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As a noncharged group, thiophene presents several advantages from a synthetic point of view, making it easier to incorporate such a side moiety into different molecules. Herein, we confirm the general applicability of the thiophene group as a mitochondrial carrier for drugs and fluorescent markers based on a new concept of nonprotonable, noncharged transporter. We implemented this concept in a medicinal chemistry application by developing an antitumor, metabolic chimeric drug based on the pyruvate dehydrogenase kinase (PDHK) inhibitor dichloroacetate (DCA). The promising features of the thiophene moiety as a noncharged carrier for targeting mitochondria may represent a starting point for the design of new metabolism-targeting drugs.<\/jats:p>","DOI":"10.3390\/pharmaceutics13020254","type":"journal-article","created":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T18:45:00Z","timestamp":1613155500000},"page":"254","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Chimeric Drug Design with a Noncharged Carrier for Mitochondrial Delivery"],"prefix":"10.3390","volume":"13","author":[{"given":"Consuelo","family":"Ripoll","sequence":"first","affiliation":[{"name":"Departamento de Fisicoquimica, Unidad de Excelencia de Qu\u00edmica Aplicada a Biomedicina y Medioambiente, Facultad de Farmacia, Universidad de Granada, Campus Cartuja, 18071 Granada, Spain"}]},{"given":"Pilar","family":"Herrero-Foncubierta","sequence":"additional","affiliation":[{"name":"Departamento de Fisicoquimica, Unidad de Excelencia de Qu\u00edmica Aplicada a Biomedicina y Medioambiente, Facultad de Farmacia, Universidad de Granada, Campus Cartuja, 18071 Granada, Spain"},{"name":"Departamento de Quimica Organica, Unidad de Excelencia de Qu\u00edmica Aplicada a Biomedicina y Medioambiente, Facultad de Ciencias, Universidad de Granada, Campus Fuentenueva, 18071 Granada, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4860-9312","authenticated-orcid":false,"given":"Virginia","family":"Puente-Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Departamento de Fisicoquimica, Unidad de Excelencia de Qu\u00edmica Aplicada a Biomedicina y Medioambiente, Facultad de Farmacia, Universidad de Granada, Campus Cartuja, 18071 Granada, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6128-0884","authenticated-orcid":false,"given":"M. Carmen","family":"Gonzalez-Garcia","sequence":"additional","affiliation":[{"name":"Departamento de Fisicoquimica, Unidad de Excelencia de Qu\u00edmica Aplicada a Biomedicina y Medioambiente, Facultad de Farmacia, Universidad de Granada, Campus Cartuja, 18071 Granada, Spain"}]},{"given":"Delia","family":"Miguel","sequence":"additional","affiliation":[{"name":"Departamento de Fisicoquimica, Unidad de Excelencia de Qu\u00edmica Aplicada a Biomedicina y Medioambiente, Facultad de Farmacia, Universidad de Granada, Campus Cartuja, 18071 Granada, Spain"}]},{"given":"Sandra","family":"Resa","sequence":"additional","affiliation":[{"name":"Departamento de Quimica Organica, Unidad de Excelencia de Qu\u00edmica Aplicada a Biomedicina y Medioambiente, Facultad de Ciencias, Universidad de Granada, Campus Fuentenueva, 18071 Granada, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3252-9174","authenticated-orcid":false,"given":"Jose M.","family":"Paredes","sequence":"additional","affiliation":[{"name":"Departamento de Fisicoquimica, Unidad de Excelencia de Qu\u00edmica Aplicada a Biomedicina y Medioambiente, Facultad de Farmacia, Universidad de Granada, Campus Cartuja, 18071 Granada, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0853-187X","authenticated-orcid":false,"given":"Maria J.","family":"Ruedas-Rama","sequence":"additional","affiliation":[{"name":"Departamento de Fisicoquimica, Unidad de Excelencia de Qu\u00edmica Aplicada a Biomedicina y Medioambiente, Facultad de Farmacia, Universidad de Granada, Campus Cartuja, 18071 Granada, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2920-2960","authenticated-orcid":false,"given":"Emilio","family":"Garcia-Fernandez","sequence":"additional","affiliation":[{"name":"Departamento de Fisicoquimica, Unidad de Excelencia de Qu\u00edmica Aplicada a Biomedicina y Medioambiente, Facultad de Farmacia, Universidad de Granada, Campus Cartuja, 18071 Granada, Spain"}]},{"given":"Mar","family":"Roldan","sequence":"additional","affiliation":[{"name":"GENYO, Pfizer-University of Granada-Junta de Andaluc\u00eda Centre for Genomics and Oncological Research. Avda. Ilustracion 114. PTS, 18016 Granada, Spain"}]},{"given":"Susana","family":"Rocha","sequence":"additional","affiliation":[{"name":"Department of Chemistry, K. U. Leuven, Celestijnenlaan 200F, B-3001 Heverlee, Belgium"}]},{"given":"Herlinde","family":"De Keersmaecker","sequence":"additional","affiliation":[{"name":"Department of Chemistry, K. U. Leuven, Celestijnenlaan 200F, B-3001 Heverlee, Belgium"}]},{"given":"Johan","family":"Hofkens","sequence":"additional","affiliation":[{"name":"Department of Chemistry, K. U. Leuven, Celestijnenlaan 200F, B-3001 Heverlee, Belgium"}]},{"given":"Miguel","family":"Martin","sequence":"additional","affiliation":[{"name":"GENYO, Pfizer-University of Granada-Junta de Andaluc\u00eda Centre for Genomics and Oncological Research. Avda. Ilustracion 114. 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[2nd ed.]."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1007\/s00018-016-2451-3","article-title":"Mitochondrial dynamics as regulators of cancer biology","volume":"74","author":"Trotta","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.cell.2016.07.002","article-title":"Mitochondria and Cancer","volume":"166","author":"Vyas","year":"2016","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1146\/annurev-cellbio-092910-154237","article-title":"Aerobic Glycolysis: Meeting the Metabolic Requirements of Cell Proliferation","volume":"27","author":"Lunt","year":"2011","journal-title":"Ann. Rev. Cell Dev. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1016\/j.bbabio.2017.01.012","article-title":"Mitochondria and cancer chemoresistance","volume":"1858","author":"Guerra","year":"2017","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.cmet.2017.05.016","article-title":"Mitochondrial Dynamics in Regulating the Unique Phenotypes of Cancer and Stem Cells","volume":"26","author":"Chen","year":"2017","journal-title":"Cell Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e1600200","DOI":"10.1126\/sciadv.1600200","article-title":"Fundamentals of cancer metabolism","volume":"2","author":"DeBerardinis","year":"2016","journal-title":"Sci. Adv."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.redox.2017.09.020","article-title":"A review of the basics of mitochondrial bioenergetics, metabolism, and related signaling pathways in cancer cells: Therapeutic targeting of tumor mitochondria with lipophilic cationic compounds","volume":"14","author":"Kalyanaraman","year":"2018","journal-title":"Redox Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/j.bbabio.2010.08.008","article-title":"Approaches for targeting mitochondria in cancer therapy","volume":"1807","author":"Wagle","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1021\/jacs.7b12545","article-title":"A Mitochondria-Specific Fluorescent Probe for Visualizing Endogenous Hydrogen Cyanide Fluctuations in Neurons","volume":"140","author":"Long","year":"2018","journal-title":"J. Am. Chem. Soc."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1021\/acs.analchem.6b04385","article-title":"Single Fluorescent Probe for Dual-Imaging Viscosity and H2O2 in Mitochondria with Different Fluorescence Signals in Living Cells","volume":"89","author":"Ren","year":"2017","journal-title":"Anal. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"374","DOI":"10.3109\/10715762.2015.1014813","article-title":"Imaging mitochondrial reactive oxygen species with fluorescent probes: Current applications and challenges","volume":"49","author":"Zhang","year":"2015","journal-title":"Free Radical Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"15614","DOI":"10.1039\/C5CC07098H","article-title":"Development and sensing applications of fluorescent motifs within the mitochondrial environment","volume":"51","author":"Kumar","year":"2015","journal-title":"Chem. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"13658","DOI":"10.1002\/anie.201510721","article-title":"Discerning the Chemistry in Individual Organelles with Small-Molecule Fluorescent Probes","volume":"55","author":"Xu","year":"2016","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ripoll, C., Roldan, M., Contreras-Montoya, R., Diaz-Mochon, J.J., Martin, M., Ruedas-Rama, M.J., and Orte, A. (2020). Mitochondrial pH Nanosensors for Metabolic Profiling of Breast Cancer Cell Lines. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103731"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3528","DOI":"10.1038\/s41598-020-60573-7","article-title":"MitoBlue as a tool to analyze the mitochondria-lysosome communication","volume":"10","author":"Vida","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Reshetnikov, V., \u00d6zkan, H.G., Daum, S., Janko, C., Alexiou, C., Sauer, C., Heinrich, M.R., and Mokhir, A. (2020). N-Alkylaminoferrocene-Based Prodrugs Targeting Mitochondria of Cancer Cells. Molecules, 25.","DOI":"10.3390\/molecules25112545"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8293","DOI":"10.1021\/acs.inorgchem.8b03380","article-title":"Enabling Mitochondrial Uptake of Lipophilic Dications Using Methylated Triphenylphosphonium Moieties","volume":"58","author":"Ong","year":"2019","journal-title":"Inorg. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"10695","DOI":"10.1002\/chem.202001366","article-title":"Self-Assembly of Mitochondria-Targeted Photosensitizer to Increase Photostability and Photodynamic Therapeutic Efficacy in Hypoxia","volume":"26","author":"Jana","year":"2020","journal-title":"Chem. A Eur. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/S0167-7799(97)01068-8","article-title":"Selective targeting of bioactive compounds to mitochondria","volume":"15","author":"Murphy","year":"1997","journal-title":"Trends Biotechnol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9455","DOI":"10.1021\/jacs.7b04415","article-title":"Delivery and Release of Small-Molecule Probes in Mitochondria Using Traceless Linkers","volume":"139","author":"Lei","year":"2017","journal-title":"J. Am. Chem. Soc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1021\/acs.jmedchem.5b01165","article-title":"Design, Synthesis, and Biological Characterization of Novel Mitochondria Targeted Dichloroacetate-Loaded Compounds with Antileukemic Activity","volume":"59","author":"Trapella","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1002\/cbic.200900159","article-title":"Small-Molecule Targeting of the Mitochondrial Compartment with an Endogenously Cleaved Reversible Tag","volume":"10","author":"Ripcke","year":"2009","journal-title":"Chembiochem"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1021\/cb400944y","article-title":"Mito-DCA: A Mitochondria Targeted Molecular Scaffold for Efficacious Delivery of Metabolic Modulator Dichloroacetate","volume":"9","author":"Pathak","year":"2014","journal-title":"ACS Chem. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"10043","DOI":"10.1021\/acs.chemrev.7b00042","article-title":"Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications","volume":"117","author":"Zielonka","year":"2017","journal-title":"Chem. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1021\/acs.bioconjchem.6b00682","article-title":"Unique Triphenylphosphonium Derivatives for Enhanced Mitochondrial Uptake and Photodynamic Therapy","volume":"28","author":"Hu","year":"2017","journal-title":"Bioconjug. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e109","DOI":"10.1093\/nar\/gkq050","article-title":"Slow non-specific accumulation of 2\u2032-deoxy and 2\u2032-O-methyl oligonucleotide probes at mitochondria in live cells","volume":"38","author":"Rhee","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"98","DOI":"10.2144\/000113610","article-title":"Mitochondrial membrane potential probes and the proton gradient: A practical usage guide","volume":"50","author":"Perry","year":"2011","journal-title":"BioTechniques"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1021\/acs.bioconjchem.0c00079","article-title":"Anionic Polymers Promote Mitochondrial Targeting of Delocalized Lipophilic Cations","volume":"31","author":"Jiang","year":"2020","journal-title":"Bioconjug. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6035","DOI":"10.1039\/C9SC01652J","article-title":"Fluorescent probes for organelle-targeted bioactive species imaging","volume":"10","author":"Gao","year":"2019","journal-title":"Chem. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0165-0270(00)00340-X","article-title":"MitoTracker labeling in primary neuronal and astrocytic cultures: Influence of mitochondrial membrane potential and oxidants","volume":"104","author":"Buckman","year":"2001","journal-title":"J. Neurosci. Meth."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1039\/C5CC09248E","article-title":"Fluorescent probes for the selective detection of chemical species inside mitochondria","volume":"52","author":"Xu","year":"2016","journal-title":"Chem. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/BJ20081386","article-title":"How mitochondria produce reactive oxygen species","volume":"417","author":"Murphy","year":"2009","journal-title":"Biochem. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3173","DOI":"10.1002\/chem.201905634","article-title":"Development of a Neutral Diketopyrrolopyrrole Phosphine Oxide for the Selective Bioimaging of Mitochondria at the Nanomolar Level","volume":"26","author":"Abelha","year":"2020","journal-title":"Chem. A Eur. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1002\/chem.201303360","article-title":"2,2,2-Trifluoroacetophenone as an Organocatalyst for the Oxidation of Tertiary Amines and Azines to N-Oxides","volume":"20","author":"Limnios","year":"2014","journal-title":"Chem. A Eur. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1021\/jo9723467","article-title":"A Simple and Efficient Method for the Preparation of Pyridine N-Oxides","volume":"63","author":"Adolfsson","year":"1998","journal-title":"J. Org. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Pouzet, P., Erdelmeier, I., Ginderow, D., Mornon, J.-P., Dansette, P., and Mansuy, D. (1995). Thiophene S-oxides: Convenient preparation, first complete structural characterization and unexpected dimerization of one of them, 2,5-diphenylthiophene-1-oxide. J. Chem. Soc. Chem. Commun., 473\u2013474.","DOI":"10.1039\/c39950000473"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1021\/tx500134g","article-title":"Bioactivation Potential of Thiophene-Containing Drugs","volume":"27","author":"Gramec","year":"2014","journal-title":"Chem. Res. Toxicol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.1016\/S0006-291X(05)81594-3","article-title":"Evidence for thiophene-s-oxide as a primary reactive metabolite of thiophene in vivo: Formation of a dihydrothiophene sulfoxide mercapturic acid","volume":"186","author":"Dansette","year":"1992","journal-title":"Biochem. Biophys. Res. Comm."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"108649","DOI":"10.1016\/j.dyepig.2020.108649","article-title":"Simple and non-charged long-lived fluorescent intracellular organelle trackers","volume":"183","author":"Resa","year":"2020","journal-title":"Dye. Pigment."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1080\/15257770.2014.992531","article-title":"Drug\u2013DNA Interaction Studies of Acridone-Based Derivatives","volume":"34","author":"Thimmaiah","year":"2015","journal-title":"Nucleosides Nucleotides Nucleic Acids"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Weissig, V., and Edeas, M. (2015). Predicting Mitochondrial Targeting by Small Molecule Xenobiotics Within Living Cells Using QSAR Models. Mitochondrial Medicine: Volume II, Manipulating Mitochondrial Function, Springer.","DOI":"10.1007\/978-1-4939-2288-8"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1038\/nrc.2016.85","article-title":"Altered metabolite levels in cancer: Implications for tumour biology and cancer therapy","volume":"16","author":"Sullivan","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.bbcan.2014.08.005","article-title":"Dichloroacetate and cancer: New home for an orphan drug?","volume":"1846","author":"Kankotia","year":"2014","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1186\/bcr2889","article-title":"Choosing the right cell line for breast cancer research","volume":"13","author":"Holliday","year":"2011","journal-title":"Breast Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1023\/B:JOFL.0000016287.56322.eb","article-title":"Acridones and quinacridones: Novel fluorophores for fluorescence lifetime studies","volume":"14","author":"Smith","year":"2004","journal-title":"J. Fluoresc."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Gonzalez-Garcia, M.C., Herrero-Foncubierta, P., Garcia-Fernandez, E., and Orte, A. (2020). Building Accurate Intracellular Polarity Maps through Multiparametric Microscopy. Methods Protoc., 3.","DOI":"10.3390\/mps3040078"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"129","DOI":"10.3389\/fchem.2019.00129","article-title":"Coupled Excited-State Dynamics in N-Substituted 2-Methoxy-9-Acridones","volume":"7","author":"Castro","year":"2019","journal-title":"Front. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1002\/chem.201303113","article-title":"Synthesis and Photophysics of a New Family of Fluorescent 9-alkyl Substituted Xanthenones","volume":"20","author":"Miguel","year":"2014","journal-title":"Chem. A Eur. J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4888","DOI":"10.1021\/ja043919h","article-title":"Evolution of Fluorescein as a Platform for Finely Tunable Fluorescence Probes","volume":"127","author":"Urano","year":"2005","journal-title":"J. Am. Chem. Soc."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s10870-006-9126-0","article-title":"X-ray diffraction, DFT, and spectroscopic study of N,N\u2032-difluoroboryl-5-(2-thienyl)dipyrrin and fluorescence studies of related dipyrromethanes, dipyrrins and BF2-dipyrrins and DFT conformational study of 5-(2-thienyl)dipyrrin","volume":"37","author":"Choi","year":"2007","journal-title":"J. Chem. Crystallogr."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5400","DOI":"10.1039\/b820742a","article-title":"Tuned lifetime, at the ensemble and single molecule level, of a xanthenic fluorescent dye by means of a buffer-mediated excited-state proton exchange reaction","volume":"11","author":"Paredes","year":"2009","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"5460","DOI":"10.1002\/ejoc.201100736","article-title":"\u03b1-\/\u03b2-Formylated Boron\u2013Dipyrrin (BODIPY) Dyes: Regioselective Syntheses and Photophysical Properties","volume":"2011","author":"Yu","year":"2011","journal-title":"Eur. J. Org. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"89375","DOI":"10.1039\/C5RA17419H","article-title":"Unusual spectroscopic and photophysical properties of meso-tert-butylBODIPY in comparison to related alkylated BODIPY dyes","volume":"5","author":"Jiao","year":"2015","journal-title":"RSC Adv."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.molmet.2013.11.005","article-title":"Identification of a novel mitochondrial uncoupler that does not depolarize the plasma membrane","volume":"3","author":"Kenwood","year":"2014","journal-title":"Mol. Metab."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"175","DOI":"10.2174\/157340606776056214","article-title":"Drug Evolution Concept in Drug Design: 2. Chimera Method","volume":"2","author":"Roman","year":"2006","journal-title":"Med. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1908","DOI":"10.1021\/acs.jmedchem.9b01456","article-title":"Designing Chimeric Molecules for Drug Discovery by Leveraging Chemical Biology","volume":"63","author":"Borsari","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"213556","DOI":"10.1016\/j.ccr.2020.213556","article-title":"Recent progress on molecularly near-infrared fluorescent probes for chemotherapy and phototherapy","volume":"427","author":"Yan","year":"2021","journal-title":"Coord. Chem. Rev."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.cbi.2012.06.005","article-title":"Novel molecular mechanisms of antitumor action of dichloroacetate against T cell lymphoma: Implication of altered glucose metabolism, pH homeostasis and cell survival regulation","volume":"199","author":"Kumar","year":"2012","journal-title":"Chem. Biol. Interact."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Ayyanathan, K., Kesaraju, S., Dawson-Scully, K., and Weissbach, H. (2012). Combination of Sulindac and Dichloroacetate Kills Cancer Cells via Oxidative Damage. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0039949"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Ripoll, C., Roldan, M., Ruedas-Rama, M.J., Martin, M., Ruedas-Rama, M.J., and Orte, A. (2020). Mitochondrial pH Nanosensors for Metabolic profiling of breast cancer cell lines. 2020, in preparation. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103731"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/j.neuro.2004.04.001","article-title":"Thiophene is Toxic to Cerebellar Granule Cells in Culture After Bioactivation by Rat Liver Enzymes","volume":"25","author":"Dreiem","year":"2004","journal-title":"Neurotoxicology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"5478","DOI":"10.1002\/anie.201100935","article-title":"A Mitochondrial Surface-Specific Fluorescent Probe Activated by Bioconversion","volume":"50","author":"Kawazoe","year":"2011","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"10620","DOI":"10.1039\/c3cc46143b","article-title":"A near-infrared dye based on BODIPY for tracking morphology changes in mitochondria","volume":"49","author":"Jiang","year":"2013","journal-title":"Chem. Commun."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"14701","DOI":"10.1002\/chem.201602639","article-title":"Water-Soluble Triarylborane Chromophores for One- and Two-Photon Excited Fluorescence Imaging of Mitochondria in Cells","volume":"22","author":"Griesbeck","year":"2016","journal-title":"Chem. Eur. J."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"7948","DOI":"10.1039\/c0cc01918f","article-title":"Fluorescent labeling of human mesenchymal stem cells by thiophene fluorophores conjugated to a lipophilic carrier","volume":"46","author":"Duca","year":"2010","journal-title":"Chem. Commun."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1039\/C7MD00074J","article-title":"In silico prediction of chemical subcellular localization via multi-classification methods","volume":"8","author":"Yang","year":"2017","journal-title":"MedChemComm"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1093\/bioinformatics\/bty707","article-title":"admetSAR 2.0: Web-service for prediction and optimization of chemical ADMET properties","volume":"35","author":"Yang","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"28196","DOI":"10.1038\/srep28196","article-title":"Pro-haloacetate Nanoparticles for Efficient Cancer Therapy via Pyruvate Dehydrogenase Kinase Modulation","volume":"6","author":"Misra","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"de Mey, S., Dufait, I., Jiang, H., Corbet, C., Wang, H., Van De Gucht, M., Kerkhove, L., Law, K.L., Vandenplas, H., and Gevaert, T. (2020). Dichloroacetate Radiosensitizes Hypoxic Breast Cancer Cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249367"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Tataranni, T., Agriesti, F., Pacelli, C., Ruggieri, V., Laurenzana, I., Mazzoccoli, C., Della Sala, G., Panebianco, C., Pazienza, V., and Capitanio, N. (2019). Dichloroacetate Affects Mitochondrial Function and Stemness-Associated Properties in Pancreatic Cancer Cell Lines. Cells, 8.","DOI":"10.3390\/cells8050478"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Rodrigues, A.S., Correia, M., Gomes, A., Pereira, S.L., Perestrelo, T., Sousa, M.I., and Ramalho-Santos, J. (2015). Dichloroacetate, the Pyruvate Dehydrogenase Complex and the Modulation of mESC Pluripotency. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0131663"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"8930","DOI":"10.1039\/C9SC02906K","article-title":"Supramolecular caging for cytosolic delivery of anionic probes","volume":"10","author":"Mosquera","year":"2019","journal-title":"Chem. Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1021\/ml200126j","article-title":"Highly Selective and Potent Thiophenes as PI3K Inhibitors with Oral Antitumor Activity","volume":"2","author":"Liu","year":"2011","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_75","unstructured":"Hanson, B.A. (2005). Understanding Medicinal Plants. Their Chemistry and Therapeutic Action, The Haworth Press Inc."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1515\/znc-2009-3-407","article-title":"Cytotoxic Thiophenes from the Root of Echinops grijisii Hance","volume":"64c","author":"Zhang","year":"2009","journal-title":"Z. Naturforsch."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1248\/cpb.c15-00115","article-title":"Synthesis and Cytotoxic Evaluation of Pyran, Dihydropyridine and Thiophene Derivatives of 3-Acetylcoumarin","volume":"63","author":"Mohareb","year":"2015","journal-title":"Chem. Pharm. Bull."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Lisboa, T., Silva, D., Duarte, S., Ferreira, R., Andrade, C., Lopes, A.L., Ribeiro, J., Farias, D., Moura, R., and Reis, M. (2020). Toxicity and Antitumor Activity of a Thiophene\u2013Acridine Hybrid. Molecules, 25.","DOI":"10.3390\/molecules25010064"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.ejmech.2014.03.018","article-title":"Rational approaches, design strategies, structure activity relationship and mechanistic insights for anticancer hybrids","volume":"77","author":"Nepali","year":"2014","journal-title":"Eur. J. Med. Chem."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/2\/254\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:23:25Z","timestamp":1760160205000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/2\/254"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,12]]},"references-count":79,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["pharmaceutics13020254"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics13020254","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints202012.0358.v1","asserted-by":"object"}]},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,12]]}}}