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

Kench, Timothy; Rahardjo, Arielle; Terrones, Gianmarco G.; Bellamkonda, Adinarayana; Maher, Thomas E.; Storch, Marko; Kulik, Heather J.; Vilar, Ramon

doi:10.1002/anie.202401808

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

Journal Article · 10 March 2024 · Angewandte Chemie (International Edition)

DOI: https://doi.org/10.1002/anie.202401808 · OSTI ID:2322595

^[1]; Rahardjo, Arielle ^[1];

^[2]; Bellamkonda, Adinarayana ^[1];

^[3]; Storch, Marko ^[4];

^[5];

^[3]

Department of Chemistry Imperial College London White City Campus W12 0BZ London UK
Department of Chemical Engineering Massachusetts Institute of Technology 02139 Cambridge MA USA
Department of Chemistry Imperial College London White City Campus W12 0BZ London UK, Institute of Chemical Biology Imperial College London White City Campus W12 0BZ London UK
Department of Infectious Disease Imperial College London South Kensington Campus SW7 2AZ London UK, London Biofoundry Imperial College Translation and Innovation Hub W12 0BZ London UK
Department of Chemical Engineering Massachusetts Institute of Technology 02139 Cambridge MA USA, Department of Chemistry Massachusetts Institute of Technology 02139 Cambridge MA USA

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.

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Research Organization:: Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)

Sponsoring Organization:: USDOE; USDOE Office of Science (SC)

Grant/Contract Number:: SC0024174

OSTI ID:: 2322595

Journal Information:: Angewandte Chemie (International Edition), Journal Name: Angewandte Chemie (International Edition) Journal Issue: 18 Vol. 63; ISSN 1433-7851

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: Germany

Language:: English

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