Intraligand Excited States Turn a Ruthenium Oligothiophene Complex into a Light-Triggered Ubertoxin with Anticancer Effects in Extreme Hypoxia

Abstract

Ru­(II) complexes that undergo photosubstitution reactions from triplet metal-centered (3MC) excited states are of interest in photochemotherapy (PCT) due to their potential to produce cytotoxic effects in hypoxia. Dual-action systems that incorporate this stoichiometric mode to complement the oxygen-dependent photosensitization pathways that define photodynamic therapy (PDT) are poised to maintain antitumor activity regardless of the oxygenation status. Herein, we examine the way in which these two pathways influence photocytotoxicity in normoxia and in hypoxia using the [Ru­(dmp)2(IP-nT)]2+ series (where dmp = 2,9-dimethyl-1,10-phenanthroline and IP-nT = imidazo­[4,5-f]­[1,10]­phenanthroline tethered to n = 0–4 thiophene rings) to switch the dominant excited state from the metal-based 3MC state in the case of Ru-phen–Ru-1T to the ligand-based 3ILCT state for Ru-3T and Ru-4T. Ru-phen–Ru-1T, having dominant 3MC states and the largest photosubstitution quantum yields, are inactive in both normoxia and hypoxia. Ru-3T and Ru-4T, with dominant 3IL/3ILCT states and long triplet lifetimes (τTA = 20–25 μs), have the poorest photosubstitution quantum yields, yet are extremely active. In the best instances, Ru-4T exhibit attomolar phototoxicity toward SKMEL28 cells in normoxia and picomolar in hypoxia, with phototherapeutic index values in normoxia of 105–1012 and 103–106 in hypoxia. While maximizing excited-state deactivation through photodissociative 3MC states did not result in bonafide dual-action PDT/PCT agents, the study has produced the most potent photosensitizer we know of to date. The extraordinary photosensitizing capacity of Ru-3T and Ru-4T may stem from a combination of very efficient 1O2 production and possibly complementary type I pathways via 3ILCT excited states.

Chalcogen Effects in the Photophysical Properties of Dimethylamino-1,8-naphthalimide Dyes Revealed by DFT Investigation

“… 13 Compared to chemotherapy, its use in anticancer therapy produces less side effects, and its high selectivity is enhanced by an invoked immune response which causes a mixture of apoptotic and necrotic cell death. 6 , 7 For these reasons, basic and applied research aimed at proposing new drugs for PDT treatment has increased considerably over the last three decades, 14 − 24 also with the aim of overcoming some of the most important limitations of current PDT, namely hypoxia and poor light penetration, focusing in particular on metallic dyes to abandon the use of traditional tetrapyrrolic structures. 16 , 24 …”

“…6 , 7 For these reasons, basic and applied research aimed at proposing new drugs for PDT treatment has increased considerably over the last three decades, 14 − 24 also with the aim of overcoming some of the most important limitations of current PDT, namely hypoxia and poor light penetration, focusing in particular on metallic dyes to abandon the use of traditional tetrapyrrolic structures. 16 , 24 …”

A multiscale free energy method reveals an unprecedented photoactivation of a bimetallic Os(ii)–Pt(ii) dual anticancer agent

“…The used protocol has been extensively validated previously. 12,[15][16][17]36 All the calculations were performed by using the Gaussian 16 program. 37 Spin-Orbit Coupling computations.…”

“…6,7 In recent years, remarkable advances have been made toward the design of next-generation PS (sometimes referred as fourthgeneration) able to display a multiple reactivity against cancer and conceived with the aim to tackle the current limitations of PDT in the clinic. 8 In this field, Ru(II)-polypyridil complexes [9][10][11][12] are receiving a growing attention especially since the McFarland's first Ru(II)-complex TLD-1433 has entered phase II clinical trials for the treatment of non-muscle invasive bladder cancer. [13][14] That compound also displays a promising TypeI/TypeII dual photoreactivity exerting its phototoxicity at a. Dipartimento di Chimica e Tecnologie Chimiche, Università della Calabria, Arcavacata di Rende 87036, Italy b. Departament de Química Física, Universitat de València, Burjassot 46100, Spain Electronic Supplementary Information (ESI) available: [NTOs for the singlet states, HOMO and LUMO orbitals, M06 and ZORA-M06 excitation energies, benchmark for the Pt-Cl bond breaking, QM/MM Mulliken spin densities, a sensitivity analysis of the PMF integration limits, histogram of the Pt-O distances collected in the umbrella sampling technique, and umbrella sampling windows and complete simulation times.].…”

Spatial and Temporal Resolution of the Oxygen-Independent Photoinduced DNA Interstrand Cross-Linking by a Nitroimidazole Derivative

“… 15 − 17 Many types of photosensitizers with very diverse chemical structures have been developed and tested in the last years to overcome the hypoxia issue. 13 , 18 − 23 In this context, the induction of biological damages must operate, at least partially, without the intervention of oxygen, 18 , 20 leading to complex mixtures of chemical and photochemical events whose spatial and temporal disentanglement is challenging.…”