Stereoselective synthesis of oxime containing Pd(II) compounds: Highly effective, selective and stereo-regulated cytotoxicity against carcinogenic PC-3 cells

Cueva Alique, Isabel de la; Torre Rubio, Elena de la|||0000-0002-0352-0154; Muñoz Moreno, Laura|||0000-0002-2322-8986; Calvo Jareño, Alicia; Pérez Redondo, Adrián|||0000-0002-0086-8825; Gude Rodríguez, Lourdes|||0000-0002-0220-3755; Cuenca Agreda, José Tomás|||0000-0001-5830-5833; Royo Cantabrana, Eva|||0000-0003-3818-6448

Stereoselective synthesis of oxime containing Pd(II) compounds: Highly effective, selective and stereo-regulated cytotoxicity against carcinogenic PC-3 cells

New palladium compounds [Pd{(1S,4R)-NOH<^>NH(R)}Cl-2] (R = Ph 1a or Bn 1b), [Pd{(1S,4R)-NOH<^>NH(R)}{(1S,4R)-NO<^>NH(R)}][Cl] (R = Ph 2a or Bn 2b) and corresponding [Pd{(1R,4S)-NOH<^>NH(R)}Cl-2] (R = Ph 1a' or Bn 1b') and [Pd{(1R,4S)-NOH<^>NH(R)}{(1R,4S)-NO<...

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Detalles Bibliográficos
Autores:	Cueva Alique, Isabel de la, Torre Rubio, Elena de la\|\|\|0000-0002-0352-0154, Muñoz Moreno, Laura\|\|\|0000-0002-2322-8986, Calvo Jareño, Alicia, Pérez Redondo, Adrián\|\|\|0000-0002-0086-8825, Gude Rodríguez, Lourdes\|\|\|0000-0002-0220-3755, Cuenca Agreda, José Tomás\|\|\|0000-0001-5830-5833, Royo Cantabrana, Eva\|\|\|0000-0003-3818-6448
Tipo de recurso:	artículo
Fecha de publicación:	2022
País:	España
Institución:	Universidad de Alcalá (UAH)
Repositorio:	e_Buah Biblioteca Digital Universidad de Alcalá
Idioma:	inglés
OAI Identifier:	oai:ebuah.uah.es:10017/59883
Acceso en línea:	http://hdl.handle.net/10017/59883 https://dx.doi.org/10.1039/D2DT01403C
Access Level:	acceso abierto
Palabra clave:	cancer palladium compounds antimetastatic DNA Química Chemistry

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spelling	Stereoselective synthesis of oxime containing Pd(II) compounds: Highly effective, selective and stereo-regulated cytotoxicity against carcinogenic PC-3 cellsCueva Alique, Isabel de laTorre Rubio, Elena de la\|\|\|0000-0002-0352-0154Muñoz Moreno, Laura\|\|\|0000-0002-2322-8986Calvo Jareño, AliciaPérez Redondo, Adrián\|\|\|0000-0002-0086-8825Gude Rodríguez, Lourdes\|\|\|0000-0002-0220-3755Cuenca Agreda, José Tomás\|\|\|0000-0001-5830-5833Royo Cantabrana, Eva\|\|\|0000-0003-3818-6448cancerpalladium compoundsantimetastaticDNAQuímicaChemistryNew palladium compounds [Pd{(1S,4R)-NOH<^>NH(R)}Cl-2] (R = Ph 1a or Bn 1b), [Pd{(1S,4R)-NOH<^>NH(R)}{(1S,4R)-NO<^>NH(R)}][Cl] (R = Ph 2a or Bn 2b) and corresponding [Pd{(1R,4S)-NOH<^>NH(R)}Cl-2] (R = Ph 1a' or Bn 1b') and [Pd{(1R,4S)-NOH<^>NH(R)}{(1R,4S)-NO<^>NH(R)}][Cl] (R = Ph 2a' or Bn 2b') have been synthesized. Novel compounds 1a, 1b, and 2b (and 1a', 1b', and 2b') were obtained in solution as a mixture of diastereomers whose relative ratios depend on the solvent and the nature of the amino substituent. In contrast, the synthetic reactions of derivatives 2a and 2a' were stereospecific, and afforded single enantiomers of absolute configuration (S-N,1S(C),4R(C))-(R-N,1S(C),4R(C)) and (R-N,1R(C),4S(C))-(S-N,1R(C),4S(C)), respectively. All compounds have been fully characterized by NMR and IR spectroscopy, time-dependent UV-spectroscopy, ESI-HR-MS in water, and CHN elemental analysis. Absolute configurations of the major epimers of 1a and 1a', both epimers of 1b and enantiomer 2a', were determined by single crystal X-ray crystallography, and confirmed by 2D NOESY NMR experiments in solution. Additionally, the pH-dependent stability of 2b in water was assessed by H-1-NMR spectroscopy. Metal derivatives have been tested in vitro against three human cancer (prostate PC-3, cervical HeLa, and breast MCF-7) cell lines. The highest anticancer activities were shown by palladium compound 2a' in all cancer cells, with IC50 values up to 80 times lower than those found for cisplatin. The cytotoxicity of 2a and 2a '' is stereo-dependent, with IC50 values that differ significantly for each enantiomer in all the cell lines tested. The cytotoxic activity of 2a and 2a' was further evaluated against the non-tumorigenic human prostate RWPE-1 cell line, revealing a selectivity index (SI) of ca. 30 for derivative 2a'. DNA interactions have been investigated by equilibrium dialysis, fluorescence resonance energy transfer (FRET) DNA melting assays, and viscometric titrations, pointing to groove and/or external binding. Cell cycle assay on PC-3 cells after treatment with 2a or 2a' shows cell cycle arrest in the S and G2/M phases, especially when the cells are treated with compound 2a'.Ministerio de Ciencia e InnovaciónMinisterio de Economía, Industria y CompetitividadUniversidad de AlcaláComunidad de Madrid20222022-08-30journal articlehttp://purl.org/coar/resource_type/c_6501NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10017/59883https://dx.doi.org/10.1039/D2DT01403Creponame:e_Buah Biblioteca Digital Universidad de Alcaláinstname:Universidad de Alcalá (UAH)InglésengMinisterio de Ciencia e Innovación http://dx.doi.org/10.13039/501100004837 Not available PID2019-108251RB-I00%2FAEI%2F10.13039%2F501100011033Ministerio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 Not available CTQ2015-72625-EXP%2FAEIMinisterio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 Not available CTQ2015-72625-EXP%2FAEIUAH Not available UAH-AE-2017-2Comunidad de Madrid http://dx.doi.org/10.13039/100012818 Not available CCG2020%2FCC-026Comunidad de Madrid http://dx.doi.org/10.13039/100012818 Not available CCG2015%2FBIO-010Comunidad de Madrid http://dx.doi.org/10.13039/100012818 Not available CCG20%2FCC-007open accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:ebuah.uah.es:10017/598832026-06-18T11:13:07Z
dc.title.none.fl_str_mv	Stereoselective synthesis of oxime containing Pd(II) compounds: Highly effective, selective and stereo-regulated cytotoxicity against carcinogenic PC-3 cells
title	Stereoselective synthesis of oxime containing Pd(II) compounds: Highly effective, selective and stereo-regulated cytotoxicity against carcinogenic PC-3 cells
spellingShingle	Stereoselective synthesis of oxime containing Pd(II) compounds: Highly effective, selective and stereo-regulated cytotoxicity against carcinogenic PC-3 cells Cueva Alique, Isabel de la cancer palladium compounds antimetastatic DNA Química Chemistry
title_short	Stereoselective synthesis of oxime containing Pd(II) compounds: Highly effective, selective and stereo-regulated cytotoxicity against carcinogenic PC-3 cells
title_full	Stereoselective synthesis of oxime containing Pd(II) compounds: Highly effective, selective and stereo-regulated cytotoxicity against carcinogenic PC-3 cells
title_fullStr	Stereoselective synthesis of oxime containing Pd(II) compounds: Highly effective, selective and stereo-regulated cytotoxicity against carcinogenic PC-3 cells
title_full_unstemmed	Stereoselective synthesis of oxime containing Pd(II) compounds: Highly effective, selective and stereo-regulated cytotoxicity against carcinogenic PC-3 cells
title_sort	Stereoselective synthesis of oxime containing Pd(II) compounds: Highly effective, selective and stereo-regulated cytotoxicity against carcinogenic PC-3 cells
dc.creator.none.fl_str_mv	Cueva Alique, Isabel de la Torre Rubio, Elena de la\|\|\|0000-0002-0352-0154 Muñoz Moreno, Laura\|\|\|0000-0002-2322-8986 Calvo Jareño, Alicia Pérez Redondo, Adrián\|\|\|0000-0002-0086-8825 Gude Rodríguez, Lourdes\|\|\|0000-0002-0220-3755 Cuenca Agreda, José Tomás\|\|\|0000-0001-5830-5833 Royo Cantabrana, Eva\|\|\|0000-0003-3818-6448
author	Cueva Alique, Isabel de la
author_facet	Cueva Alique, Isabel de la Torre Rubio, Elena de la\|\|\|0000-0002-0352-0154 Muñoz Moreno, Laura\|\|\|0000-0002-2322-8986 Calvo Jareño, Alicia Pérez Redondo, Adrián\|\|\|0000-0002-0086-8825 Gude Rodríguez, Lourdes\|\|\|0000-0002-0220-3755 Cuenca Agreda, José Tomás\|\|\|0000-0001-5830-5833 Royo Cantabrana, Eva\|\|\|0000-0003-3818-6448
author_role	author
author2	Torre Rubio, Elena de la\|\|\|0000-0002-0352-0154 Muñoz Moreno, Laura\|\|\|0000-0002-2322-8986 Calvo Jareño, Alicia Pérez Redondo, Adrián\|\|\|0000-0002-0086-8825 Gude Rodríguez, Lourdes\|\|\|0000-0002-0220-3755 Cuenca Agreda, José Tomás\|\|\|0000-0001-5830-5833 Royo Cantabrana, Eva\|\|\|0000-0003-3818-6448
author2_role	author author author author author author author
dc.subject.none.fl_str_mv	cancer palladium compounds antimetastatic DNA Química Chemistry
topic	cancer palladium compounds antimetastatic DNA Química Chemistry
description	New palladium compounds [Pd{(1S,4R)-NOH<^>NH(R)}Cl-2] (R = Ph 1a or Bn 1b), [Pd{(1S,4R)-NOH<^>NH(R)}{(1S,4R)-NO<^>NH(R)}][Cl] (R = Ph 2a or Bn 2b) and corresponding [Pd{(1R,4S)-NOH<^>NH(R)}Cl-2] (R = Ph 1a' or Bn 1b') and [Pd{(1R,4S)-NOH<^>NH(R)}{(1R,4S)-NO<^>NH(R)}][Cl] (R = Ph 2a' or Bn 2b') have been synthesized. Novel compounds 1a, 1b, and 2b (and 1a', 1b', and 2b') were obtained in solution as a mixture of diastereomers whose relative ratios depend on the solvent and the nature of the amino substituent. In contrast, the synthetic reactions of derivatives 2a and 2a' were stereospecific, and afforded single enantiomers of absolute configuration (S-N,1S(C),4R(C))-(R-N,1S(C),4R(C)) and (R-N,1R(C),4S(C))-(S-N,1R(C),4S(C)), respectively. All compounds have been fully characterized by NMR and IR spectroscopy, time-dependent UV-spectroscopy, ESI-HR-MS in water, and CHN elemental analysis. Absolute configurations of the major epimers of 1a and 1a', both epimers of 1b and enantiomer 2a', were determined by single crystal X-ray crystallography, and confirmed by 2D NOESY NMR experiments in solution. Additionally, the pH-dependent stability of 2b in water was assessed by H-1-NMR spectroscopy. Metal derivatives have been tested in vitro against three human cancer (prostate PC-3, cervical HeLa, and breast MCF-7) cell lines. The highest anticancer activities were shown by palladium compound 2a' in all cancer cells, with IC50 values up to 80 times lower than those found for cisplatin. The cytotoxicity of 2a and 2a '' is stereo-dependent, with IC50 values that differ significantly for each enantiomer in all the cell lines tested. The cytotoxic activity of 2a and 2a' was further evaluated against the non-tumorigenic human prostate RWPE-1 cell line, revealing a selectivity index (SI) of ca. 30 for derivative 2a'. DNA interactions have been investigated by equilibrium dialysis, fluorescence resonance energy transfer (FRET) DNA melting assays, and viscometric titrations, pointing to groove and/or external binding. Cell cycle assay on PC-3 cells after treatment with 2a or 2a' shows cell cycle arrest in the S and G2/M phases, especially when the cells are treated with compound 2a'.
publishDate	2022
dc.date.none.fl_str_mv	2022 2022-08-30
dc.type.none.fl_str_mv	journal article http://purl.org/coar/resource_type/c_6501 NA http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv	info:eu-repo/semantics/article
format	article
dc.identifier.none.fl_str_mv	http://hdl.handle.net/10017/59883 https://dx.doi.org/10.1039/D2DT01403C
url	http://hdl.handle.net/10017/59883 https://dx.doi.org/10.1039/D2DT01403C
dc.language.none.fl_str_mv	Inglés eng
language_invalid_str_mv	Inglés
language	eng
dc.relation.none.fl_str_mv	Ministerio de Ciencia e Innovación http://dx.doi.org/10.13039/501100004837 Not available PID2019-108251RB-I00%2FAEI%2F10.13039%2F501100011033 Ministerio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 Not available CTQ2015-72625-EXP%2FAEI Ministerio de Economía y Competitividad http://dx.doi.org/10.13039/501100003329 Not available CTQ2015-72625-EXP%2FAEI UAH Not available UAH-AE-2017-2 Comunidad de Madrid http://dx.doi.org/10.13039/100012818 Not available CCG2020%2FCC-026 Comunidad de Madrid http://dx.doi.org/10.13039/100012818 Not available CCG2015%2FBIO-010 Comunidad de Madrid http://dx.doi.org/10.13039/100012818 Not available CCG20%2FCC-007
dc.rights.none.fl_str_mv	open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv	info:eu-repo/semantics/openAccess
rights_invalid_str_mv	open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.source.none.fl_str_mv	reponame:e_Buah Biblioteca Digital Universidad de Alcalá instname:Universidad de Alcalá (UAH)
instname_str	Universidad de Alcalá (UAH)
reponame_str	e_Buah Biblioteca Digital Universidad de Alcalá
collection	e_Buah Biblioteca Digital Universidad de Alcalá
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repository.mail.fl_str_mv
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Stereoselective synthesis of oxime containing Pd(II) compounds: Highly effective, selective and stereo-regulated cytotoxicity against carcinogenic PC-3 cells

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