A Red‐Light‐Activated Ruthenium‐Caged NAMPT Inhibitor Remains Phototoxic in Hypoxic Cancer Cells

Abstract

We describe two water‐soluble ruthenium complexes, [1]Cl2 and [2]Cl2, that photodissociate to release a cytotoxic nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with a low dose (21 J cm−2) of red light in an oxygen‐independent manner. Using a specific NAMPT activity assay, up to an 18‐fold increase in inhibition potency was measured upon red‐light activation of [2]Cl2, while [1]Cl2 was thermally unstable. For the first time, the dark and red‐light‐induced cytotoxicity of these photocaged compounds could be tested under hypoxia (1 % O2). In skin (A431) and lung (A549) cancer cells, a 3‐ to 4‐fold increase in cytotoxicity was found upon red‐light irradiation for [2]Cl2, whether the cells were cultured and irradiated with 1 % or 21 % O2. These results demonstrate the potential of photoactivated chemotherapy for hypoxic cancer cells, in which classical photodynamic therapy, which relies on oxygen activation, is poorly efficient.

New RuII Scaffold for Photoinduced Ligand Release with Red Light in the Photodynamic Therapy (PDT) Window

“…Related Ru II complexes with the tridentate ligand tpy (tpy=2,2′:6′,2“‐terpyridine) have also proven useful towards ligand exchange for PCT applications . The tpy ligand serves to provide steric distortion around the metal center through its tighter bite angles, 78° and 157° in [Ru(tpy) 2 ] 2+ , as compared to 90° and 180° in an ideal octahedral geometry .…”

“…These values represent a five‐ to seven‐fold increase in quantum yield while red‐shifting the 1 MLCT maximum by ≈3300 cm −1 . Similar complexes for py dissociation suffered a reduction in quantum yield of three‐ to five‐fold by incorporating 2,2′‐biquinoline (biq) as the bidentate ligand instead of 6,6′‐dimethyl‐bpy; the former was introduced in an effort to shift the absorption of those complexes into the PDT window . This reduction in quantum yield observed for the py complexes is attributed to a change in the lowest energy MLCT state to Ru(dπ)→biq(π*).…”

“…[28][29][30] Related Ru II complexesw ith the tridentate ligand tpy (tpy = 2,2':6',2"-terpyridine) have also provenu seful towards ligand exchange for PCT applications. [31][32][33] The tpy ligand serves to provide steric distortion aroundt he metal centert hrough its tighter bite angles,7 8 8 and 1578 in [Ru(tpy) 2 ] 2 + ,a sc ompared to 908 and 1808 in an ideal octahedral geometry. [34] This distortion lowerst he relative energy of the 3 LF state(s) and resultsi n ar ed-shifto ft he absorption spectrum of the complex as compared to [Ru(bpy) 3 ] 2 + .S imilarly,t he model complex [Ru(tpy)-(bpy)(CH 3 CN)] 2 + possessesa na bsorption spectrum that tails to % 550 nm and photoreleases the CH 3 CN ligand with F 450 = 0.0026(2)i nH 2 O.…”

“…[35] The monodentate ligand in this cage can easily be replaced with ah ost of different nitrile-substituted small molecule drugs or inhibitors. [28,36] Additionally,d ue to its tridentate coordination motif,t he tpy ligand also provides a convenient synthetic pathway to allow for the facile installation of av ariety of bidentate ancillary ligandst hat can serve to generate reactive oxygen speciess uch as 1 O 2 , [37] provide additional steric bulk, [37, 38b,c,e, 39] further red-shift the absorption of [a] L.the complex, [32,39] or interactw ith biological targets such as DNA. [40,41] Ad rawback of polypyridylR u II complexes typically designed for PCT is their lack of or low absorption in the photodynamic therapy (PDT) window, % 600-900nm.…”

Strong Influence of the Ancillary Ligand over the Photodynamic Anticancer Properties of Neutral Biscyclometalated IrIII Complexes Bearing 2‐Benzoazole‐Phenolates

“…The latter strategy is called photoactivated chemotherapy (PACT) and gives rise to chemotherapeutic agents with potential dual activity when both the free ligand and the metal fragment or organic caging exhibit cytotoxic action. [5,6] In particular, the more conventionalO 2 -dependent type II-PDT strategy involves the combination of three essential and separately non-toxic components:aphotochemically active drug (PS), light of suitable wavelength, and the O 2 dissolved in the tissues. [7] Useful light in PDT mustc ombine two requirements:e fficiency in penetration of tissues and high ability in 1 O 2 generation.…”