanism of phosphonate anchoring to a molecular metal oxide model. Specifically, we use in situ 31P NMR spectroscopy to follow the acid-catalyzed deprotection of a model phosphonate and its subsequent condensation to form a phosphonate-functionalized Dawson-polyoxometalate. Our study shows that the nucleophilicity of the acid anion is a key parameter which controls the clean and selective deprotection and polyoxometalate attachment of phosphonates. This insight will allow researchers to expand the scope of phosphonate anchoring to metal oxides by enabling the development of mild and scalable syntheses.

Harvesting phosphorus-containing moieties for their antibacterial effects.

Clinically manifested resistance of bacteria to antibiotics has emerged as a global threat to society and there is an urgent need for the development of novel classes of antibacterial agents. Recently, the use of phosphorus in antibacterial agents has been explored in quite an unprecedent manner. In this comprehensive review, we summarize the use of phosphorus-containing moieties (phosphonates, phosphonamidates, phosphonopeptides, phosphates, phosphoramidates, phosphinates, phosphine oxides, and phosphoniums) in compounds with antibacterial effect, including their use as ß-lactamase inhibitors and antibacterial disinfectants. We show that phosphorus-containing moieties can serve as novel pharmacophores, bioisosteres, and prodrugs to modify pharmacodynamic and pharmacokinetic properties. We further discuss the mechanisms of action, biological activities, clinical use and highlight possible future prospects.

Enantioselective total syntheses of (S)-phosphonothrixin and unexpected cyclic derivative (S)-cyclic phosphonothrixin via enzymatic resolution.

(S)-Phosphonothrixin is a phosphonate natural product produced by Saccharothrix sp. ST-888 that exhibits herbicidal activity. The previously reported asymmetric synthesis of (S)-phosphonothrixin is laborious and difficult to reproduce. In this study, we developed a scalable and concise enantioselective total synthesis of (S)-phosphonothrixin via two different synthetic routes by the enzymatic resolution of a known racemic epoxy alcohol. The second-generation synthesis was more efficient in terms of the overall yield (15%) and the number of steps (7) and afforded a unique cyclic phosphonate (phostone) as the product of the C-P bond formation reaction, which was converted to (S)-cyclic phosphonothrixin. Both (S)-phosphonothrixin and (S)-cyclic phosphonothrixin induced chlorosis in the plant Arabidopsis thaliana. However, (S)-cyclic phosphonothrixin exhibited lower activity than (S)-phosphonothrixin owing to its fixed conformation, as evidenced by a structure-activity relationship study. This study paves the way for the elucidation of the detailed mode of action of (S)-phosphonothrixin.

Structure of a reaction intermediate mimic in t6A biosynthesis bound in the active site of the TsaBD heterodimer from Escherichia coli.

The tRNA modification N6-threonylcarbamoyladenosine (t6A) is universally conserved in all organisms. In bacteria, the biosynthesis of t6A requires four proteins (TsaBCDE) that catalyze the formation of t6A via the unstable intermediate l-threonylcarbamoyl-adenylate (TC-AMP). While the formation and stability of this intermediate has been studied in detail, the mechanism of its transfer to A37 in tRNA is poorly understood. To investigate this step, the structure of the TsaBD heterodimer from Escherichia coli has been solved bound to a stable phosphonate isosteric mimic of TC-AMP. The phosphonate inhibits t6A synthesis in vitro with an IC50 value of 1.3 µM in the presence of millimolar ATP and L-threonine. The inhibitor binds to TsaBD by coordination to the active site Zn atom via an oxygen atom from both the phosphonate and the carboxylate moieties. The bound conformation of the inhibitor suggests that the catalysis exploits a putative oxyanion hole created by a conserved active site loop of TsaD and that the metal essentially serves as a binding scaffold for the intermediate. The phosphonate bound crystal structure should be useful for the rational design of potent, drug-like small molecule inhibitors as mechanistic probes or potentially novel antibiotics.

Enzymatic Synthesis of a Novel Coumarin Aminophosphonates: Antibacterial Effects and Oxidative Stress Modulation on Selected E. coli Strains.

The objective of the present study was to evaluate the synergistic effect of two important pharmacophores, coumarin and α-amino dimethyl phosphonate moieties, on antimicrobial activity toward selected LPS-varied E. coli strains. Studied antimicrobial agents were prepared via a Kabachnik-Fields reaction promoted by lipases. The products were provided with an excellent yield (up to 92%) under mild, solvent- and metal-free conditions. A preliminary exploration of coumarin α-amino dimethyl phosphonate analogs as novel antimicrobial agents was carried out to determine the basic features of the structure responsible for the observed biological activity. The structure-activity relationship revealed that an inhibitory activity of the synthesized compounds is strongly related to the type of the substituents located in the phenyl ring. The collected data demonstrated that coumarin-based α-aminophosphonates can be potential antimicrobial drug candidates, which is particularly crucial due to the constantly increasing resistance of bacteria to commonly used antibiotics.

The Microbial Degradation of Natural and Anthropogenic Phosphonates.

Phosphonates are compounds containing a direct carbon-phosphorus (C-P) bond, which is particularly resistant to chemical and enzymatic degradation. They are environmentally ubiquitous: some of them are produced by microorganisms and invertebrates, whereas others derive from anthropogenic activities. Because of their chemical stability and potential toxicity, man-made phosphonates pose pollution problems, and many studies have tried to identify biocompatible systems for their elimination. On the other hand, phosphonates are a resource for microorganisms living in environments where the availability of phosphate is limited; thus, bacteria in particular have evolved systems to uptake and catabolize phosphonates. Such systems can be either selective for a narrow subset of compounds or show a broader specificity. The role, distribution, and evolution of microbial genes and enzymes dedicated to phosphonate degradation, as well as their regulation, have been the subjects of substantial studies. At least three enzyme systems have been identified so far, schematically distinguished based on the mechanism by which the C-P bond is ultimately cleaved-i.e., through either a hydrolytic, radical, or oxidative reaction. This review summarizes our current understanding of the molecular systems and pathways that serve to catabolize phosphonates, as well as the regulatory mechanisms that govern their activity.