A Semi‐Automated, High‐Throughput Approach for the Synthesis and Identification of Highly Photo‐Cytotoxic Iridium Complexes

Abstract

The discovery of new compounds with pharmacological properties is usually a lengthy, laborious and expensive process. Thus, there is increasing interest in developing workflows that allow for the rapid synthesis and evaluation of libraries of compounds with the aim of identifying leads for further drug development. Herein, we apply combinatorial synthesis to build a library of 90 iridium(III) complexes (81 of which are new) over two synthesise‐and‐test cycles, with the aim of identifying potential agents for photodynamic therapy. We demonstrate the power of this approach by identifying highly active complexes that are well‐tolerated in the dark but display very low nM phototoxicity against cancer cells. To build a detailed structure‐activity relationship for this class of compounds we have used density functional theory (DFT) calculations to determine some key electronic parameters and study correlations with the experimental data. Finally, we present an optimised semi‐automated synthesise‐and‐test protocol to obtain multiplex data within 72 hours.

Molecular engineering of metal-based photosensitizers with narrow band gap for efficient photodynamic therapy

“…Transition metal-based agents are a class of promising photosensitizers due to their inherent merits, such as high intersystem crossing efficiency, unique rigid skeletons, subcellular organelle-targeting capability, and so on. 1–8 Besides, the rich excited-state electronic configurations endow metal-based agents with tunable photo-physicochemical properties and functions via molecular engineering. 9–12 The notable example is TLD1433 with a long-lived oligothiophene-based triplet intraligand charge transfer ( 3 ILCT) state, which is currently undergoing phase II clinical trials for nonmuscle-invasive bladder cancer photodynamic therapy.…”