In this paper, Dr. McFarland and colleagues explore how the structure of the
TLD1433 molecule leads to increased photocytoxicity.
TLD1433, (
Ru-ip-3T in the diagram), has 3 thiophene rings attached to the ligand. Photocytoxicity increases as the number of thiophene rings increases and 3 seems to be the optimum number.
It Takes Three to Tango: The Length of the Oligothiophene Chain Determines the Nature of the LongLived Excited State and the Resulting Photocytotoxicity of a Ruthenium(II) Photodrug Avinash Chettri John A. Roque III Kilian R. A. Schneider Houston D. Cole Dr. Colin G. Cameron Prof.Dr. Sherri A. McFarland Prof.Dr. Benjamin Dietzek
First published: 19 January 2021
Abstract
TLD1433 is the first Ru(II) complex to be tested as a photodynamic therapy agent in a clinical trial. In this contribution we study TLD1433 in the context of structurallyrelated Ru(II)imidozo[4,5f][1,10]phenanthroline (ip) complexes appended with thiophene rings to decipher the unique photophysical properties which are associated with increasing oligothiophene chain length. Substitution of the ip ligand with ter or quaterthiophene changes the nature of the longlived triplet state from metaltoligand chargetransfer to 3ππ* character. The addition of the third thiophene thus presents a critical juncture which not only determines the photophysics of the complex but most importantly its capacity for O2 generation and hence the potential of the complex to be used as a photocytotoxic agent.
Recent developments highlight Ru(II) polypyridyl complexes with πexpanded ligands as a promising class of new compounds for photodynamic therapy (PDT).1-11 By extending the pyridyl ligands with organic chromophores, lowlying intraligand (IL) excited states become accessible, and these appear to be crucial to the photophysical function of these systems.12
Our TLD1433 (Ruip3T in this manuscript, Figure1) is a compound of this type, having three appended thiophene rings, and has the distinction of being the first Ru(II)based PDT agent ever to enter a human clinical trial;1, 10, 13 Ruip3T is currently being tested in a Phase II PDT trial for noninvasive bladder cancer (ClinicalTrials.gov identifier: NCT03945162). 
In vitro studies have been previously conducted on the
RuipnT series of compounds, where
n indicates the number of appended thiophene rings attached to an imidazo[4,5f][1,10]phenanthroline (ip) ligand (Figure1). Visible light illumination of SKMEL28 cancer cells treated with the compounds in the series led to increased photocytotoxicity with increasing n. The light EC50 values (effective concentration to reduce cell viability by 50 %) were 0.72μM, 0.26μM, 1.9×10−4μM and 2.8×10−9μM for Ruip1T to Ruip4T, respectively (Figure2d)1 and the corresponding PI values (ratio of dark to light EC50) were 225, 434, 7.2×105 and 45×109 respectively.
While these previous findings demonstrate a clear correlation between the length of the thiophene chain and the invitro phototherapeutic effects, herein we present the key photophysical properties of the compounds in the RuipnT series that could be responsible for the observed photocytotoxicity. ....................................................................