Previous research on mitochondria-targeting moieties (MTMs) has been limited, as relatively little effort has been devoted to developing alternatives to the current gold standard, the triphenylphosphonium (TPP⁺) moiety, which has been shown to possess intrinsic biological activity independent of its mitochondrial targeting properties. Furthermore, the development of TPP⁺ derivatives or other phosphonium-free MTMs has generally not been carried out in a systematic or standardized manner that evaluates mitochondrial targeting efficiency, compatibility with functional cargo, and intrinsic biological activity within the same study. The aim of this doctoral research was to design, synthesize, and characterize a broad range of MTMs and to establish a standardized approach to their biological evaluation using three types of cargo: fluorescent cargo (microscopy and flow cytometry studies of cellular uptake and mitochondrial localization), functional cargo (assessment of on-target activity, including in vitro and in vivo studies), and "inert" cargo (hydrocarbon chains used to assess the intrinsic biological activity of the MTMs).
A historical overview of the theoretical background of mitochondrial targeting, together with recent advances in the development of novel MTMs, is presented in the Perspective article entitled Lipophilic Cations as Mitochondria-Targeting Moieties: Recent Progress and Design Principles for Medicinal Chemistry. This review is the first to propose a systematic and standardized tripartite approach to MTM development as described above. In the original research article Lipophilic Pyridinium Cations as Biocompatible Mitochondria-Targeting Moieties, it was demonstrated that 3,5-diphenylpyridinium (DPPy⁺) is an effective alternative to triphenylphosphonium (TPP⁺), providing efficient mitochondrial targeting with lower intrinsic mitochondrial toxicity and improved selectivity of a mitochondria-targeted anticancer conjugate.
The dataset deposited in the RUL repository comprises the structures of novel MTM conjugates incorporating three different types of cargo: fluorescent cargo (initially based on a fluorescein scaffold and later replaced by the in-house developed large-Stokes-shift fluorescent dye Spidye), functional cargo (a PAP-1-derived Kv1.3 inhibitor and an NCLX inhibitor derived from CGP-37157), and "inert" cargo (primarily butyl and decyl chains). The dataset further includes compound structures provided as ChemDraw files and SMILES strings, complete compound characterization (UPLC, HRMS, and NMR), physicochemical characterization (LogD₇.₄ and thermodynamic solubility), and biological characterization (JC-10 and resazurin assays). In addition, computationally derived molecular descriptors are provided for all synthesized compounds, including Vs,max; molecular polarity index (MPI), Hirschfeld charge, ΔGsolv, molecular volume, and molecular surface area.
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