Samantha J. Carrington

Design strategies to improve the sensitivity of photoactive metal carbonyl complexes (photoCORMs) to visible light and their potential as CO-donors to biological targets.

The recent surprising discovery of the beneficial effects of carbon monoxide (CO) in mammalian physiology has drawn attention toward site-specific delivery of CO to biological targets. To avoid difficulties in handling of this noxious gas in hospital settings, researchers have focused their attention on metal carbonyl complexes as CO-releasing molecules (CORMs). Because further control of such CO delivery through light-triggering can be achieved with photoactive metal carbonyl complexes (photoCORMs), we and other groups have attempted to isolate such complexes in the past few years. Typical metal carbonyl complexes release CO when exposed to UV light, a fact that often deters their use in biological systems. From the very beginning, our effort therefore was directed toward identifying design principles that could lead to photoCORMs that release CO upon illumination with low-power (5-15 mW/cm(2)) visible and near-IR light. In our work, we have utilized Mn(I), Re(I), and Ru(II) centers (all d(6) ground state configuration) to ensure overall stability of the carbonyl complexes. We also hypothesized that transfer of electron density from the electron-rich metal centers to π* MOs of the ligand frame via strong metal-to-ligand charge transfer (MLCT) transitions in the visible/near-IR region would weaken metal-CO back-bonding and promote rapid CO photorelease. This expectation has been realized in a series of carbonyl complexes derived from a variety of designed ligands and smart choice of ligand/coligand combinations. Several principles have emerged from our systematic approach to the design of principal ligands and the choice of auxiliary ligands (in addition to the number of CO) in synthesizing these photoCORMs. In each case, density functional theory (DFT) and time-dependent DFT (TDDFT) study afforded insight into the dependence of the CO photorelease from a particular photoCORM on the wavelength of light. Results of these theoretical studies indicate that extended conjugation in the principal ligand frames as well as the nature of the donor groups lower the energy of the lowest unoccupied MOs (LUMOs) while auxiliary ligands like PPh3 and Br(-) modulate the energy of the occupied orbitals depending on their strong σ- or π-donating abilities. As a consequence, the ligand/coligand combination dictates the energy of the MLCT bands of the resulting carbonyl complexes. The rate of CO photorelease can be altered further by proper disposition of the coligands in the coordination sphere to initiate trans-effect or alter the extent of π back-bonding in the metal-CO bonds. Addition of more CO ligands blue shift the MLCT bands, while intersystem crossing impedes labilization of metal-CO bonds in several Re(I) and Ru(II) carbonyl complexes. We anticipate that our design principles will provide help in the future design of photoCORMs that could eventually find use in clinical studies.

Photodelivery of CO by designed PhotoCORMs: correlation between absorption in the visible region and metal-CO bond labilization in carbonyl complexes.

The therapeutic potential of photoactive CO‐releasing molecules (photoCORMs) have called for close examination of the roles of the ligand(s) and the central metal atoms on the overall photochemical labilization of the metal–CO bonds. Along this line, we have synthesized four metal complexes, namely, [MnBr(azpy)(CO)3] (1), [Mn(azpy)(CO)3(PPh3)]ClO4 (2), [ReBr(azpy)(CO)3] (3), and [Re(azpy)(CO)3(PPh3)]ClO4 (4), derived from 2‐phenylazopyridine. These complexes were characterized by spectroscopic and crystallographic studies. Although both 1 and 3 exhibit strong metal‐to‐ligand charge‐transfer bands in the 500–600 nm region, only 1 photoreleases CO upon illumination with visible light. Results of theoretical studies were used to gain insight into this surprising difference. Strong spin‐orbit coupling (prominent in heavy metals) appears to promote intersystem crossing to a triplet state in 3, a step that discourages CO release upon illumination with visible light. Slow release of CO from 2 and 4 also indicates that strong σ‐donating ligands, such as Br−, accelerate the rate of CO photorelease relative to π‐acid ligands, such as PPh3.

Synthesis and Characterization of a "Turn-On" photoCORM for Trackable CO Delivery to Biological Targets

A designed photoactive CO releasing molecule (photoCORM), namely, fac-[MnBr(CO)3(pbt)] (1, pbt = 2-(2-pyridyl)benzothiazole), promotes CO-induced death of MDA-MB-231 human breast cancer cells upon illumination with broadband visible light. The CO release from this photoCORM can be tracked by rise in fluorescence within the cellular matrix due to deligation of the pbt ligand. The results of this study suggest the potential of 1 in eradication of cancer cells through CO delivery.

A Theranostic Two-Tone Luminescent PhotoCORM Derived from Re(I) and (2-Pyridyl)-benzothiazole: Trackable CO Delivery to Malignant Cells

A Re(I) carbonyl complex derived from 2-(2-pyridyl)-benzothiazole (pbt), [Re(H2O)(CO)3(pbt)](CF3SO3) (1), rapidly releases CO under low-power UV illumination. CO photorelease from 1 is accompanied by a change in luminescence from orange to deep blue. These two distinct luminescence signals have been successfully employed to track (a) the entry of the pro-drug 1 into cancer cells and (b) the end of the CO (drug) delivery step within the target.

Synthesis, Structures, and CO Release Capacity of a Family of Water-Soluble PhotoCORMs: Assessment of the Biocompatibility and Their Phototoxicity toward Human Breast Cancer Cells

Two manganese(I) carbonyl complexes derived from 2-(pyridyl)benzothiazole (pbt) and 1,10-phenanthroline (phen) release carbon monoxide (CO) under low-power broad-band visible-light illumination. CO photorelease from [Mn(CO)3(pbt)(PTA)]CF3SO3 (1, where PTA = 1,3,5-triaza-7-phosphaadamantane) is accompanied by an emergence of a strong fluorescence around 400 nm from almost nonfluorescent preirradiated 1. However, [Mn(CO)3(phen)(PTA)]CF3SO3 (2) showed no such phenomenon upon prolonged illumination under similar experimental conditions. The two analogous rhenium(I) complexes, namely, [Re(CO)3(pbt)(PTA)]CF3SO3 (3) and [Re(CO)3(phen)(PTA)]CF3SO3 (4), have also been synthesized and characterized to compare their photo properties with the manganese congeners. Complexes 3 and 4 exhibit moderate CO release upon irradiation with low-power UV light. All four complexes are highly soluble in anaerobic/aerobic aqueous media and are also considerably more stable when kept under dark conditions. The inherently luminescent rhenium complex 3 was utilized to demonstrate cellular internalization of these types of compounds by MDA-MB-231 (human breast cancer) cells, while the two biocompatible manganese(I) complexes (1 and 2) have been applied to assess the cell viability of these malignant cells upon CO delivery.

Differences in the CO photolability of cis- and trans-[RuCl2(azpy)(CO)2] complexes: Effect of metal-to-ligand back-bonding

Abstract Reaction of [RuCl2(CO)3]2 with 2-phenylazopyridine (azpy) in methanolic solution affords cis-[RuCl2(azpy)(CO)2] (1) and trans-[RuCl2(azpy)(CO)2] (2) depending on the temperature of the reaction mixture. In both complexes, the two CO ligands are cis to each other. Competition in π backbonding labilizes CO trans to the azo-N (N3) in 2 and increases the rate of CO photorelease of 2 (the trans isomer) compared to 1 (the cis isomer).

Attenuation of Antioxidant Capacity in Human Breast Cancer Cells by Carbon Monoxide Through Inhibition of Cystathionine β-synthase Activity: Implications in Chemotherapeutic Drug Sensitivity

Drug resistance is a major impediment to effective treatment of breast cancer. Compared to normal cells, cancer cells have an increased antioxidant potential due to an increased ratio of reduced to oxidized glutathione (GSH/GSSG). This is known to confer therapeutic resistance. Here, we have identified a mechanism, unique to breast cancer cells, whereby cystathionine β-synthase (CBS) promotes elevated GSH/GSSG. Lentiviral silencing of CBS in human breast cancer cells attenuated GSH/GSSG, total GSH, nuclear factor erythroid 2-related factor 2 (Nrf2), and processes downstream of Nrf2 that promote GSH synthesis and regeneration of GSH from GSSG. Carbon monoxide (CO) reduced GSH/GSSG in three breast cancer cell lines by inhibiting CBS. Furthermore, CO sensitized breast cancer cells to doxorubicin. These results provide insight into mechanism(s) by which CBS increases the antioxidant potential and the ability for CO to inhibit CBS activity to alter redox homeostasis in breast cancer, increasing sensitivity to a chemotherapeutic.