Straightforward access to novel mitochondriotropics derived from 2-arylethanol as potent and selective antiproliferative agents
| العنوان: | Straightforward access to novel mitochondriotropics derived from 2-arylethanol as potent and selective antiproliferative agents |
|---|---|
| المؤلفون: | Jelena Dinić, José M. Padrón, José G. Fernández-Bolaños, Milica Pešić, Óscar López, Adrián Puerta, Francisco J. Hicke |
| المصدر: | European Journal of Medicinal Chemistry |
| بيانات النشر: | Elsevier, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Phosphonium salts, Tariquidar, Chemosensitizer, Antineoplastic Agents, Mitochondriotropics, 03 medical and health sciences, chemistry.chemical_compound, Structure-Activity Relationship, 0302 clinical medicine, Cell Line, Tumor, Multidrug resistant cells, Drug Discovery, medicine, Humans, Cytotoxicity, 030304 developmental biology, Cell Proliferation, Pharmacology, Membrane Potential, Mitochondrial, 0303 health sciences, Cell Death, Dose-Response Relationship, Drug, Ethanol, Molecular Structure, Chemistry, Organic Chemistry, Antiproliferative agents, General Medicine, 3. Good health, Tyrosol, Biochemistry, Cell culture, 030220 oncology & carcinogenesis, Mitocans, Hydroxytyrosol, Phenethyl alcohol, Efflux, Drug Screening Assays, Antitumor, medicine.drug |
| الوصف: | [EN] The necessity for developing novel cytostatic agents with improved activities and reduced side-effects to tackle cancer prompted us to investigate mitochondria-targeted compounds, an approach that is gaining attention for the selective transportation of cytotoxic agents. We envisioned the possibility of conjugating a phenethyl alcohol motif, decorated with a series of phenol-based substituents on the aryl moiety, with a triphenyl phosphonium scaffold (a mitochondriadirected vector), through a hydrocarbon chain of different lengths. Thus, such compounds that incorporate the phenethyl skeleton can be considered as masked phenolic compounds derived from relevant natural counterparts found in olive tree (e.g. tyrosol, hydroxytyrosol). Title compounds exhibited very strong in vitro antiproliferative activities against the panel of six human tumor cell lines tested, with GI50 values ranging from the nanomolar (0.026 ± 0.010 mM for 36) to the submicromolar range in most of the cases; this represents an improvement of up to 350-fold compared to classical chemotherapeutic agents, like 5-fluorouracil or cisplatin. Interestingly, decrease in the linker length led to an increase of GI50 values against non-tumor cells, thus allowing a remarkable improvement of selectivity (SI up to 269). The very promising antiproliferative activities prompted us to further investigate their behaviour against multidrug resistant cell lines (MDR). The results indicated a reduced sensitivity of the multidrug resistant cells to compounds, probably due to P-gp-mediated efflux of these antiproliferative agents. Interestingly, activities were completely restored to the same levels by co-administration of tariquidar, a well-known inhibitor of P-gp. Flow cytometry analysis on sensitive cell lines revealed a decrease in the percentage of cells in G1 phase accompanied by increase in S and G2/M phases. In addition, a significant increase in subG1 area, was observed. These results are compatible with the necrotic and apoptotic cell death detected in the Annexin V assay, and with the depolarization of the mitochondria membrane. Thus, the new mitochondriotropic agents reported herein can be considered as promising antiproliferative agents, endowed with remarkable potency and selectivity, including MDR cells, upon coadministration with a pump-efflux inhibitor. We thank Grant PID2020-116460RB-I00 funded by MCIN/AEI/10.13039/501100011033, and Junta de Andalucia (FQM134) for financial support. A.P. and J.M.P. thank the Spanish Government (PGC2018-094503-B-C22, MCIU/AEI/FEDER, UE) and the Canary Islands Government (ProID2020010101, ACIISI/FEDER, UE) for financial support. A.P. thanks the EU Social Fund (FSE) and the Canary Islands ACIISI for a predoctoral grant TESIS2020010055. J.D. and M.P thank the Ministry of Education, Science and Technological Development of the Republic of Serbia for financial support (451-03-9/2021e14/200007). This work was performed within the framework of COST Action CA17104 STRATAGEM -"New diagnostic and therapeutic tools against multidrug resistant tumors". We would also like to thank the Servicio de Resonancia Magn~etica Nuclear, CITIUS (University of Seville) for the performance of NMR experiments. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f1cf625474f013f6a8a9a89e60b64df8Test http://cherry.chem.bg.ac.rs/handle/123456789/4869Test |
| حقوق: | RESTRICTED |
| رقم الانضمام: | edsair.doi.dedup.....f1cf625474f013f6a8a9a89e60b64df8 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |