20.500.12556/RUL-183683 Načrtovanje, sinteza in vrednotenje kvarternih dušikovih heterociklov kot fragmentov za ciljanje mitohondrijev raziskovalni podatki, obravnavani v doktorskem delu Design, synthesis, and evaluation of quaternary nitrogen heterocycles as mitochondria-targeting moieties research data underlying the doctoral dissertation Pretekle raziskave fragmentov za ciljanje mitohondrijev (MTM) so bile omejene, saj je bilo vloženega zelo malo dela v razvoj alternativ v trenutno uveljavljenemu standardu, trifenilfosfonijevemu (TPP⁺) fragmentu, za katerega je bilo dokazano, da poleg sposobnosti ciljanja mitohondrijev izkazuje tudi lastno biološko aktivnost. Poleg tega razvoj derivatov TPP⁺ ali drugih, nefosfonijevih MTM doslej praviloma ni potekal sistematično oziroma po enotni metodologiji, ki bi v isti raziskavi ovrednotila sposobnost ciljanja mitohondrijev, združljivost z različnimi funkcionalnimi tovori ter lastno biološko aktivnost posameznih fragmentov. Namen doktorske raziskave je bil načrtovati, sintetizirati in ovrednotiti širok nabor MTM ter razviti standardiziran pristop k njihovi biološki karakterizaciji z uporabo treh vrst tovora: fluorescenčnega tovora (mikroskopske analize in pretočna citometrija za določanje celičnega privzema in mitohondrijske lokalizacije spojin), funkcionalnega tovora (ocena aktivnosti na tarči ter študije in vitro in in vivo) ter »inertnega« tovora (hidrokarbonske verige za oceno lastne biološke aktivnosti MTM). Teoretični pregled področja ciljanja mitohondrijev ter sodobnih pristopov k razvoju novih MTM je predstavljen v preglednem članku tipa Perspective z naslovom Lipophilic Cations as Mitochondria-Targeting Moieties: Recent Progress and Design Principles for Medicinal Chemistry. Članek prvi predlaga sistematičen in standardiziran tripartitni pristop k razvoju MTM, kot je opisan zgoraj. V izvirnem znanstvenem članku Lipophilic Pyridinium Cations as Biocompatible Mitochondria-Targeting Moieties je bilo ugotovljeno, da je 3,5-difenilpiridinijev kation (DPPy⁺) učinkovita alternativa trifenilfosfonijevemu kationu (TPP⁺), saj omogoča učinkovito ciljanje mitohondrijev ob manjši intrinzični mitohondrijski toksičnosti ter izboljšani selektivnosti mitohondrijsko usmerjenega protirakavega konjugata. Podatki, naloženi v repozitorij RUL, vključujejo strukture novih konjugatov MTM s tremi vrstami tovora: fluorescenčnim tovorom (sprva je bilo uporabljeno fluoresceinsko jedro, kasneje pa v laboratoriju razvito fluorescenčno barvilo z velikim Stokesovim zamikom, poimenovano Spidye), funkcionalnim tovorom (zaviralec Kv1.3 na osnovi spojine PAP-1 ter zaviralec NCLX na osnovi spojine CGP-37157) in »inertnim« tovorom (pretežno butilne in decilne verige). Podatkovni niz vključuje tudi strukture spojin v obliki objektov ChemDraw in zapisov SMILES, popolno karakterizacijo spojin (UPLC, HRMS in NMR), njihove fizikalno-kemijske lastnosti (LogD₇.₄ in termodinamska topnost) ter rezultate biološke karakterizacije (testa JC-10 in resazurinskega testa). Poleg tega so vključeni računsko določeni parametri sintetiziranih spojin (Vs,max), MPI, Hirschfeldov naboj, ΔGsolv, volumen in površina). 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. ciljanje mitohondrijev ionski kanali rak organelno usmerjena terapija mitochondria targeting ion channels cancer organelle-targeted therapy true false false Slovenski jezik Angleški jezik Neznano 2026-06-17 09:56:16 2026-06-26 21:00:30 2026-06-27 04:15:12 0000-00-00 00:00:00 2026 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 2027-06-17 PREBERI_ME.txt PREBERI_ME.txt PREBERI ME 1 4EA7AC504025E6DF3D510BF2ED0917D3 426abf147f373930e455981f18f877e682991c10b5ac3148b1f9a23e20cfd983 189031c3-6a22-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=235815 IC50__VSE_spojine_FFA_14.6.2026..xlsx IC50__VSE_spojine_FFA_14.6.2026..xlsx IC50 vse spojine 1 B5688897A744ED4929E0DC31159B1CC2 5f8f5dc687806ba49900431d89a08ffd257a6ab0bdcf003c2f8f5a191c60bfa0 5f1a14bc-6a22-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=235817 SMILES_Tabela_z_vsemi_spojinami_+_COLO,_NHLF,_LogD,_TS.xlsx SMILES_Tabela_z_vsemi_spojinami_+_COLO,_NHLF,_LogD,_TS.xlsx SMILES Tabela z vsemi spojinami + COLO, NHLF, LogD, TS 1 8BDCA542B3341ED0209DBB964FDB9AAB 40a7acf46573ac7db6e484599133cbfa25b15550478b7fef935b8a903dfcc616 87be9fc6-6a22-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=235818 STRUKTURE_SPOJIN_UL-EID-1-124.xlsx STRUKTURE_SPOJIN_UL-EID-1-124.xlsx Strukture spojin UL-EID-1-124 1 EA84D066DDD32B269C078A3123D7A2B2 407f9f9f4e491b97f7e7ec53a74e08b28857e4c22e93aaf7dfe7dabdf2c150ff 9912d313-6a22-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=235819 table_analysis_with_volume_area.csv table_analysis_with_volume_area.csv Table analysis with volume area 1 7B94F5FD8365202C39AD99410D2D2580 43395b619f2ced8a0121630a3ac8c3533c5ab3b7fc228f5d1de5d819039b7115 9ec22264-6a22-11f1-9b0d-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=235820 Fakulteta za farmacijo Poskus: Laboratorij 0 0 0