Novel ureido-dihydropyridine scaffolds as theranostic agents F. Auria-Luna 1 , S. Ardevines 1 , M. E. Marqués-López 1 , E. Romanos 1,2,3 , V. Fernández- Moreira 2, *, M. C. Gimeno 2 , I. Marzo 4 , R. P. Herrera 1, * 1 Laboratorio de Organocatálisis Asimétrica, Departamento de Química Orgánica. Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC-Universidad de Zaragoza. C/ Pedro Cerbuna 12, E-50009 Zaragoza, Spain. 2 Departamento de Química Inorgánica. Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC- Universidad de Zaragoza. C/ Pedro Cerbuna 12, E-50009 Zaragoza, Spain. 3 Departamento de Imagen y Fenotipado, Instituto Aragonés de Ciencias de la Salud. Centro de Investigación Biomédica de Aragón (CIBA), Avda. San Juan Bosco, 13, planta D. E-50009 Zaragoza, Spain 2 Departamento de Química Inorgánica. Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC-Universidad de Zaragoza. C/ Pedro Cerbuna 12, E-50009 Zaragoza, Spain. 4 Departamento de Bioquímica y Biología Celular, Universidad de Zaragoza, C/ Pedro Cerbuna 12, E-50009 Zaragoza, Spain. * Corresponding author: [email protected]; [email protected]1
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Novel ureido-dihydropyridine scaffolds as theranostic agents
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Novel ureido-dihydropyridine scaffolds as theranostic agents
F. Auria-Luna 1, S. Ardevines 1, M. E. Marqués-López 1, E. Romanos 1,2,3, V. Fernández-Moreira 2,*, M. C. Gimeno 2, I. Marzo 4, R. P. Herrera 1,*
1 Laboratorio de Organocatálisis Asimétrica, Departamento de Química Orgánica. Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC-Universidad de Zaragoza. C/ Pedro Cerbuna 12, E-50009 Zaragoza, Spain.2 Departamento de Química Inorgánica. Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC-Universidad de Zaragoza. C/ Pedro Cerbuna 12, E-50009 Zaragoza, Spain.3 Departamento de Imagen y Fenotipado, Instituto Aragonés de Ciencias de la Salud. Centro de Investigación Biomédica de Aragón (CIBA), Avda. San Juan Bosco, 13, planta D. E-50009 Zaragoza, Spain2 Departamento de Química Inorgánica. Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC-Universidad de Zaragoza. C/ Pedro Cerbuna 12, E-50009 Zaragoza, Spain.4 Departamento de Bioquímica y Biología Celular, Universidad de Zaragoza, C/ Pedro Cerbuna 12, E-50009 Zaragoza, Spain.
Novel ureido-dihydropyridine scaffolds as theranostic agents
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Abstract
The potential as anticancer agents of 1,4-dihydropyridines (1,4-DHPs) and their pioneeringurea derivatives have been evaluated.in HeLa (cervix), Jurkat (leukaemia) and A549 (lung)cancer cell lines as well as on healthy mice. 1,4-DHPs show moderate cytotoxicity. However,when the urea moiety is introduced, an extraordinary increase in their antiproliferativeactivity is observed, proving an interesting synergy between these two scaffolds. Remarkably,when enantiomerically enriched samples are examined, they result to be in almost all casesless to equally active. This effect could be caused by a complex amalgam of physical andchemical contributions. The studied compounds present luminescent properties and abiodistribution study in cancer cells has been performed. Fluorescence microscopy showedthat some of the 1,4-DHP derivatives accumulated in the lysosomes, whilst their ureacounterparts targeted the cell membrane, which can be key to explain the different cytotoxicactivity and imply a different mechanism of action. Finally, a preliminary in vivo studyregarding the acute toxicity of some of these compounds on healthy mice has beenconducted, using a concentration up to 7200 times higher than the corresponding IC50 value.No downgrade in the welfare of the test subjects was observed, which could support theiruse in preclinical tumour models. Recently, we have been exploring the biological propertiesof 1-benzamido-1,4-dihydropyridine derivatives and the preliminary results on cytotoxicitywill be commented.