Peroxo Compounds of Vanadium(V) and Niobium(V) as Potent Inhibitors of Calcineurin Activity towards RII‐Phosphopeptide

Abstract

Calcineurin (CN) is a major calmodulin binding serine/threonine phosphatase which plays a crucial role in numerous mammalian signal transduction pathways. Calcineurin inhibitors represent a valuable tool for elucidating CN dependent cellular processes. The present work deals with the synthesis and comprehensive characterization of a new polymer anchored peroxo niobium complex, [Nb2(O2)6(carboxylate)2]‐PA (Nb2) [PA=poly(sodium acrylate)], and identification of a set comprising of neat homoleptic as well as polymer immobilized peroxo complexes of vanadium(V) and niobium(V) as potent CN inhibitors. The in‐vitro effect of the complexes on calmodulin mediated dephosphorylation activity of CN was investigated using a physiological substrate of calcineurin, RII‐phosphopeptide as well as a non‐protein substrate p‐nitrophenyl phosphate (p‐NPP). Enzyme kinetic analysis data revealed that the compounds inhibit function of CN via uncompetitive pathway with Ki values ranging between 1–3 μM, suggesting the formation of an enzyme‐inhibitor‐substrate complex during the course of inhibition.

Selective and Mild Oxidation of 5‐Hydroxymethylfurfural to 5‐Hydroxymethyl‐2‐furancarboxylic Acid over Organic Polymer‐Supported Peroxidoniobium(V) Catalysts

“…The presence of only one signal in the spectrum further showed the existence of Nb(V) in a single coordination environment in the compound. The position and pattern of the peak thus validate the formula assigned and resembled closely the spectra of other pNb complexes bound to polyacrylate and polystyrene sulphonate macromolecules reported previously by us [20b,39c] . It is likely that inter‐chain interaction between the PMA bound triperoxido‐Nb(V) centers and neighboring pendant carboxylate groups of the polymer chain would result in the completion of eightfold coordination around each Nb(V) center in Nb ‐ PMA , as has been observed in a majority of the reported pNb complexes [20,21,32,39c,42] …”

“…The considerable downfield shift, Δδ (δ complex ‐δ free carboxylate )≈34 ppm suggested the presence of strong metal‐ligand interaction in the macromolecular complex [20a,24a,27a] . The observation is in conformity with some other polyacrylate and PMA ‐bound peroxidometal systems reported earlier [23a,27a,c,39b,c] …”

“…The complex, Nb ‐ PMA showed the first step of degradation occurring within the range of 48–97 °C corresponding to the liberation of lattice water from the complex. This step was followed by the loss of the coordinated peroxido groups from the complex in the range of 107–224 °C [20b,39c] . A broad degradation step observed within 312–594 °C is attributable to the decomposition of the base polymer [27a,c] .…”

Newly-Obtained Two Organic-Inorganic Hybrid Compounds Based on Potassium Peroxidomolybdate and Dicarboxypyridinic Acid: Structure Determination, Catalytic Properties, and Cytotoxic Effects of Eight Peroxidomolybdates in Colon and Hepatic Cancer Cells

“…In the same year, Paul et al published a report showing DNA nuclease activity of oxo-peroxomolybdenum(VI) complexes [ 22 ]. Saikia et al used peroxocompounds as inhibitors of calcineurin activity towards RII-phosphopeptide [ 23 ]. The wide range of applications of POMs encourages further intensification of synthesis efforts and investigations of new compounds.…”

Vanadium Complexes with Thioanilidine Derivatives of Aminoacids: Inhibition of Human Phosphatases and Cell-Type Specificity in Various Models of Metabolic Disturbances

“…Very few publications on the biological activity of vanadium include the study of phosphatases from other classes and groups with different substrate specificity, such as CDC25A, which is the oncoprotein regulating the cell cycle [76][77][78]. Orthovanadate can inhibit the activity of calcineurin, which is a serine/threonine protein phosphatase and plays a crucial role in numerous signal transduction pathways [31,79]. Our results for PP2A are consistent with these findings and confirm that vanadium complexes inhibit not only protein tyrosine phosphatases, but also serine/threonine phosphatases.…”