TY - JOUR
T1 - Exploring Structure-Activity Relationships in Photodynamic Therapy Anticancer Agents Based on Ir(III)-COUPY Conjugates
AU - Rovira, Anna
AU - Ortega-Forte, Enrique
AU - Hally, Cormac
AU - Jordà-Redondo, Mireia
AU - Abad-Montero, Diego
AU - Vigueras, Gloria
AU - Martínez, Jesús I.
AU - Bosch, Manel
AU - Nonell, Santi
AU - Ruiz, José
AU - Marchán, Vicente
N1 - Funding Information:
This work was supported by funds from the Spanish Ministerio de Ciencia e Innovación-Agencia Estatal de Investigación (MCI/AEI/10.13039/501100011033) and FEDER funds (Projects CTQ2017-84779-R, RTI2018-096891-B-I00, PID2020-117508RB-I00, PID2021-122850NB-I00, CTQ2016-78454-C2-1-R, and PID2020-115801RB-C22).
Funding Information:
The authors wish to thank Nicole Miller for synthesizing some coumarin precursors. The authors acknowledge helpful assistance from Dr. Francisco Cárdenas (NMR) and Dr. Irene Fernández and Laura Ortiz (MS) from CCiTUB. A.R. was recipient fellow of the University of Barcelona (APIF). E.O.F. thanks AECC (Project PRDMU19003ORTE). C.H. thanks the SUR del DEC de la Generalitat de Catalunya and the FSE for his predoctoral fellowship (grants no. 2017 FI_B_00617, 2018 FI_B1 00174 and 2019 FI_B2 00167). This work was supported by funds from the Spanish Ministerio de Ciencia e Innovación-Agencia Estatal de Investigación (MCI/AEI/10.13039/501100011033) and FEDER funds (Projects CTQ2017-84779-R, RTI2018-096891-B-I00, PID2020-117508RB-I00, PID2021-122850NB-I00, CTQ2016-78454-C2-1-R, and PID2020-115801RB-C22).
Funding Information:
The authors wish to thank Nicole Miller for synthesizing some coumarin precursors. The authors acknowledge helpful assistance from Dr. Francisco Cárdenas (NMR) and Dr. Irene Fernández and Laura Ortiz (MS) from CCiTUB. A.R. was recipient fellow of the University of Barcelona (APIF). E.O.F. thanks AECC (Project PRDMU19003ORTE). C.H. thanks the SUR del DEC de la Generalitat de Catalunya and the FSE for his predoctoral fellowship (grants no. 2017 FI_B_00617, 2018 FI_B1 00174 and 2019 FI_B2 00167).
Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.
PY - 2023/6/22
Y1 - 2023/6/22
N2 - Photodynamic therapy holds great promise as a non-invasive anticancer tool against drug-resistant cancers. However, highly effective, non-toxic, and reliable photosensitizers with operability under hypoxic conditions remain to be developed. Herein, we took the advantageous properties of COUPY fluorophores and cyclometalated Ir(III) complexes to develop novel PDT agents based on Ir(III)-COUPY conjugates with the aim of exploring structure-activity relationships. The structural modifications carried out within the coumarin scaffold had a strong impact on the photophysical properties and cellular uptake of the conjugates. All Ir(III)-COUPY conjugates exhibited high phototoxicity under green light irradiation, which was attributed to the photogeneration of ROS, while remaining non-toxic in the dark. Among them, two hit conjugates showed excellent phototherapeutic indexes in cisplatin-resistant A2780cis cancer cells, both in normoxia and in hypoxia, suggesting that photoactive therapy approaches based on the conjugation of far-red/NIR-emitting COUPY dyes and transition metal complexes could effectively tackle in vitro acquired resistance to cisplatin.
AB - Photodynamic therapy holds great promise as a non-invasive anticancer tool against drug-resistant cancers. However, highly effective, non-toxic, and reliable photosensitizers with operability under hypoxic conditions remain to be developed. Herein, we took the advantageous properties of COUPY fluorophores and cyclometalated Ir(III) complexes to develop novel PDT agents based on Ir(III)-COUPY conjugates with the aim of exploring structure-activity relationships. The structural modifications carried out within the coumarin scaffold had a strong impact on the photophysical properties and cellular uptake of the conjugates. All Ir(III)-COUPY conjugates exhibited high phototoxicity under green light irradiation, which was attributed to the photogeneration of ROS, while remaining non-toxic in the dark. Among them, two hit conjugates showed excellent phototherapeutic indexes in cisplatin-resistant A2780cis cancer cells, both in normoxia and in hypoxia, suggesting that photoactive therapy approaches based on the conjugation of far-red/NIR-emitting COUPY dyes and transition metal complexes could effectively tackle in vitro acquired resistance to cisplatin.
UR - http://www.scopus.com/inward/record.url?scp=85163368847&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.3c00189
DO - 10.1021/acs.jmedchem.3c00189
M3 - Article
C2 - 37265008
AN - SCOPUS:85163368847
SN - 0022-2623
VL - 66
SP - 7849
EP - 7867
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 12
ER -
