{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T16:57:45Z","timestamp":1762102665028,"version":"build-2065373602"},"reference-count":23,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,9,11]],"date-time":"2021-09-11T00:00:00Z","timestamp":1631318400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/QUI-QFI\/2870\/2020","project UIDB\/00081\/2020","UIDB\/05748\/2020","UIDB\/4255\/2020","UIDB\/50006\/2020","CEECIND\/01425\/2017","IF\/00092\/2014\/CP1255\/CT0004","SFRH\/BD\/143211\/2019"],"award-info":[{"award-number":["PTDC\/QUI-QFI\/2870\/2020","project UIDB\/00081\/2020","UIDB\/05748\/2020","UIDB\/4255\/2020","UIDB\/50006\/2020","CEECIND\/01425\/2017","IF\/00092\/2014\/CP1255\/CT0004","SFRH\/BD\/143211\/2019"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomedicines"],"abstract":"<jats:p>Photodynamic therapy (PDT) is an anticancer therapeutic modality with remarkable advantages over more conventional approaches. However, PDT is greatly limited by its dependence on external light sources. Given this, PDT would benefit from new systems capable of a light-free and intracellular photodynamic effect. Herein, we evaluated the heavy-atom effect as a strategy to provide anticancer activity to derivatives of coelenterazine, a chemiluminescent single-molecule widespread in marine organisms. Our results indicate that the use of the heavy-atom effect allows these molecules to generate readily available triplet states in a chemiluminescent reaction triggered by a cancer marker. Cytotoxicity assays in different cancer cell lines showed a heavy-atom-dependent anticancer activity, which increased in the substituent order of hydroxyl &lt; chlorine &lt; bromine. Furthermore, it was found that the magnitude of this anticancer activity is also dependent on the tumor type, being more relevant toward breast and prostate cancer. The compounds also showed moderate activity toward neuroblastoma, while showing limited activity toward colon cancer. In conclusion, the present results indicate that the application of the heavy-atom effect to marine coelenterazine could be a promising approach for the future development of new and optimized self-activating and tumor-selective sensitizers for light-free PDT.<\/jats:p>","DOI":"10.3390\/biomedicines9091199","type":"journal-article","created":{"date-parts":[[2021,9,12]],"date-time":"2021-09-12T21:45:57Z","timestamp":1631483157000},"page":"1199","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Target-Oriented Synthesis of Marine Coelenterazine Derivatives with Anticancer Activity by Applying the Heavy-Atom Effect"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9152-7865","authenticated-orcid":false,"given":"Carla M.","family":"Magalh\u00e3es","sequence":"first","affiliation":[{"name":"Chemistry Research Unit (CIQUP), Faculty of Sciences, University of Porto, Rua do Campo Alegre 687, 4169-007 Porto, Portugal"}]},{"given":"Patricia","family":"Gonz\u00e1lez-Berdullas","sequence":"additional","affiliation":[{"name":"Chemistry Research Unit (CIQUP), Faculty of Sciences, University of Porto, Rua do Campo Alegre 687, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1420-5042","authenticated-orcid":false,"given":"Diana","family":"Duarte","sequence":"additional","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8231-1560","authenticated-orcid":false,"given":"Ana Salom\u00e9","family":"Correia","sequence":"additional","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"given":"Jos\u00e9 E.","family":"Rodr\u00edguez-Borges","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre 697, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1283-1042","authenticated-orcid":false,"given":"Nuno","family":"Vale","sequence":"additional","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8478-3441","authenticated-orcid":false,"given":"Joaquim C. G.","family":"Esteves da Silva","sequence":"additional","affiliation":[{"name":"Chemistry Research Unit (CIQUP), Faculty of Sciences, University of Porto, Rua do Campo Alegre 687, 4169-007 Porto, Portugal"},{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5647-8455","authenticated-orcid":false,"given":"Lu\u00eds","family":"Pinto da Silva","sequence":"additional","affiliation":[{"name":"Chemistry Research Unit (CIQUP), Faculty of Sciences, University of Porto, Rua do Campo Alegre 687, 4169-007 Porto, Portugal"},{"name":"LACOMEPHI, GreenUPorto, Department of Geosciences, Environment and Territorial Planning, Faculty of Sciences, University of Porto, Rua do Campo Alegre 697, 4169-007 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3127","DOI":"10.1039\/D1CC00645B","article-title":"A 2-pyridone modified zinc phthalocyanine with three-in-one multiple functions for photodynamic therapy","volume":"57","author":"Li","year":"2021","journal-title":"Chem. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7537","DOI":"10.1039\/D0CC02194F","article-title":"Lighting up metallohelices: From DNA binders to chemotherapy and photodynamic therapy","volume":"56","author":"Li","year":"2020","journal-title":"Chem. Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4902","DOI":"10.1039\/D0CC08323B","article-title":"Achieving high singlet-oxygen generation by applying the heavy-atom effect to thermally activated delayed fluorescent materials","volume":"57","author":"Xiao","year":"2021","journal-title":"Chem. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6488","DOI":"10.1039\/C6CS00616G","article-title":"Overcoming the Achilles\u2019 heel of photodynamic therapy","volume":"45","author":"Fan","year":"2016","journal-title":"Chem. Soc. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.jphotochemrev.2011.06.001","article-title":"Current states and future views in photodynamic therapy","volume":"12","author":"Yano","year":"2011","journal-title":"J. Photochem. Photobiol. C Photochem. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2286","DOI":"10.1002\/cphc.201600270","article-title":"Chemiluminescence and Bioluminescence as an Excitation Source in the Photodynamic Therapy of Cancer: A Critical Review","volume":"17","year":"2016","journal-title":"ChemPhysChem"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1039\/c5pp00456j","article-title":"Lighting up bioluminescence with coelenterazine: Strategies and applications","volume":"15","author":"Jiang","year":"2016","journal-title":"Photochem. Photobiol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1007\/s11307-015-0896-7","article-title":"Multimodality Imaging of Cancer Superoxide Anion Using the Small Molecule Coelenterazine","volume":"18","author":"Bronsart","year":"2016","journal-title":"Mol. Imaging Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3343","DOI":"10.1002\/slct.201600688","article-title":"Interstate Crossing-Induced Chemiexcitation Mechanism as the Basis for Imidazopyrazinone Bioluminescence","volume":"1","author":"Magalhaes","year":"2016","journal-title":"ChemistrySelect"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6048","DOI":"10.1039\/C6CS00296J","article-title":"1001 lights: Luciferins, luciferases, their mechanisms of action and applications in chemical analysis, biology and medicine","volume":"45","author":"Kaskova","year":"2016","journal-title":"Chem. Soc. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.jlumin.2018.03.069","article-title":"Study of coelenterazine luminescence: Electrostatic interactions as the controlling factor for efficient chemiexcitation","volume":"199","year":"2018","journal-title":"J. Lumin."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"111683","DOI":"10.1016\/j.ejmech.2019.111683","article-title":"Single-molecule chemiluminescent photosensitizer for a self-activating and tumor-selective photodynamic therapy of cancer","volume":"183","author":"Ferreira","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Pinto da Silva, L., Magalh\u00e3es, C.M., N\u00fa\u00f1ez-Montenegro, A., Ferreira, P.J.O., Duarte, D., Rodr\u00edguez-Borges, J.E., Vale, N., and Esteves da Silva, J.C.G. (2019). Study of the Combination of Self-Activating Photodynamic Therapy and Chemotherapy for Cancer Treatment. Biomolecules, 9.","DOI":"10.3390\/biom9080384"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6615","DOI":"10.1039\/b810189b","article-title":"Long-range corrected hybrid density functionals with damped atom-atom dispersion corrections","volume":"10","author":"Chai","year":"2008","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1039\/C2CS35394F","article-title":"The calculations of excited-state properties with time-dependent density functional theory","volume":"42","author":"Adamo","year":"2013","journal-title":"Chem. Soc. Rev."},{"key":"ref_16","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Petersson, G.A., and Nakatsuji, H. (2016). Gaussian 09, Revision D.01, Gaussian, Inc."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.jphotobiol.2018.11.006","article-title":"Comparative study of the chemiluminescence of coelenterazine, coelenterazine-e and Cypridina luciferin with an experimental and theoretical approach","volume":"190","year":"2019","journal-title":"J. Photochem. Photobiol. B Biol."},{"key":"ref_18","first-page":"e25881","article-title":"Mechanistic insights into the efficient intramolecular chemiexcitation of dioxetanones from TD-DFT and multireference calculations","volume":"119","year":"2018","journal-title":"Int. J. Quantum Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6927","DOI":"10.1021\/acs.chemrev.7b00649","article-title":"Chemi- and Bioluminescence of Cyclic Peroxides","volume":"118","author":"Vacher","year":"2018","journal-title":"Chem. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1021\/cr010371d","article-title":"Physical mechanisms of generation and deactivation of singlet oxygen","volume":"103","author":"Schweitzer","year":"2003","journal-title":"Chem. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1021\/ja00288a022","article-title":"Effects of Methylation on the Thermal Stability and Chemiluminescence Properties of 1,2-Dioxetanes","volume":"107","author":"Adam","year":"1985","journal-title":"J. Am. Chem. Soc."},{"key":"ref_22","unstructured":"Kozyrev, D., and Slutsky, V. (2010). Mitochondrial reactive oxygen species and cancer. Handbook of Free Radicals: Formation, Types and Effects, Nova Science Pub. Inc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.1089\/ars.2012.4729","article-title":"Mitochondria as a Source of Reactive Oxygen and Nitrogen Species: From Molecular Mechanisms to Human Health","volume":"18","author":"Figueira","year":"2013","journal-title":"Antioxid. Redox Signal."}],"container-title":["Biomedicines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9059\/9\/9\/1199\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:00:59Z","timestamp":1760166059000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9059\/9\/9\/1199"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,11]]},"references-count":23,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["biomedicines9091199"],"URL":"https:\/\/doi.org\/10.3390\/biomedicines9091199","relation":{},"ISSN":["2227-9059"],"issn-type":[{"type":"electronic","value":"2227-9059"}],"subject":[],"published":{"date-parts":[[2021,9,11]]}}}