Ruthenium-based PACT compounds based on an N,S non-toxic ligand: a delicate balance between photoactivation and thermal stability

Abstract

Abstract:In photoactivated chemotherapy, the photocleavable protecting group that prevents the bioactive compound from interacting with biomolecules in the dark is sometimes cytotoxic, which makes interpretation of phototoxicity challenging. For ruthenium polypyridyl complexes new, non-toxic protecting ligands that prevent a toxic metal complex from binding to biomolecules in the dark, but that can be efficiently photosubstituted upon visible light irradiation to recover the high toxicity of the metal complex, are necessary. In this work, we report on the synthesis, stereochemical characterization and cytotoxicity of a series of polypyridyl complexes; [Ru(bpy) 2 (mtpa)](PF 6 ) 2 ([1](PF 6 ) 2 , bpy = 2,2'-bipyridine), [Ru(bpy)(dmbpy)(mtpa)](PF 6 ) 2 ([2](PF 6 ) 2 , dmbpy = 6,6'-dimethyl-2,2'-bipyridine), and [Ru(dmbpy) 2 (mtpa)](PF 6 ) 2 ([3](PF 6 ) 2 ) based on the non-toxic 3-(methylthio)propylamine protecting ligand (mtpa). The number of methyl groups had a crucial effect on the photochemistry and cytotoxicity of these complexes. The non-strained complex [1] 2+ was not capable of fully releasing mtpa and was not phototoxic in lung cancer cells (A549). In the most strained complex [3] 2+ , thermal stability was lost, leading to poor photoactivation in vitro and a generally high toxicity also without light activation. The heteroleptic complex [2] 2+ with intermediate strain showed, upon blue light irradiation, efficient mtpa photosubstitution and increased cytotoxicity in cancer cells, but photosubstitution was not selective. Overall, fine-tuning of the lipophilicity and steric strain of ruthenium complexes appears as an efficient method to obtain phototoxic ruthenium-based photoactivated chemotherapeutic prodrugs, at the cost of synthetic simplicity and photosubstitution selectivity.

Selective Preparation of a Heteroleptic Cyclometallated Ruthenium Complex Capable of Undergoing Photosubstitution of a Bidentate Ligand

“…Thus, for each of the four Λ coordination isomers, a pair of diastereoisomers Λ‐ R and Λ‐ S may exist, giving a total of eight possible Λ‐isomers for [ 3 ] + and [ 5 ] + . Finally, for the complexes [ 2 ] + and [ 4 ] + , the N,S chelate creates a six‐membered ring that can switch between two chair conformations, in which the methyl group of the thioether is in either an equatorial ( eq ) or an axial ( ax ) position (Scheme ) . These configurations are not identical, and hence there are as many as 16 possible Λ‐isomers for these two complexes.…”

“…In all calculations, only the Λ enantiomers with the six‐membered chelate ring in a chair conformation were considered, but the sulfur atom was placed in either the R or S configuration. To reduce the number of structures, only those isomers with the methyl group in the equatorial position were calculated . The optimized structures and their energies in water are given in Figures S1 and S2 and Table S1, respectively.…”

Intracellular Photophysics of an Osmium Complex bearing an Oligothiophene Extended Ligand

“…Only PDT has been approved clinically, and its underlying mechanism of action involves the generation of cytotoxic singlet oxygen ( 1 O 2 ) and other reactive oxygen species (ROS) [13–15] . PCT has focused on avoiding this oxygen dependence mainly through photoinduced ligand loss and subsequent covalent modification of biomolecules as an alternate mechanism [16–25] . While the Ru II systems that have been investigated for PDT and PCT absorb visible light, many cannot be activated with wavelengths in the so‐called biological window (650–850 nm) that are desirable for deeper tissue penetration.…”

“…[13][14][15] PCT has focused on avoiding this oxygen dependence mainly throughp hotoinducedl igand loss and subsequentc ovalentm odification of biomolecules as an alternate mechanism. [16][17][18][19][20][21][22][23][24][25] While the Ru II systems that have been investigated for PDT and PCT absorb visiblel ight, many cannotb ea ctivatedw ith wavelengthsi n the so-called biological window (650-850 nm) that are desirable for deeper tissue penetration.…”

Antiproliferative properties of iron supramolecular cylinders

“…gene expression and protein synthesis) or the replication, ultimately resulting in cell death [10]. Consequently, the design of molecules aiming at disturbing DNA's biological activity has been explored extensively [11][12][13]. DNA-protein recognition processes typically take place in the major groove of the double helix, through supramolecular contacts; these interactions usually occur with specific protein-surface motifs like helixturn-helix motifs, zinc fingers, zipper motifs, β sheets or β hairpins [14,15].…”