Characterization of Locally Excited and Charge-Transfer States of the Anticancer Drug Lapatinib by Ultrafast Spectroscopy and Computational Studies

This is the peer reviewed version of the following article: I. Vayá, I. Andreu, E. Lence, C. González-Bello, M. Consuelo Cuquerella, M. Navarrete-Miguel, D. Roca-Sanjuán, M. A. Miranda, Chem. Eur. J. 2020, 26, 15922, which has been published in final form at https://doi.org/10.1002/chem.202001336. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.[EN] Lapatinib (LAP) is an anticancer drug, which is metabolized to theN- and O-dealkylated products (N-LAP andO-LAP, respectively). In view of the photosensitizing potential of related drugs, a complete experimental and theoretical study has been performed on LAP,N-LAP andO-LAP, both in solution and upon complexation with human serum albumin (HSA). In organic solvents, coplanar locally excited (LE) emissive states are generated; they rapidly evolve towards twisted intramolecular charge-transfer (ICT) states. By contrast, within HSA only LE states are detected. Accordingly, femtosecond transient absorption reveals a very fast switching (ca. 2 ps) from LE (lambda(max)=550 nm) to ICT states (lambda(max)=480 nm) in solution, whereas within HSA the LE species become stabilized and live much longer (up to the ns scale). Interestingly, molecular dynamics simulation studies confirm that the coplanar orientation is preferred for LAP (or to a lesser extentN-LAP) within HSA, explaining the experimental results.Financial support from the Spanish Government (RYC-2015-17737, CTQ2017-89416-R, ISCIII grants RD16/0006/0004, PI16/01877 and CPII16/00052, SAF2016-75638-R, RYC-2015-19234, CTQ2017-87054-C2-2-P, and MDM-2015-0538), Conselleria d'Educacio Cultura i Esport (PROMETEO/2017/075), the Xunta de Galicia [ED431B 2018/04 and Centro singular de investigacion de Galicia accreditation 2019-2022 (ED431G 2019/03)] and the European Regional Development Fund is gratefully acknowledged. We thank the Centro de Supercomputacion de Galicia (CESGA) for use of the Finis Terrae computer.Vayá Pérez, I.; Andreu Ros, MI.; Lence, E.; González-Bello, C.; Cuquerella Alabort, MC.; Navarrete-Miguel, M.; Roca-Sanjuán, D.... (2020). Characterization of Locally Excited and Charge-Transfer States of the Anticancer Drug Lapatinib by Ultrafast Spectroscopy and Computational Studies. Chemistry - A European Journal. 26(68):15922-15930. https://doi.org/10.1002/chem.20200133615922159302668Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 68(6), 394-424. doi:10.3322/caac.21492Nicholson, R. ., Gee, J. M. ., & Harper, M. . (2001). EGFR and cancer prognosis. European Journal of Cancer, 37, 9-15. doi:10.1016/s0959-8049(01)00231-3Yashiro, M., Qiu, H., Hasegawa, T., Zhang, X., Matsuzaki, T., & Hirakawa, K. (2011). An EGFR inhibitor enhances the efficacy of SN38, an active metabolite of irinotecan, in SN38-refractory gastric carcinoma cells. British Journal of Cancer, 105(10), 1522-1532. doi:10.1038/bjc.2011.397Gonzalez, G., & Lage, A. (2007). Cancer Vaccines for Hormone/Growth Factor Immune Deprivation:A Feasible Approach for Cancer Treatment. Current Cancer Drug Targets, 7(3), 229-241. doi:10.2174/156800907780618310Sigismund, S., Avanzato, D., & Lanzetti, L. (2017). Emerging functions of the EGFR in cancer. Molecular Oncology, 12(1), 3-20. doi:10.1002/1878-0261.12155Thomas, R., & Weihua, Z. (2019). Rethink of EGFR in Cancer With Its Kinase Independent Function on Board. Frontiers in Oncology, 9. doi:10.3389/fonc.2019.00800MEDINA, P., & GOODIN, S. (2008). Lapatinib: A dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clinical Therapeutics, 30(8), 1426-1447. doi:10.1016/j.clinthera.2008.08.008Nolting, M., Schneider-Merck, T., & Trepel, M. (2014). Lapatinib. Small Molecules in Oncology, 125-143. doi:10.1007/978-3-642-54490-3_7Schroeder, R., Stevens, C., & Sridhar, J. (2014). Small Molecule Tyrosine Kinase Inhibitors of ErbB2/HER2/Neu in the Treatment of Aggressive Breast Cancer. Molecules, 19(9), 15196-15212. doi:10.3390/molecules190915196Spector, N. L., Xia, W., Burris, H., Hurwitz, H., Dees, E. C., Dowlati, A., … Bacus, S. (2005). Study of the Biologic Effects of Lapatinib, a Reversible Inhibitor of ErbB1 and ErbB2 Tyrosine Kinases, on Tumor Growth and Survival Pathways in Patients With Advanced Malignancies. Journal of Clinical Oncology, 23(11), 2502-2512. doi:10.1200/jco.2005.12.157Krasner, J. (1972). Drug-Protein Interaction. Pediatric Clinics of North America, 19(1), 51-63. doi:10.1016/s0031-3955(16)32666-9Peters, T. (1995). Ligand Binding by Albumin. All About Albumin, 76-132. doi:10.1016/b978-012552110-9/50005-2Molins-Molina, O., Lence, E., Limones-Herrero, D., González-Bello, C., Miranda, M. A., & Jiménez, M. C. (2019). Identification of a common recognition center for a photoactive non-steroidal antiinflammatory drug in serum albumins of different species. Organic Chemistry Frontiers, 6(1), 99-109. doi:10.1039/c8qo01045eMolins-Molina, O., Pérez-Ruiz, R., Lence, E., González-Bello, C., Miranda, M. A., & Jiménez, M. C. (2019). Photobinding of Triflusal to Human Serum Albumin Investigated by Fluorescence, Proteomic Analysis, and Computational Studies. Frontiers in Pharmacology, 10. doi:10.3389/fphar.2019.01028Monteiro, A. F., Rato, M., & Martins, C. (2016). Drug-induced photosensitivity: Photoallergic and phototoxic reactions. Clinics in Dermatology, 34(5), 571-581. doi:10.1016/j.clindermatol.2016.05.006Vayá, I., Andreu, I., Monje, V. T., Jiménez, M. C., & Miranda, M. A. (2015). Mechanistic Studies on the Photoallergy Mediated by Fenofibric Acid: Photoreactivity with Serum Albumins. Chemical Research in Toxicology, 29(1), 40-46. doi:10.1021/acs.chemrestox.5b00357Vayá, I., Lhiaubet-Vallet, V., Jiménez, M. C., & Miranda, M. A. (2014). Photoactive assemblies of organic compounds and biomolecules: drug–protein supramolecular systems. Chem. Soc. Rev., 43(12), 4102-4122. doi:10.1039/c3cs60413fIshikawa, T., Kamide, R., & Niimura, M. (1994). Photoleukomelanodermatitis (Kobori) Induced by Afloqualone. The Journal of Dermatology, 21(6), 430-433. doi:10.1111/j.1346-8138.1994.tb01768.xKabir, M. Z., Mukarram, A. K., Mohamad, S. B., Alias, Z., & Tayyab, S. (2016). Characterization of the binding of an anticancer drug, lapatinib to human serum albumin. Journal of Photochemistry and Photobiology B: Biology, 160, 229-239. doi:10.1016/j.jphotobiol.2016.04.005Shen, G.-F., Liu, T.-T., Wang, Q., Jiang, M., & Shi, J.-H. (2015). Spectroscopic and molecular docking studies of binding interaction of gefitinib, lapatinib and sunitinib with bovine serum albumin (BSA). Journal of Photochemistry and Photobiology B: Biology, 153, 380-390. doi:10.1016/j.jphotobiol.2015.10.023Wilson, J. N., Liu, W., Brown, A. S., & Landgraf, R. (2015). Binding-induced, turn-on fluorescence of the EGFR/ERBB kinase inhibitor, lapatinib. Organic & Biomolecular Chemistry, 13(17), 5006-5011. doi:10.1039/c5ob00239gLi, M.-D., Yan, Z., Zhu, R., Phillips, D. L., Aparici-Espert, I., Lhiaubet-Vallet, V., & Miranda, M. A. (2018). Enhanced Drug Photosafety by Interchromophoric Interaction Owing to Intramolecular Charge Separation. Chemistry - A European Journal, 24(25), 6654-6659. doi:10.1002/chem.201800716Vayá, I., Bonancía, P., Jiménez, M. C., Markovitsi, D., Gustavsson, T., & Miranda, M. A. (2013). Excited state interactions between flurbiprofen and tryptophan in drug–protein complexes and in model dyads. Fluorescence studies from the femtosecond to the nanosecond time domains. Physical Chemistry Chemical Physics, 15(13), 4727. doi:10.1039/c3cp43847cAndersson, K., Malmqvist, P., & Roos, B. O. (1992). Second‐order perturbation theory with a complete active space self‐consistent field reference function. The Journal of Chemical Physics, 96(2), 1218-1226. doi:10.1063/1.462209Andersson, K., Malmqvist, P. A., Roos, B. O., Sadlej, A. J., & Wolinski, K. (1990). Second-order perturbation theory with a CASSCF reference function. The Journal of Physical Chemistry, 94(14), 5483-5488. doi:10.1021/j100377a012Roca-Sanjuán, D., Aquilante, F., & Lindh, R. (2011). Multiconfiguration second-order perturbation theory approach to strong electron correlation in chemistry and photochemistry. Wiley Interdisciplinary Reviews: Computational Molecular Science, 2(4), 585-603. doi:10.1002/wcms.97In:http://www.ccdc.cam.ac.uk/solutions/csd-discovery/components/gold/(accessed January 22 2020).Zunszain, P. A., Ghuman, J., Komatsu, T., Tsuchida, E., & Curry, S. (2003). BMC Structural Biology, 3(1), 6. doi:10.1186/1472-6807-3-6D. A. Case R. M. Betz D. S. Cerutti T. E. Cheatham T. A. Darden R. E. Duke T. J. Giese H. Gohlke A. W. Goetz N. Homeyer S. Izadi P. Janowski J. J. Kaus A. Kovalenko T. S. Lee S. LeGrand P. Li C. Lin T. Luchko R. Luo B. Madej D. Mermelstein K. M. M. Merz G. Monard H. Nguyen H. Nguyen I. Omelyan A. Onufriev D. R. R. Roe A. Roitberg C. Sagui C. L. Simmerling W. M. Botello-Smith J. Swails R. Walker J. Wang R. M. Wolf X. Wu L. Xiao P. A. Kollman AMBER2016 University of California San Francisco.Wybranowski, T., Cyrankiewicz, M., Ziomkowska, B., & Kruszewski, S. (2008). The HSA affinity of warfarin and flurbiprofen determined by fluorescence anisotropy measurements of camptothecin. Biosystems, 94(3), 258-262. doi:10.1016/j.biosystems.2008.05.034Itoh, T., Saura, Y., Tsuda, Y., & Yamada, H. (1997). Stereoselectivity and enantiomer-enantiomer interactions in the binding of ibuprofen to human serum albumin. Chirality, 9(7), 643-649. doi:10.1002/(sici)1520-636x(1997)9:73.0.co;2-8Pérez-Ruíz, R., Lence, E., Andreu, I., Limones-Herrero, D., González-Bello, C., Miranda, M. A., & Jiménez, M. C. (2017). A New Pathway for Protein Haptenation by β-Lactams. Chemistry - A European Journal, 23(56), 13986-13994. doi:10.1002/chem.201702643Gaussian 09 Revision D.01 M. J. Frisch G. W. Trucks H. B. Schlegel G. E. Scuseria M. A. Robb J. R. Cheeseman G. Scalmani V. Barone B. Mennucci G. A. Petersson H. Nakatsuji M. Caricato X. Li H. P. Hratchian A. F. Izmaylov J. Bloino G. Zheng J. L. Sonnenberg M. Hada M. Ehara K. Toyota R. Fukuda J. Hasegawa M. Ishida T. Nakajima Y. Honda O. Kitao H. Nakai T. Vreven J. J. A. Montgomery J. E. Peralta F. Ogliaro M. Bearpark J. J. Heyd E. Brothers K. N. Kudin V. N. Staroverov R. Kobayashi J. Normand K. Raghavachari A. Rendell J. C. Burant S. S. Iyengar J. Tomasi M. Cossi N. Rega J. M. Millam M. Klene J. E. Knox J. B. Cross V. Bakken C. Adamo J. Jaramillo R. Gomperts R. E. Stratmann O. Yazyev A. J. Austin R. Cammi C. Pomelli J. W. Ochterski R. L. Martin K. Morokuma V. G. Zakrzewski G. A. Voth P. Salvador J. J. Dannenberg S. Dapprich A. D. Daniels Ö. Farkas J. B. Foresman J. V. Ortiz J. Cioslowski D. J. Fox 2013 Wallingford CT.Aquilante, F., Autschbach, J., Carlson, R. K., Chibotaru, L. F., Delcey, M. G., De Vico, L., … Lindh, R. (2015). Molcas 8: New capabilities for multiconfigurational quantum chemical calculations across the periodic table. Journal of Computational Chemistry, 37(5), 506-541. doi:10.1002/jcc.24221Forsberg, N., & Malmqvist, P.-Å. (1997). Multiconfiguration perturbation theory with imaginary level shift. Chemical Physics Letters, 274(1-3), 196-204. doi:10.1016/s0009-2614(97)00669-6W. L. DeLano in The PyMOL Molecular Graphics System.http://www.pymol.org/