Amino acid-linked platinum(II) compounds: non-canonical nucleoside preferences and influence on glycosidic bond stabilities

Abstract

Nucleobases serve as ideal targets where drugs bind and exert their anticancer activities. Cisplatin (cisPt) preferentially coordinates to 2′-deoxyguanosine (dGuo) residues within DNA. The dGuo adducts that are formed alter the DNA structure, contributing to inhibition of function and ultimately cancer cell death. Despite its success as an anticancer drug, cisPt has a number of drawbacks that reduce its efficacy, including repair of adducts and drug resistance. Some approaches to overcome this problem involve development of compounds that coordinate to other purine nucleobases, including those found in RNA. In this work, amino acid-linked platinum(II) (AAPt) compounds of alanine and ornithine (AlaPt and OrnPt, respectively) were studied. Their reactivity preferences for DNA and RNA purine nucleosides (i.e., 2′-deoxyadenosine (dAdo), adenosine (Ado), dGuo, and guanosine (Guo)) were determined. The chosen compounds form predominantly monofunctional adducts by reacting at the N1, N3, or N7 positions of purine nucleobases. In addition, features of AAPt compounds that impact the glycosidic bond stability of Ado residues were explored. The glycosidic bond cleavage is activated differentially for AlaPt-Ado and OrnPt-Ado isomers. Formation of unique adducts at non-canonical residues and subsequent destabilization of the glycosidic bonds are important features that could circumvent platinum-based drug resistance.Graphic abstract Electronic supplementary materialThe online version of this article (10.1007/s00775-019-01693-y) contains supplementary material, which is available to authorized users.

From Preassociation to Chelation: A Survey of Cisplatin Interaction with Methionine at Molecular Level by IR Ion Spectroscopy and Computations

“… 28 − 34 In particular, cisplatin related platinum(II) complexes have been characterized. 34 − 36 Previous reports have highlighted the versatility of ESI-MS together with the specificity of IRMPD spectroscopy in delivering detailed structural information on the monofunctional complexes cis -[PtCl(NH 3 ) 2 (AA)] + , where AA is either Met or His. 20 − 22 Furthermore, solutions of cisplatin and a simple ligand (L, chosen to model the nucleophilic functionalities of amino acids and nucleobases), assayed by ESI-MS and IRMPD spectroscopy have revealed the presence and role of the encounter complexes { cis -[PtCl(NH 3 ) 2 (H 2 O)] + ·L}.…”

“…It is worthy of note that the species is assayed in the gas phase, in the absence of solvent and associated band-broadening effects. IRMPD spectroscopy has been extensively used for the vibrational and structural characterization of transition metal complexes of both catalytic and biological relevance. − In particular, cisplatin related platinum­(II) complexes have been characterized. − Previous reports have highlighted the versatility of ESI-MS together with the specificity of IRMPD spectroscopy in delivering detailed structural information on the monofunctional complexes cis -[PtCl­(NH 3 ) 2 (AA)] + , where AA is either Met or His. − Furthermore, solutions of cisplatin and a simple ligand (L, chosen to model the nucleophilic functionalities of amino acids and nucleobases), assayed by ESI-MS and IRMPD spectroscopy have revealed the presence and role of the encounter complexes { cis -[PtCl­(NH 3 ) 2 (H 2 O)] + ·L}. , These species are formed by the diffusion controlled encounter of the aqua complex of cisplatin with the incoming ligand L and are the early actors in the substitution reaction of metal complexes in aqueous media, conforming to the Eigen–Wilkins reactant preassociation model. − In the reported cases, the role of the encounter complex along the substitution reaction path of the cisplatin aqua complex with model ligands was assessed by observing the reaction to occur in the isolated species after collisional- or photoactivation, while IRMPD spectroscopy has afforded its vibrational and structural features. Moving one step further in assaying the cisplatin reaction with nucleophiles approaching the biomolecular targets, herein is reported the isolation and characterization of the adduct formally obtained by the preassociation of cisplatin aqua complex with methionine, [PtCl­(NH 3 ) 2 (H 2 O)­(Met)] + .…”