Reactions of Arsenoplatin-1 with Protein Targets: A Combined Experimental and Theoretical Study.

Iogann Tolbatov,Tiziano Marzo,Luigi Messori,Alessandro Marrone,Damiano Cirri,Nazzareno Re,Matteo Tarchi,Cecilia Coletti,Lara Massai

doi:10.1021/acs.inorgchem.1c03732

Abstract

Arsenoplatin-1 (AP-1) is a dual-action anticancer metallodrug with a promising pharmacological profile that features the simultaneous presence of a cisplatin-like center and an arsenite center. We investigated its interactions with proteins through a joint experimental and theoretical approach. The reactivity of AP-1 with a variety of proteins, including carbonic anhydrase (CA), superoxide dismutase (SOD), myoglobin (Mb), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and human serum albumin (HSA), was analyzed by means of electrospray ionization mass spectrometry (ESI MS) measurements. In accordance with previous observations, ESI MS experiments revealed that the obtained metallodrug–protein adducts originated from the binding of the [(AP-1)-Cl]+ fragment to accessible protein residues. Remarkably, in two cases, i.e., Mb and GAPDH, the formation of a bound metallic fragment that lacked the arsenic center was highlighted. The reactions of AP-1 with various nucleophiles side chains of neutral histidine, methionine, cysteine, and selenocysteine, in neutral form as well as cysteine and selenocysteine in anionic form, were subsequently analyzed through a computational approach. We found that the aquation of AP-1 is energetically disfavored, with a reaction free energy of +19.2 kcal/mol demonstrating that AP-1 presumably attacks its biological targets through the exchange of the chloride ligand. The theoretical analysis of thermodynamics and kinetics for the ligand-exchange processes of AP-1 with His, Met, Cys, Sec, Cys–, and Sec– side chain models unveils that only neutral histidine and deprotonated cysteine and selenocysteine are able to effectively replace the chloride ligand in AP-1.

Highlights

Transition-metal complexes are widely used in medicinal chemistry;[1−4] the case of cisplatin as an anticancer agent being the most representative.[5]
As a matter of fact, there is a continuous interest in the development of cisplatin derivatives with the objective of ameliorating their antitumor potency while decreasing systemic toxicity.[6−8] The toxicity of cisplatin originates from the relatively easy in vivo replacement of the chloride ligands by donor atoms of endogenous targets; the testing of a plethora of less reactive Pt ligands in the place of chloride has permitted the production of metallodrugs with lower systemic toxicity and a higher therapeutic index.[9−13] This proves that the design of new active Pt(II)-based compounds should involve the structurebased control of the substitution reaction.[14,15]
The analysis of the biomolecular interactions of AP-1 grounded on electrospray ionization mass spectrometry (ESI MS) measurements was extended here to a larger number of proteins than in the past, including carbonic anhydrase, superoxide dismutase, myoglobin, glyceraldehyde 3phosphate dehydrogenase, and human serum albumin

Summary

Introduction

Transition-metal complexes are widely used in medicinal chemistry;[1−4] the case of cisplatin as an anticancer agent being the most representative.[5] As a matter of fact, there is a continuous interest in the development of cisplatin derivatives with the objective of ameliorating their antitumor potency while decreasing systemic toxicity.[6−8] The toxicity of cisplatin originates from the relatively easy in vivo replacement of the chloride ligands by donor atoms of endogenous targets; the testing of a plethora of less reactive Pt ligands in the place of chloride has permitted the production of metallodrugs with lower systemic toxicity and a higher therapeutic index.[9−13] This proves that the design of new active Pt(II)-based compounds should involve the structurebased control of the substitution reaction.[14,15]. The mechanism of action of AP-1 is not yet completely comprehended at the molecular level, several experimental[16−19] and computational[20−22] investigations have been reported so far.

Objectives

Methods

Results

Conclusion