Synthesis and Photobiological Activity of Ru(II) Dyads Derived from Pyrrole-2-carboxylate Thionoesters

Abstract

The synthesis and characterization of a series of heteroleptic ruthenium(II) dyads derived from pyrrole-2-carboxylate thionoesters are reported. Ligands bearing a conjugated thiocarbonyl group were found to be more reactive toward Ru(II) complexation compared to analogous all-oxygen pyrrole-2-carboxylate esters, and salient features of the resulting complexes were determined using X-ray crystallography, electronic absorption, and NMR spectroscopy. Selected complexes were evaluated for their potential in photobiological applications, whereupon all compounds demonstrated in vitro photodynamic therapy effects in HL-60 and SK-MEL-28 cells, with low nanomolar activities observed, and exhibited some of the largest photocytotoxicity indices to date (>2000). Importantly, the Ru(II) dyads could be activated by relatively soft doses of visible (100 J cm, 29 mW cm) or red light (100 J cm, 34 mW cm), which is compatible with therapeutic applications. Some compounds even demonstrated up to five-fold selectivity for malignant cells over noncancerous cells. These complexes were also shown to photocleave, and in some cases unwind, DNA in cell-free experiments. Thus, this new class of Ru(II) dyads has the capacity to interact with and damage biological macromolecules in the cell, making them attractive agents for photodynamic therapy.

Topoisomerase I inhibitory and photocleavage activity of non‐dppz DNA ‘light switches’ based on ruthenium complexes containing nitro group

“…Recent studies suggest that ruthenium‐based compounds can act as potential photosensitizers for photodynamic therapy (PDT), since they can produce reactive oxygen species (ROS) by light activation, and such ROS lead to cell apoptosis . In the present case, the DNA cleaving abilities of the two complexes were assessed using argose gel electrophoresis upon treatment with light at 365 nm.…”

Applications of Ruthenium Complex in Tumor Diagnosis and Therapy

“…For example, KP1339, the sodium salt of KP1019, which is currently in clinical studies, has better water solubility and transmembrane absorption efficiency than KP1019 ( Bytzek et al, 2016 ). The Ru(II) complex TLD1443, as a promising photosensitizer, significantly enhanced the efficacy of phototherapy and produced less toxicity in vitro and in vivo ( Smithen et al, 2017 ).…”

“…Using the potent photophysical and chemical properties of Ru(II) complex, researchers have synthesized a photosensitizer TLD1443 (Figure 1E ), which has immensely enhanced photodynamic therapy ( Zeng et al, 2017a ). It has a significant therapeutic efficacy on bladder cancer and is currently in phase II clinical trials ( Smithen et al, 2017 ).…”

Bis[Pyrrolyl Ru(II)] Triads: a New Class of Photosensitizers for Metal-Organic Photodynamic Therapy

“…Initial studies concerned the design and synthesis of a monopyrrolic ligand bearing extended conjugation, with intent to optimize the synthetic protocol. 67,78 As such, N-Boc-2-vinyl pyrrole (1a) 79 was synthesized in a two-step procedure from 2-formyl pyrrole and, following a modified procedure, 80 was successfully employed as a Heck substrate with bromobenzene, providing the in situ-deprotected styryl-pyrrole 2a in good yield (64%, Scheme 1). Employing 1,4-dibromobenzene as the aryl halide along with 2 equivalents of vinylpyrrole 1a resulted in the conjugated, symmetric bis(pyrrole) 2b in high yield (86%).…”

“…Red-shifts of almost 100 nm for the lowest-energy 1 MLCT transitions (relative to the corresponding Ru(II) systems containing neutral diimine ligands) agrees with what we have previously observed for Ru(II) complexes bearing anionic cyclometalating ligands, such as thionoester-substituted pyrrolides and deprotonated phenylpyridines. 55,57,67,78 Presumably, this shift of the 1 MLCT absorption band is a direct result of a concomitant increase in the energy of the Ru(d) orbitals arising from the strong N- ( 1 ) donation of the pyrrolide nitrogen.…”