Dicarboxyl-terminated iron(ii) clathrochelates as ICD-reporters for globular proteins

Abstract

Cage metal complexes iron(II) clathrochelates, which are inherently CD silent, were discovered to demonstrate intensive output in induced circular dichroism (ICD) spectra upon their assembly to albumins. With the aim to design clathrochelates as protein-sensitive CD reporters, the approach for the functionalization of one chelate a-dioximate fragment of the clathrochelate framework with two nonequivalent substituents was developed, and constitutional isomers of clathrochelate with two nonequivalent carboxyphenylsulfide groups were synthesized. The interaction of designed iron(II) clathrochelates and their symmetric homologues with globular proteins (serum albumins, lysozyme, blactoglobulin (BLG), trypsin, insulin) was studied by protein fluorescence quenching and CD techniques. A highly-intensive ICD output of the clathrochelates was observed upon their association with albumins and BLG. It was shown that in the presence of BLG, different clathrochelate isomers gave spectra of inverted signs, indicating the stabilization of opposite configurations (L or D) of the clathrochelate framework in the assembly with this protein. So, we suggest that the isomerism of the terminal carboxy group determined preferable configurations of the clathrochelate framework for the fixation in the protein binding site. MALDI TOF results show the formation of BLG-clathrochelate complex with ratio 1 : 1. Based on the docking simulations, the binding of the clathrochelate molecule (all isomers) to the main BLG binding site (calyx) in its open conformation is suggested. The above results point that the variation of the ribbed substituents at the clathrochelate framework is an effective tool to achieve the specificity of clathrochelate ICD reporting properties to the target protein. Scheme 1 Chemical drawings of the isomeric dicarboxyl-terminated iron(II) cage complexes and their dichloroclathrochelate precursor. 24220 | RSC Adv., 2019, 9, 24218-24230 This journal is View Article Online 2.6. Study of the BLG-clathrochelate 3 assembly by MALDI-TOF mass-spectrometry The corresponding spectra were obtained on a Bruker Daltonics MALDI-TOF mass spectrometer. The sample was prepared by mixing 50 ml of BLG solution (2 mg ml À1 in 0.1 M aqueous 24222 | RSC Adv., 2019, 9, 24218-24230 This journal is Scheme 2 Synthesis of the dicarboxyphenylsulfide iron(II) clathrochelates with equivalent (on top) and non-equivalent (on bottom) ribbed substituents. R 1 s R 2 .This journal is

Sensing of Proteins by ICD Response of Iron(II) Clathrochelates Functionalized by Carboxyalkylsulfide Groups

“…To obtain the values of K and n, the experimentally obtained dependences of a protein fluorescence quenching were presented as the plots of (1 − I/I 0 ) (where I 0 and I are the protein fluorescence intensities in the absence and presence of clathrochelate 3) versus the concentration of 3 (c clt ). Then, they were fitted by using Equation (2) (which was obtained as described in [27]):…”

“…Since CD spectra are known to be sensitive to geometrical distortions of the absorbing chromophores, the ability of the clathrochelate framework to adopt left or right TP-TAP twisted conformations makes these cage metal complexes suitable for the detection of the certain elements of protein tertiary structure and discerning between these elements [24]. It should also be mentioned that the intensities and shapes of the clathrochelate CD spectra induced by the presence of the proteins are substantially affected by the constitutional isomerism of the clathrochelates with carboxyphenylsulfide ribbed substituent-i.e., the ortho-, meta-or para-position(s) of their terminal carboxyl group(s) [26,27]. Moreover, the data of isothermal titration calorimetry (ITC) suggest that the clathrochelates-to-protein binding stoichiometry is also affected by this type of isomerism being equal to 1:2 for the para-substituted isomer and to 1:1 for its ortho-and meta-substituted analogs [26].…”

Fluorinated Iron(ii) clathrochelate units in metalorganic based copolymers: improved porosity, iodine uptake, and dye adsorption properties

“…[26][27][28] Iron(II) clathrochelate is a robust metalorganic unit with a considerable internal free volume (IFV) and which can be easily synthesized and functionalized, especially when employed as a building block in cross-coupling reactions. [29][30][31] Iron(II) clathrochelate complexes were tested as biosensors, 32,33 catalysts for hydrogen generation, 34,35 materials for electronic transport, 36 organogels, 37 and to make supramolecular structures of denite shapes and sizes. [38][39][40][41] Recently, several iron(II) clathrochelate based polymers were reported disclosing prominent porous properties.…”

Synthesis and Structure of the Bis- and Tris-Polyhedral Hybrid Carboranoclathrochelates with Functionalizing Biorelevant Substituents—The Derivatives of Propargylamine Iron(II) Clathrochelates with Terminal Triple C≡C Bond(s)

“…Among the earlier-described d-metal monomacrobicyclic complexes (clathrochelates [1,2]) and their bis-cage analogs, shown in Scheme 1 with terminal biorelevant, first of all, carboxyl group(s), compounds 1-5 are reported to be the most prospective bioeffectors, including the so-called "topological drugs" [2,3] and molecular optical probes [4][5][6]. They possess the highest inhibitory activities in the transcription systems of T7 RNA [7,8] and Taq DNA [9] polymerases, the best antifibrillogenic properties [10] and the most intensive CD outputs on their supramolecular binding to albumins [4][5][6] as well. The latter results are explained [4][5][6] by strong supramolecular interactions of the terminal polar and/or H-donor group(s) of a given macrobicyclic "guest" with appropriate aminoacid residues of a suitable protein macromolecule as a "host" upon their non-covalent host-guest clathrochelate-protein self-assembly.…”

“…They possess the highest inhibitory activities in the transcription systems of T7 RNA [7,8] and Taq DNA [9] polymerases, the best antifibrillogenic properties [10] and the most intensive CD outputs on their supramolecular binding to albumins [4][5][6] as well. The latter results are explained [4][5][6] by strong supramolecular interactions of the terminal polar and/or H-donor group(s) of a given macrobicyclic "guest" with appropriate aminoacid residues of a suitable protein macromolecule as a "host" upon their non-covalent host-guest clathrochelate-protein self-assembly. Moreover, very recently, one of the macrobicyclic iron(II) complexes, the molecule that contains one terminal functionalizing carboxyl group, has been found [11] to possess both high in vitro cytotoxicity and selectivity (as compared with normal cells) against the human promyelocytic leukemia cell line.…”