Effects of the Bidentate Ligand on the Photophysical Properties, Cellular Uptake, and (Photo)cytotoxicity of Glycoconjugates Based on the [Ru(tpy)(NN)(L)]²⁺ Scaffold

Abstract

Ruthenium polypyridyl complexes have received widespread attention as potential chemotherapeutics in photodynamic therapy (PDT) and in photochemotherapy (PACT). Here, we investigate a series of sixteen ruthenium polypyridyl complexes with general formula [Ru(tpy)(N−N)(L)]+/2+ (tpy=2,2′:6′,2′′‐terpyridine, N−N=bpy (2,2′‐bipyridine), phen (1,10‐phenanthroline), dpq (pyrazino[2,3‐f][1,10]phenanthroline), dppz (dipyrido[3,2‐a:2′,3′‐c]phenazine, dppn (benzo[i]dipyrido[3,2‐a:2′,3′‐c]phenazine), pmip (2‐(4‐methylphenyl)‐1H‐imidazo[4,5‐f][1,10]phenanthroline), pymi ((E)‐N‐phenyl‐1‐(pyridin‐2‐yl)methanimine), or azpy (2‐(phenylazo)pyridine), L=Cl− or 2‐(2‐(2‐(methylthio)ethoxy)ethoxy)ethyl‐β‐d‐glucopyranoside) and their potential for either PDT or PACT. We demonstrate that although increased lipophilicity is generally related to increased uptake of these complexes, it does not necessarily lead to increased (photo)cytotoxicity. However, the non‐toxic complexes are excellent candidates as PACT carriers.

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

“…The monodentate ligand in this cage can easily be replaced with a host of different nitrile‐substituted small molecule drugs or inhibitors . Additionally, due to its tridentate coordination motif, the tpy ligand also provides a convenient synthetic pathway to allow for the facile installation of a variety of bidentate ancillary ligands that can serve to generate reactive oxygen species such as 1 O 2 , provide additional steric bulk,,, further red‐shift the absorption of the complex, or interact with biological targets such as DNA …”

“…[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. This absorption range is important for the tissue penetration of light in vivo, which is highly wavelength dependent.…”

“…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. This absorption range is important for the tissue penetration of light in vivo, which is highly wavelength dependent.…”

Red‐Light‐Controlled Release of Drug–Ru Complex Conjugates from Metallopolymer Micelles for Phototherapy in Hypoxic Tumor Environments

“…Thus, PACT represents a promising approach against hypoxic tumors. We and other groups have shown photoinhibition of tumor cell growth using photoactivatable Ru complexes based on combined PDT and PACT . True PACT in hypoxic cancer cells is difficult to achieve due to insufficient anticancer efficiencies of uncaged ligands and Ru species.…”

Fighting against Drug‐Resistant Tumors using a Dual‐Responsive Pt(IV)/Ru(II) Bimetallic Polymer

“…In particular, some Ru(II) complexes can generate 1 O 2 and undergo ligand substitution under light irradiation. [25][26][27][28][29][30] Photocaged Ru(II) complexes are usually nontoxic to nonirradiated tissues and can become toxic in cancer cells through phot oactivation. [24,29] This photoactivation strategy can improve selectivity in cancer treatment.…”