New generation of smart mitochondrial staining agents exploiting diketopyrrolopyrroles chemistries Hannah Crawford 1 , M. Dimitriadi 1 , M.T. Cook 2 , J.P. Bassin 1 , C.J. McHugh 3 , T.F. Abelha 4 , and J. Calvo-Castro 1 1 University of Hertfordshire, School of Life and Medical Sciences, AL109AB, Hatfield (UK), 2 University College London, School of Pharmacy, 29–39 Brunswick Square, WC1N 1AX, London (UK), 3 School of Computing, Engineering and Physical Sciences, University of the West of Scotland, Paisley Campus, Paisley, PA1 2BE, Scotland (UK), 4 Department of Pharmacology, Toxicology and Therapeutic Chemistry Faculty of Pharmacy and Food Science, University of Barcelona, 08028, Barcelona (Spain) Mitochondria are responsible for key processes including generation of adenosine triphosphate. However, there is a known association between mitochondrial DNA mutations and the onset of human diseases. 1 A pressing need remains to develop novel, neutral superior imaging agents which exhibit specific organelle bioaccumulation without the negative aspects of those currently available. 2 Among the different chemistries exploited for this purpose, diketopyrrolopyrroles, a class of conjugated organic materials comprising an electron deficient p-conjugated bicyclic dilactam unit, have attracted increasing interest on account of their large brightness and excellent photostability. 3 Further refinements through chemical modifications, typically at the 3 and/or 6 positions of the core ring (R 1 and R 2 in Scheme 1), has enabled a plethora of derivatives to be utilised in a wide range of applications. Motivated by this and the recent development of a neutral probe for selective mitochondrial imaging, 4 a diketopyrrolopyrrole core has been exploited in the design and synthesis of a novel toolbox of neutral probes. To refine the photophysical properties, different substituents, R 1 and R 2, have been asymmetrically introduced to increase the polarity of the dye whereas the addition of symmetrical groups, R 3 , improve the solubility of the dye. The substituents for R 3 have also been varied to gain an understanding on their effect on facilitating mitochondrial accumulation. Of importance is the neutrality of the probes and thus, all molecules do not exhibit a formal charge. A toolbox of novel molecules were synthesised and characterised, including the evaluation of the photophysical and electrochemical properties both experimentally and computationally. As a result, we report an interesting series of diketopyrrolopyrrole-based architectures. Overall, the synthesised systems were characterised by strong brightness and excellent photostability which represent key parameters for their application. References 1. C. Lawless, L. Greaves, A. K. Reeve, D. M. Turnbull and A. E. Vincent, Open Biol. , 2020, 10 , 1–12.Z. Xu and L. Xu, Chem. Commun. , 2016, 52 , 1094–1119.H. 2. Crawford, M. Dimitriadi, J. Bassin, M. T. Cook, T. F. Abelha and J. Calvo‐Castro, Chemistry A European J , 2022, 28 , 1–33.T. 3. F. Abelha, G. Morris, S. M. Lima, L. H. C. Andrade, A. J. McLean, C. Alexander, J. Calvo‐Castro and C. J. McHugh, Chem. Eur. J. , 2020, 26 , 3173–3180.
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