Design, Synthesis and Actual Applications of the Polymers Containing Acidic P-OH Fragments: Part 2-Sidechain Phosphorus-Containing Polyacids.

Macromolecules containing acidic fragments in side-groups­polyacids­occupy a special place among synthetic polymers. Properties and applications of polyacids are directly related to the chemical structure of macromolecules: the nature of the acidic groups, polymer backbone, and spacers between the main chain and acidic groups. The chemical nature of the phosphorus results in the diversity of acidic >P(O)OH fragments in sidechain phosphorus-containing polyacids (PCPAs) that can be derivatives of phosphoric or phosphinic acids. Sidechain PCPAs have many similarities with other polyacids. However, due to the relatively high acidity of −P(O)(OH)2 fragment, bone and mineral affinity, and biocompatibility, sidechain PCPAs have immense potential for diverse applications. Synthetic approaches to sidechain PCPAs also have their own specifics. All these issues are discussed in the present review.

Single-Stage Extraction and Separation of Co2+ from Ni2+ Using Ionic Liquid of [C4H9NH3][Cyanex 272].

The purpose of this study was to optimize the extraction conditions for separating Co2+ from Ni2+ using N-butylamine phosphinate ionic liquid of [C4H9NH3][Cyanex 272]. A Box-Behnken design of response surface methodology was used to analyze the effects of the initial pH, extraction time, and extraction temperature on the separation factor of Co2+ from sulfuric acid solution containing Ni2+. The concentrations of Co2+ and Ni2+ in an aqueous solution were determined using inductively coupled plasma-optical emission spectrometry. The optimized extraction conditions were as follows: an initial pH of 3.7, an extraction time of 55.8 min, and an extraction temperature of 330.4 K. The separation factor of Co2+ from Ni2+ under optimized extraction conditions was 66.1, which was very close to the predicted value of 67.2, and the error was 1.7%. The equation for single-stage extraction with high reliability can be used for optimizing the multi-stage extraction process of Co2+ from Ni2+. The stoichiometry of chemical reaction for ion-exchange extraction was also investigated using the slope method.

Practical Synthesis of Phosphinic Dipeptides by Tandem Esterification of Aminophosphinic and Acrylic Acids under Silylating Conditions.

In this report, a synthetic protocol for the preparation of phosphinic dipeptides of type 5 is presented. These compounds serve as valuable building blocks for the development of highly potent phosphinopeptidic inhibitors of medicinally relevant Zn-metalloproteases and aspartyl proteases. The proposed method is based on the tandem esterification of α-aminophosphinic and acrylic acids under silylating conditions in order to subsequently participate in a P-Michael reaction. The scope of the transformation was investigated by using a diverse set of readily available acrylic acids and (R)-α-aminophosphinic acids, and high yields were achieved in all cases. In most examples reported herein, the isolation of biologically relevant (R,S)-diastereoisomers became possible by simple crystallization from the crude products, thus enhancing the operational simplicity of the proposed method. Finally, functional groups corresponding to acidic or basic natural amino acids are also compatible with the reaction conditions. Based on the above, we expect that the practicality of the proposed protocol will facilitate the discovery of pharmacologically useful bioactive phosphinic peptides.

ERAP2 Inhibition Induces Cell-Surface Presentation by MOLT-4 Leukemia Cancer Cells of Many Novel and Potentially Antigenic Peptides.

Recent studies have linked the activity of ER aminopeptidase 2 (ERAP2) to increased efficacy of immune-checkpoint inhibitor cancer immunotherapy, suggesting that pharmacological inhibition of ERAP2 could have important therapeutic implications. To explore the effects of ERAP2 inhibition on the immunopeptidome of cancer cells, we treated MOLT-4 T lymphoblast leukemia cells with a recently developed selective ERAP2 inhibitor, isolated Major Histocompatibility class I molecules (MHCI), and sequenced bound peptides by liquid chromatography tandem mass spectrometry. Inhibitor treatment induced significant shifts on the immunopeptidome so that more than 20% of detected peptides were either novel or significantly upregulated. Most of the inhibitor-induced peptides were 9mers and had sequence motifs and predicted affinity consistent with being optimal ligands for at least one of the MHCI alleles carried by MOLT-4 cells. Such inhibitor-induced peptides could serve as triggers for novel cytotoxic responses against cancer cells and synergize with the therapeutic effect of immune-checkpoint inhibitors.

Investigating the phosphinic acid tripeptide mimetic DG013A as a tool compound inhibitor of the M1-aminopeptidase ERAP1.

ERAP1 is a zinc-dependent M1-aminopeptidase that trims lipophilic amino acids from the N-terminus of peptides. Owing to its importance in the processing of antigens and regulation of the adaptive immune response, dysregulation of the highly polymorphic ERAP1 has been implicated in autoimmune disease and cancer. To test this hypothesis and establish the role of ERAP1 in these disease areas, high affinity, cell permeable and selective chemical probes are essential. DG013A 1, is a phosphinic acid tripeptide mimetic inhibitor with reported low nanomolar affinity for ERAP1. However, this chemotype is a privileged structure for binding to various metal-dependent peptidases and contains a highly charged phosphinic acid moiety, so it was unclear whether it would display the high selectivity and passive permeability required for a chemical probe. Therefore, we designed a new stereoselective route to synthesize a library of DG013A 1 analogues to determine the suitability of this compound as a cellular chemical probe to validate ERAP1 as a drug discovery target.

New insights into structure and function of bis-phosphinic acid derivatives and implications for CFTR modulation.

C407 is a compound that corrects the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein carrying the p.Phe508del (F508del) mutation. We investigated the corrector effect of c407 and its derivatives on F508del-CFTR protein. Molecular docking and dynamics simulations combined with site-directed mutagenesis suggested that c407 stabilizes the F508del-Nucleotide Binding Domain 1 (NBD1) during the co-translational folding process by occupying the position of the p.Phe1068 side chain located at the fourth intracellular loop (ICL4). After CFTR domains assembly, c407 occupies the position of the missing p.Phe508 side chain. C407 alone or in combination with the F508del-CFTR corrector VX-809, increased CFTR activity in cell lines but not in primary respiratory cells carrying the F508del mutation. A structure-based approach resulted in the synthesis of an extended c407 analog G1, designed to improve the interaction with ICL4. G1 significantly increased CFTR activity and response to VX-809 in primary nasal cells of F508del homozygous patients. Our data demonstrate that in-silico optimized c407 derivative G1 acts by a mechanism different from the reference VX-809 corrector and provide insights into its possible molecular mode of action. These results pave the way for novel strategies aiming to optimize the flawed ICL4-NBD1 interface.

Intra-individual dynamic comparison of 18F-PSMA-11 and 68Ga-PSMA-11 in LNCaP xenograft bearing mice.

Recently, a 18F-labeled derivative of the widely used 68Ga-PSMA-11 was developed for PET imaging of prostate cancer. Although 18F-PSMA-11 has already been evaluated in a Phase I and Phase II clinical trial, preclinical evaluation of this radiotracer is important for further understanding its dynamic behavior. Saturation binding experiments were conducted by incubation of LNCaP cells with 18F-PSMA-11 or 68Ga-PSMA-11 for 1 h, followed by determination of the specific and aspecific binding. Mice bearing LNCaP or PC-3 xenografts each received ± 3.7 MBq 18F-PSMA-11 and 68Ga-PSMA-11 followed by dynamic acquisition of 2.5 h as well as ± 15 MBq 18F-FDG followed by static acquisition at 1 h post injection (p.i.). Uptake was evaluated by comparison of uptake parameters (SUVmean, SUVmax, TBRmean and TBRmax). Mice underwent ex vivo biodistribution where 18F-PSMA-11 activity was measures in excretory organs (kidneys, bladder and liver) as well as bone fragments (femur, humerus, sternum and skull) to evaluate bone uptake. The dissociation constant (Kd) of 18F-PSMA-11 and 68Ga-PSMA-11 was 2.95 ± 0.87 nM and 0.49 ± 0.20 nM, respectively. Uptake parameters were significantly higher in LNCaP compared to PC-3 xenografts for both 18F-PSMA-11 and 68Ga-PSMA-11, while no difference was found for 18F-FDG uptake (except for SUVmax). Tumor uptake of 18F-PSMA-11 showed a similar trend over time as 68Ga-PSMA-11, although all uptake parameter curves of the latter were considerably lower. When comparing early (60 min p.i.) to delayed (150 min p.i.) imaging for both radiotracers individually, TBRmean and TBRmax were significantly higher at the later timepoint, as well as the SUVmax of 68Ga-PSMA-11. The highest %ID/g was determined in the kidneys (94.0 ± 13.6%ID/g 1 h p.i.) and the bladder (6.48 ± 2.18%ID/g 1 h p.i.). No significant increase in bone uptake was seen between 1 and 2 h p.i. Both radiotracers showed high affinity for the PSMA receptor. Over time, all uptake parameters were higher for 18F-PSMA-11 compared to 68Ga-PSMA-11. Delayed imaging with the latter may improve tumor visualization, while no additional benefits could be found for late 18F-PSMA-11 imaging. Ex vivo biodistribution demonstrated fast renal clearance of 18F-PSMA-11 as well as no significant increase in bone uptake.

Development of Novel Polyamide 11 Multifilaments and Fabric Structures Based on Industrial Lignin and Zinc Phosphinate as Flame Retardants.

Biobased lignin represents one of the possible materials for next-generation flame retardant additives due to its sustainability, environmental benefits and comparable efficiency to other flame retardant (FR) additives. In this context, this study presents the development of FR polyamide 11 (PA11) multifilament yarns and fabric structures containing different industrial lignins (i.e., lignosulfonate lignin (LL), and Kraft lignin (KL)) and zinc phosphinate (ZnP). The combination of ZnP and lignin (KL or LL) at different weight ratios were used to prepare flame retarded PA11 blends by melt mixing using a twin-screw extruder. These blends were transformed into continuous multifilament yarns by the melt-spinning process even at a high concentration of additives as 20 wt%. The mechanical test results showed that the combination of KL and ZnP achieved higher strength and filaments showed regularity in structure as compared to the LL and ZnP filaments. Thermogravimetric (TG) analysis showed the incorporation of lignin induces the initial decomposition (T5%) at a lower temperature; at the same time, maximum decomposition (Tmax) shifts to a higher temperature region and a higher amount of char residue is reported at the end of the test. Further, the TGA-FTIR study revealed that the ternary blends (i.e., the combination of LL or KL, ZnP, and PA11) released mainly the phosphinate compound, hydrocarbon species, and a small amount of phosphinic acid during the initial decomposition stage (T5%), while hydrocarbons, carbonyls, and phenolic compounds along with CO2 are released during main decomposition stage (Tmax). The analysis of decomposition products suggests the stronger bonds formation in the condensed phase and the obtainment of a stable char layer. Cone calorimetry exploited to study the fire behavior on sheet samples (polymer bulk) showed an improvement in flame retardant properties with increasing lignin content in blends and most enhanced results were found when 10 wt% of LL and ZnP were combined such as a reduction in heat release rate (HRR) up to 64% and total heat release (THR) up to 22%. Besides, tests carried out on knitted fabric structure showed less influence on HRR and THR but the noticeable effect on postponing the time to ignition (TTI) and reduction in the maximum average rate of heat emission (MARHE) value during combustion.

Co(II) and Ni(II) transport from model and real sulfate solutions by extraction with bis(2,4,4-trimethylpentyl)phosphinic acid (Cyanex 272).

This paper presents the results of Co(II) and Ni(II) extraction from model and real solutions using bis(2,4,4-trimethylpentyl)phosphinic acid (i.e. Cyanex 272) that are in agreement with waste-to-resources approach, i.e. the recovery of valuable components from wastes. The results from this study shows that, extraction using Cyanex 272 is an efficient method to recover Co(II) selectively from sulfate electrolytes obtained from the leaching of steel scraps of aircraft engines. The highest selectivity value (∼160) of Co(II) extraction over Ni(II) was obtained at a pH of 4.8, the lowest selectivity value (∼30) was observed at a pH of 5.5, while above this value the selectivity only increased slightly with increasing pH. A pH of 5.2 was selected as a compromise between Co(II) selectivity and Ni(II) amount in the organic phase. The essence of the investigation is to propose important parameters to extract Co(II) from real leach solutions, and to further recover valuable Co(II) from the loaded organic phase by stripping with 1 M H2SO4, thus producing an electrolyte of Co(II) for electrowinning - a possible alternative route for resource recovery. Small volume of the stripping phase (w/o = 1:5) used in this study, lead to an enrichment of sulfate electrolyte in Co(II), resulting in ∼50 g/dm3 of Co(II) in the solution, which is a great advantage of the approach proposed. Such a solution is a valuable source for the electrowinning of metallic cobalt, which can be used for the production of steel alloys, Li-ion batteries or catalysts.

Polymer-Supported Phosphoric, Phosphonic and Phosphinic Acids-From Synthesis to Properties and Applications in Separation Processes.

Efficient separation technologies are crucial to the environment and world economy. The challenge posed to scientists is how to engineer selectivity towards a targeted substrate, especially from multicomponent solutions. Polymer-supported reagents have gained a lot of attention in this context, as they eliminate a lot of inconveniences concerning widely used solvent extraction techniques. Nevertheless, the choice of an appropriate ligand for immobilization may be derived from the behavior of soluble compounds under solvent extraction conditions. Organophosphorus compounds play a significant role in separation science and technology. The features they possess, such as variable oxidation states, multivalence, asymmetry and metal-binding properties, highlight their status as a unique and versatile class of compounds, capable of selective separations proceeding through different mechanisms. This review provides a detailed survey of polymers containing phosphoric, phosphonic and phosphinic acid functionalities in the side chain and covers main advances in the preparation and application of these materials in separation science, including the most relevant synthesis routes (Arbuzov, Perkow, Mannich, Kabachnik-Fields reactions, etc.), as well as the main stages in the development of organophosphorus resins and the most important achievements in the field.

Click-Chemistry (CuAAC) Trimerization of an αv ß6 Integrin Targeting Ga-68-Peptide: Enhanced Contrast for in-Vivo PET Imaging of Human Lung Adenocarcinoma Xenografts.

αv ß6 Integrin is an epithelial transmembrane protein that recognizes latency-associated peptide (LAP) and primarily activates transforming growth factor beta (TGF-ß). It is overexpressed in carcinomas (most notably, pancreatic) and other conditions associated with αv ß6 integrin-dependent TGF-ß dysregulation, such as fibrosis. We have designed a trimeric Ga-68-labeled TRAP conjugate of the αv ß6 -specific cyclic pentapeptide SDM17 (cyclo[RGD-Chg-E]-CONH2 ) to enhance αv ß6 integrin affinity as well as target-specific in-vivo uptake. Ga-68-TRAP(SDM17)3 showed a 28-fold higher αv ß6 affinity than the corresponding monomer Ga-68-NOTA-SDM17 (IC50 of 0.26 vs. 7.4 nM, respectively), a 13-fold higher IC50 -based selectivity over the related integrin αv ß8 (factors of 662 vs. 49), and a threefold higher tumor uptake (2.1 vs. 0.66 %ID/g) in biodistribution experiments with H2009 tumor-bearing SCID mice. The remarkably high tumor/organ ratios (tumor-to-blood 11.2; -to-liver 8.7; -to-pancreas 29.7) enabled high-contrast tumor delineation in PET images. We conclude that Ga-68-TRAP(SDM17)3 holds promise for improved clinical PET diagnostics of carcinomas and fibrosis.

Effects of Irgacure 2959 and lithium phenyl-2,4,6-trimethylbenzoylphosphinate on cell viability, physical properties, and microstructure in 3D bioprinting of vascular-like constructs.

Photocrosslinkable polymers such as gelatin methacrylate (GelMA) have various 3D bioprinting applications. These polymers crosslink upon exposure to UV irradiation with the existence of an appropriate photoinitiator. Two photoinitiators, Irgacure 2959 and lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) are commonly used. This study systematically investigates the effects of photoinitiator types on the cell viability, physical properties, and microstructure in 3D bioprinting of GelMA-based cellular constructs. The main conclusions are: (1) during the 3D bioprinting, the cell viability generally decreases as the photoinitiator concentration and printing time increase using both Irgacure 2959 and LAP. At the low photoinitiator concentrations (such as 0.3% and 0.5% (w/v)), the overall cell viability is good within the printing time of 60 min using both Irgacure 2959 and LAP. However, at the high photoinitiator concentrations (such as 0.7% and 0.9% (w/v)), the overall cell viability using LAP is much higher than that using Irgacure 2959 within the printing time of 60 min; (2) after the 3D bioprinting, the photoinitiator types, either Irgacure 2959 or LAP, have negligible effects on the post-printing cell viability after crosslinking; (3) after the 3D bioprinting, GelMA samples cured with Irgacure 2959 have slightly larger pore size, faster degradation rate, and greater swelling ratio compared to those cured with LAP; (4) 3D GelMA-based vascular-like constructs have been fabricated using dynamic optical projection stereolithography, and the measured dimensions have been compared with the designed dimensions showing good shape fidelity.

Synthesis of benzyl sulfides via substitution reaction at the sulfur of phosphinic acid thioesters.

An ambident electrophilicity of phosphinic acid thioesters is disclosed. Unexpected carbon-sulfur bond formation took place in the reaction between phosphinic acid thioesters and benzyl Grignard reagents. The developed method for benzyl sulfides has a wide substrate scope and was applicable for the synthesis of a drug analog.

Rapid Thermodynamically Stable Complex Formation of [nat/111In]In3+, [nat/90Y]Y3+, and [nat/177Lu]Lu3+ with H6dappa.

A phosphinate-bearing picolinic acid-based chelating ligand (H6dappa) was synthesized and characterized to assess its potential as a bifunctional chelator (BFC) for inorganic radiopharmaceuticals. Nuclear magnetic resonance (NMR) spectroscopy was employed to investigate the chelator coordination chemistry with a variety of nonradioactive trivalent metal ions (In3+, Lu3+, Y3+, Sc3+, La3+, Bi3+). Density functional theory (DFT) calculations explored the coordination environments of aforementioned metal complexes. The thermodynamic stability of H6dappa with four metal ions (In3+, Lu3+, Y3+, Sc3+) was deeply investigated via potentiometric and spectrophotometric (UV-vis) titrations, employing a combination of acidic in-batch, joint potentiometric/spectrophotometric, and ligand-ligand competition titrations; high stability constants and pM values were calculated for all four metal complexes. Radiolabeling conditions for three clinically relevant radiometal ions were optimized ([111In]In3+, [177Lu]Lu3+, [90Y]Y3+), and the serum stability of [111In][In(dappa)]3- was studied. Through concentration-, time-, temperature-, and pH-dependent labeling experiments, it was determined that H6dappa radiolabels most effectively at near-physiological pH for all radiometal ions. Furthermore, very rapid radiolabeling at ambient temperature was observed, as maximal radiolabeling was achieved in less than 1 min. Molar activities of 29.8 GBq/µmol and 28.2 GBq/µmol were achieved for [111In]In3+ and [177Lu]Lu3+, respectively. For H6dappa, high thermodynamic stability did not correlate with kinetic inertness-lability was observed in serum stability studies, suggesting that its metal complexes might not be suitable as a BFC in radiopharmaceuticals.

Removal of Zinc from Aqueous Solutions Using Lamellar Double Hydroxide Materials Impregnated with Cyanex 272: Characterization and Sorption Studies.

Removal of heavy metals from wastewater is mandatory in order to avoid water pollution of natural reservoirs. In the present study, layered double hydroxide (LDH) materials were evaluated for removal of zinc from aqueous solutions. Materials thus prepared were impregnated with cyanex 272 using the dry method. These materials were characterized through X-ray diffraction (XRD), Fourier transform infrared (FTIR), and thermal analysis. Batch shaking adsorption experiments were performed in order to examine contact time and extraction capacity in the removal process. Results showed that the equilibrium time of Zn (II) extraction is about 4 h for Mg2Al-CO3 and Mg2Al-CO3-cyanex 272, 6 h for Zn2Al-CO3, and 24 h for Zn2Al-CO3-cyanex 272. The experimental equilibrium data were tested for Langmuir, and Freundlich isotherm models. Correlation coefficients indicate that experimental results are in a good agreement with Langmuir's model for zinc ions. Pseudo-first, second-order, Elovich, and intraparticular kinetic models were used to describe kinetic data. It was determined that removal of Zn2+ was well-fitted by a second-order reaction kinetic. A maximum capacity of 280 mg/g was obtained by Zn2Al-CO3-cyanex 272.

Continuous Flow Esterification of a H-Phosphinic Acid, and Transesterification of H-phosphinates and H-Phosphonates under Microwave Conditions.

The microwave (MW)-assisted direct esterification of phenyl-H-phosphinic acid, transesterification of the alkyl phenyl-H-phosphinates so obtained, and the similar reaction of dibenzyl phosphite (DBP) were investigated in detail, and the batch accomplishments were translated into a continuous flow operation that, after optimization of the parameters, such as temperature and flow rate, proved to be more productive. Alcoholysis of DBP is a two-step process involving an intermediate phosphite with two different alkoxy groups. The latter species are of synthetic interest, as precursors for optically active reagents.

Comparison of Photo Cross Linkable Gelatin Derivatives and Initiators for Three-Dimensional Extrusion Bioprinting.

The objective of this study was to evaluate the utility of gelatin-norbornene (GelNB), which is cross-linkable via thiol-ene click chemistry, and the photoinitiator lithium phenyl-2,4,6 trimethylbenzoylphosphinate (LAP) for 3D bioprinting. These materials were compared to two widely used materials, gelatin-methacryloyl (GelMA) and 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone (I2959). Characterization of photocuring kinetics revealed that LAP markedly improved the kinetics compared to I2959, which improved stability and print fidelity. Additionally, GelNB exhibited improved photocuring kinetics, improved stability, and decreased filament spreading compared to GelMA. However, inks containing GelMA yielded at lower stress, were more easily extruded, and produced smoother filaments. NIH 3T3 fibroblasts exhibited high viability in printed constructs, regardless of the gelatin derivative or photoinitiator used. Overall, these results support the selection of LAP over I2959 and suggest that GelNB could be a useful alternative to GelMA, although further work is needed to optimize GelNB extrusion.

Coordination Behavior of 1,4-Disubstituted Cyclen Endowed with Phosphonate, Phosphonate Monoethylester, and H-Phosphinate Pendant Arms.

Three 1,4,7,10-tetraazacyclododecane-based ligands disubstituted in 1,4-positions with phosphonic acid, phosphonate monoethyl-ester, and H-phosphinic acid pendant arms, 1,4-H4do2p, 1,4-H2do2pOEt, and 1,4-H2Bn2do2pH, were synthesized and their coordination to selected metal ions, Mg(II), Ca(II), Mn(II), Zn(II), Cu(II), Eu(III), Gd(III), and Tb(III), was investigated. The solid-state structure of the phosphonate ligand, 1,4-H4do2p, was determined by single-crystal X-ray diffraction. Protonation constants of the ligands and stability constants of their complexes were obtained by potentiometry, and their values are comparable to those of previously studied analogous 1,7-disubstitued cyclen derivatives. The Gd(III) complex of 1,4-H4do2p is ~1 order of magnitude more stable than the Gd(III) complex of the 1,7-analogue, probably due to the disubstituted ethylenediamine-like structural motif in 1,4-H4do2p enabling more efficient wrapping of the metal ion. Stability of Gd(III)-1,4-H2do2pOEt and Gd(III)-H2Bn2do2pH complexes is low and the constants cannot be determined due to precipitation of the metal hydroxide. Protonations of the Cu(II), Zn(II), and Gd(III) complexes probably takes place on the coordinated phosphonate groups. Complexes of Mn(II) and alkali-earth metal ions are significantly less stable and are not formed in acidic solutions. Potential presence of water molecule(s) in the coordination spheres of the Mn(II) and Ln(III) complexes was studied by variable-temperature NMR experiments. The Mn(II) complexes of the ligands are not hydrated. The Gd(III)-1,4-H4do2p complex undergoes hydration equilibrium between mono- and bis-hydrated species. Presence of two-species equilibrium was confirmed by UV-Vis spectroscopy of the Eu(III)-1,4-H4do2p complex and hydration states were also determined by luminescence measurements of the Eu(III)/Tb(III)-1,4-H4do2p complexes.

Potential chemical transformation of phosphinic acid derivatives and their applications in the synthesis of drugs.

The chemical transformation of phosphinic acid is a well-considered mature area of research on account of the historical significant reactions such as Kabachnik-Fields, Mannich, Arbuzov, Michaelis-Becker, etc. Considerable advances have been made over last years especially in metal-catalyzed, free-radical processes and asymmetric synthesis using catalytic enantioselective. As a result, the aim of this synopsis is to make the reader familiar with advances in the approaches of phosphinic acids toward the synthesis of highly functionalized and valuable buildings blocks. Another purpose of this survey is to provide the current status of the applications of phosphinic acids in the synthesis of drugs.

Phosphonic and Phosphinic Acid Derivatives as Novel Tyrosinase Inhibitors: Kinetic Studies and Molecular Docking.

A dozen of phosphonic and phosphinic acid derivatives containing pyridine moiety were synthesized and its inhibitory activity toward mushroom tyrosinase was investigated. Moreover, molecular docking of these compounds to the active site of the enzyme was performed. All the compounds (1-10) demonstrated the inhibitory effect with the IC50 and inhibition constants ranging millimolar concentrations. The obtained results indicate that the compounds show different types of inhibition (competitive, noncompetitive, mixed), but all of them are reversible inhibitors. The obtained outcomes allowed to make the structure-activity relationship (SAR) analysis. Compound 4 ([(benzylamino)(pyridin-2-yl)methyl]phenylphosphinic acid) revealed the lowest IC50 value of 0.3 mm and inhibitory constant of Ki 0.076 mm, with noncompetitive type and reversible mechanism of inhibition. According to SAR analysis, introducing bulky phenyl moieties to phosphonic and amino groups plays an important role in the inhibitory potency on activity of mushroom tyrosinase and could be useful in design and development of a new class of potent organophosphorus inhibitors of tyrosinase. Combined results of molecular docking and SAR analysis can be helpful in designing novel tyrosinase inhibitors of desired properties. They may have broad application in food industry and cosmetology.