Complexos fosfínicos de Pd(II) com produtos naturais: síntese, caracterização, avaliação da citotoxicidade e interação com biomoléculas
Autor(a) principal: | |
---|---|
Data de Publicação: | 2023 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFSCAR |
Texto Completo: | https://repositorio.ufscar.br/handle/ufscar/19261 |
Resumo: | This thesis details the synthesis, characterization and evaluation of antitumor activity of twelve monocationic PdII/phosphine complexes featuring ligands derived from products natural. The complexes were categorized in three Series: Series A; complexes with the general formula [Pd(cur)(P-P)]PF6, where cur=curcumin, PF6=hexafluorophosphate and P-P= PPh3=triphenylphosphine (A1), dppe=1,2-bis(diphenylphosphine)ethane (A2), dppp= 1,3-bis(diphenylphosphine)propane (A3), dppb=1,4'-bis(diphenylphosphine)butane (A4) and dppf=1,1'-bis(diphenylphosphine)ferrocene (A5); Series B, complexes with the general formula [Pd(dppe)(O-O)]PF6, where O-O= lau=lausone (B1), lap=lapachol (B2), lpm=3-styryl-lausone (B3) and ali=alizarin (B4); Series C, complexes of the type [Pd(P-P)(lap)]PF6, where P-P= dppp (C1), dppb (C2) and dppf (C3). Their characterization involves elemental analysis, molar conductivity, absorption spectroscopy in the infrared region, 1D and 2D nuclear magnetic resonance (31P{1H}, 1H and 13C{1H}), mass spectrometry and single-crystal X-ray diffraction. Stability assessment in biological relevant solvents, using UV-vis absorption spectroscopy, revealed instability on Series A, due to the self-oxidation of curcumin, as previously reported, while the Series B and C complexes were stable. The antitumor activity was evaluated in variety of cell lines, such as breast (MDA-MB-237, MCF-7 and SKBR-3), lung (A549), prostate (DU-145), ovarian (A2780 and A2780cis) and non-tumor cells of the breast (MCF-10A) and lung (MRC-5), varying the number of lines in each Series. Series A complexes showed low IC50 in several of the tumor lines tested, including some cell lines which the activity is superior to curcumin and cisplatin. The [Pd(cur)(PPh3)2]PF6 stands out in tumor lines MDA-MB-231 (5,0 ± 0,2 M), A2780 (0,5 ± 0,1 M) and A2780cis (1,4 ± 0,4 M) than the other complexes in the series, with the highest selectivity index displayed for the A2780 lineage (≥40). Series B systematically demonstrates the effects of naphthoquinones and anthraquinone coordination to Pd on IC50 values, highlighting the lapachol complex (B2) as the most active in of tumor cells tested, especially for A2780 (IC50 3.5 ± 0,1 µM, SI ≥ 11.4). In series C, C3 complex stands out presenting IC50 1.1 ± 0.2 M and SI ≥ 36.4 in A2780cis. In general, complexes A1, B2 and C3 were able to inhibit colony formation and induce morphological changes in tumor lines. Furthermore, the A1, B2, and C3 complexes promoted a cycle cell arrest in the Sub-G1 phase, which represents the fraction of dead cells with fragmented DNA. The flow cytometry assay with Annexin-V and 7-AAD showed that the complexes induce cell death by apoptosis. The complexes demonstrated weak and reversible interactions with the minor groove of DNA, without affecting its secondary and tertiary structures. Interaction assays with HSA were performed, revealing moderate to strong interactions with the complexes. The possible mechanism of death for the complexes is by inducing the formation of ROS in cells, as demonstrated for the A1 complex in A2780cis cells. |
id |
SCAR_6f2d5ff63298bad003dd9f7208507eeb |
---|---|
oai_identifier_str |
oai:repositorio.ufscar.br:ufscar/19261 |
network_acronym_str |
SCAR |
network_name_str |
Repositório Institucional da UFSCAR |
repository_id_str |
4322 |
spelling |
Dutra, Jocely de LucenaBatista, Alzir Azevedohttp://lattes.cnpq.br/6469642481998660http://lattes.cnpq.br/7966283355473231https://orcid.org/0000-0002-1911-2470https://orcid.org/0000-0002-4671-27542024-02-09T18:46:44Z2024-02-09T18:46:44Z2023-11-29DUTRA, Jocely de Lucena. Complexos fosfínicos de Pd(II) com produtos naturais: síntese, caracterização, avaliação da citotoxicidade e interação com biomoléculas. 2023. Tese (Doutorado em Química) – Universidade Federal de São Carlos, São Carlos, 2023. Disponível em: https://repositorio.ufscar.br/handle/ufscar/19261.https://repositorio.ufscar.br/handle/ufscar/19261This thesis details the synthesis, characterization and evaluation of antitumor activity of twelve monocationic PdII/phosphine complexes featuring ligands derived from products natural. The complexes were categorized in three Series: Series A; complexes with the general formula [Pd(cur)(P-P)]PF6, where cur=curcumin, PF6=hexafluorophosphate and P-P= PPh3=triphenylphosphine (A1), dppe=1,2-bis(diphenylphosphine)ethane (A2), dppp= 1,3-bis(diphenylphosphine)propane (A3), dppb=1,4'-bis(diphenylphosphine)butane (A4) and dppf=1,1'-bis(diphenylphosphine)ferrocene (A5); Series B, complexes with the general formula [Pd(dppe)(O-O)]PF6, where O-O= lau=lausone (B1), lap=lapachol (B2), lpm=3-styryl-lausone (B3) and ali=alizarin (B4); Series C, complexes of the type [Pd(P-P)(lap)]PF6, where P-P= dppp (C1), dppb (C2) and dppf (C3). Their characterization involves elemental analysis, molar conductivity, absorption spectroscopy in the infrared region, 1D and 2D nuclear magnetic resonance (31P{1H}, 1H and 13C{1H}), mass spectrometry and single-crystal X-ray diffraction. Stability assessment in biological relevant solvents, using UV-vis absorption spectroscopy, revealed instability on Series A, due to the self-oxidation of curcumin, as previously reported, while the Series B and C complexes were stable. The antitumor activity was evaluated in variety of cell lines, such as breast (MDA-MB-237, MCF-7 and SKBR-3), lung (A549), prostate (DU-145), ovarian (A2780 and A2780cis) and non-tumor cells of the breast (MCF-10A) and lung (MRC-5), varying the number of lines in each Series. Series A complexes showed low IC50 in several of the tumor lines tested, including some cell lines which the activity is superior to curcumin and cisplatin. The [Pd(cur)(PPh3)2]PF6 stands out in tumor lines MDA-MB-231 (5,0 ± 0,2 M), A2780 (0,5 ± 0,1 M) and A2780cis (1,4 ± 0,4 M) than the other complexes in the series, with the highest selectivity index displayed for the A2780 lineage (≥40). Series B systematically demonstrates the effects of naphthoquinones and anthraquinone coordination to Pd on IC50 values, highlighting the lapachol complex (B2) as the most active in of tumor cells tested, especially for A2780 (IC50 3.5 ± 0,1 µM, SI ≥ 11.4). In series C, C3 complex stands out presenting IC50 1.1 ± 0.2 M and SI ≥ 36.4 in A2780cis. In general, complexes A1, B2 and C3 were able to inhibit colony formation and induce morphological changes in tumor lines. Furthermore, the A1, B2, and C3 complexes promoted a cycle cell arrest in the Sub-G1 phase, which represents the fraction of dead cells with fragmented DNA. The flow cytometry assay with Annexin-V and 7-AAD showed that the complexes induce cell death by apoptosis. The complexes demonstrated weak and reversible interactions with the minor groove of DNA, without affecting its secondary and tertiary structures. Interaction assays with HSA were performed, revealing moderate to strong interactions with the complexes. The possible mechanism of death for the complexes is by inducing the formation of ROS in cells, as demonstrated for the A1 complex in A2780cis cells.Esta tese detalha a síntese, caracterização e avaliação de atividade antitumoral de doze complexos de PdII/fosfina, monocatiônicos, contendo ligantes derivados de produtos naturais. Os complexos foram divididos em três séries, sendo elas: Série A; complexos de fórmula geral [Pd(cur)(P-P)]PF6, onde cur = curcumina, PF6- = íon hexafluorfosfato e P-P= PPh3=trifenilfosfina (A1), dppe = 1,2-bis(difenilfosfina)etano (A2), dppp = 1,3-bis(difenilfosfina)propano (A3), dppb = 1,4´-bis(difenilfosfina)butano (A4) e dppf = 1,1´-bis(difenilfosfina)ferroceno (A5); Série B, complexos de fórmula geral [Pd(dppe)(O-O)]PF6, onde O-O= lau = lausona (B1), lap = lapachol (B2), lpm = 3-estiril-lausona (B3) e ali = alizarina (B4); Série C, complexos do tipo [Pd(P-P)(lap)]PF6, onde P-P = dppp (C1), dppb (C2) e dppf (C3). A caracterização dos complexos foi realizada por análise elementar, condutividade molar, espectroscopia de absorção na região do infravermelho, ressonância magnética nuclear 1D e 2D (31P{1H}, 1H e 13C{1H}), espectrometria de massas e difração de raios X de monocristal, para alguns dos complexos obtidos. A avaliação da estabilidade em solventes biológicos relevantes, utilizando espectroscopia de absorção na região do UV-vis, revelou instabilidade na Série A, devido à auto-oxidação da curcumina, conforme relatado em literatura, enquanto os complexos da Série B e C foram estáveis. A viabilidade celular foi avaliada em diversas linhagens celulares, como células tumorais de mama (MDA-MB-237, MCF-7 e SKBR-3), pulmão (A549), próstata (DU-145), ovário (A2780 e A2780cis) e as não tumorais de mama (MCF-10A) e pulmão (MRC-5), variando o número de linhagens em cada série. Para a Série A os complexos apresentaram baixos valores de IC50 em diversas das linhagens tumorais testadas, sendo maioria deles menores que o IC50 da curcumina e da cisplatina. O [Pd(cur)(PPh3)2]PF6 se destacou nas linhagens tumorais MDA-MB-231 (5,0 ± 0,2 M), A2780 (0,5 ± 0,1 M) e A2780cis (1,4 ± 0,4 M) que os demais complexos da série, sendo o maior índice de seletividade exibido para a linhagem A2780 (≥40). A Série B demonstra sistematicamente os efeitos da coordenação de naftoquinonas e antraquinonas ao Pd nos valores de IC50, destacando o complexo com o ligante lapachol (B2) como o mais ativo nas células tumorais testadas, especialmente para A2780 (IC50 3,5 ± 0,1 µM, SI ≥ 11,4). Na Série C, [Pd(dppf)(lap)]PF6 se destacou apresentando IC50 de 1,1 ± 0,2 M e IS ≥ 36,4 na A2780cis. De modo geral, os complexos A1, B2 e C3 foram capazes de inibir a formação de colônias, induzir alterações morfológicas nas linhagens tumorais, no entanto não inibiram a migração celular. Além disso, os complexos A1, B2, e C3 promoveram acúmulo na fase Sub-G1, que representa a fração de células mortas e com DNA fragmentado. O ensaio por citometria de fluxo com Anexina-V e 7-AAD mostraram que os complexos induzem a morte das células por apoptose. Os complexos demonstraram interações fracas e reversíveis com o sulco menor do DNA, sem afetar as suas estruturas secundárias e terciárias. Ensaios de interação com a HSA foram realizados, revelando interações moderadas a fortes com os complexos. O possível mecanismo de morte celular causada pelos complexos é por indução à formação de ERO (Espécies Reativas de Oxigênio) nas células, como demonstrado para o complexo A1 nas células A2780cis .Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)88887.373238/2019-00porUniversidade Federal de São CarlosCâmpus São CarlosPrograma de Pós-Graduação em Química - PPGQUFSCarAttribution-NonCommercial-NoDerivs 3.0 Brazilhttp://creativecommons.org/licenses/by-nc-nd/3.0/br/info:eu-repo/semantics/openAccessBioinorganicPalladiumNatural productsCytotoxicityCurcuminBioinorgânicaPaládioProdutos naturaisCitotoxicidadeCurcuminaCIENCIAS EXATAS E DA TERRA::QUIMICAComplexos fosfínicos de Pd(II) com produtos naturais: síntese, caracterização, avaliação da citotoxicidade e interação com biomoléculasPhosphine complexes of Pd(II) with natural products: synthesis, characterization, evaluation of cytotoxicity and interaction with biomoleculesinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisreponame:Repositório Institucional da UFSCARinstname:Universidade Federal de São Carlos (UFSCAR)instacron:UFSCARORIGINALTESE Jocely de Lucena Dutra_final.pdfTESE Jocely de Lucena Dutra_final.pdfTeseapplication/pdf15885236https://repositorio.ufscar.br/bitstream/ufscar/19261/3/TESE%20Jocely%20de%20Lucena%20Dutra_final.pdf392e72c08a5b373add652e70c788f8cbMD53CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8810https://repositorio.ufscar.br/bitstream/ufscar/19261/4/license_rdff337d95da1fce0a22c77480e5e9a7aecMD54TEXTTESE Jocely de Lucena Dutra_final.pdf.txtTESE Jocely de Lucena Dutra_final.pdf.txtExtracted texttext/plain350187https://repositorio.ufscar.br/bitstream/ufscar/19261/5/TESE%20Jocely%20de%20Lucena%20Dutra_final.pdf.txt377b99f2049a7729340b8153ed51b3b7MD55ufscar/192612024-05-14 17:30:56.608oai:repositorio.ufscar.br:ufscar/19261Repositório InstitucionalPUBhttps://repositorio.ufscar.br/oai/requestopendoar:43222024-05-14T17:30:56Repositório Institucional da UFSCAR - Universidade Federal de São Carlos (UFSCAR)false |
dc.title.por.fl_str_mv |
Complexos fosfínicos de Pd(II) com produtos naturais: síntese, caracterização, avaliação da citotoxicidade e interação com biomoléculas |
dc.title.alternative.eng.fl_str_mv |
Phosphine complexes of Pd(II) with natural products: synthesis, characterization, evaluation of cytotoxicity and interaction with biomolecules |
title |
Complexos fosfínicos de Pd(II) com produtos naturais: síntese, caracterização, avaliação da citotoxicidade e interação com biomoléculas |
spellingShingle |
Complexos fosfínicos de Pd(II) com produtos naturais: síntese, caracterização, avaliação da citotoxicidade e interação com biomoléculas Dutra, Jocely de Lucena Bioinorganic Palladium Natural products Cytotoxicity Curcumin Bioinorgânica Paládio Produtos naturais Citotoxicidade Curcumina CIENCIAS EXATAS E DA TERRA::QUIMICA |
title_short |
Complexos fosfínicos de Pd(II) com produtos naturais: síntese, caracterização, avaliação da citotoxicidade e interação com biomoléculas |
title_full |
Complexos fosfínicos de Pd(II) com produtos naturais: síntese, caracterização, avaliação da citotoxicidade e interação com biomoléculas |
title_fullStr |
Complexos fosfínicos de Pd(II) com produtos naturais: síntese, caracterização, avaliação da citotoxicidade e interação com biomoléculas |
title_full_unstemmed |
Complexos fosfínicos de Pd(II) com produtos naturais: síntese, caracterização, avaliação da citotoxicidade e interação com biomoléculas |
title_sort |
Complexos fosfínicos de Pd(II) com produtos naturais: síntese, caracterização, avaliação da citotoxicidade e interação com biomoléculas |
author |
Dutra, Jocely de Lucena |
author_facet |
Dutra, Jocely de Lucena |
author_role |
author |
dc.contributor.authorlattes.por.fl_str_mv |
http://lattes.cnpq.br/7966283355473231 |
dc.contributor.authororcid.por.fl_str_mv |
https://orcid.org/0000-0002-1911-2470 |
dc.contributor.advisor1orcid.por.fl_str_mv |
https://orcid.org/0000-0002-4671-2754 |
dc.contributor.author.fl_str_mv |
Dutra, Jocely de Lucena |
dc.contributor.advisor1.fl_str_mv |
Batista, Alzir Azevedo |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/6469642481998660 |
contributor_str_mv |
Batista, Alzir Azevedo |
dc.subject.eng.fl_str_mv |
Bioinorganic Palladium Natural products Cytotoxicity Curcumin |
topic |
Bioinorganic Palladium Natural products Cytotoxicity Curcumin Bioinorgânica Paládio Produtos naturais Citotoxicidade Curcumina CIENCIAS EXATAS E DA TERRA::QUIMICA |
dc.subject.por.fl_str_mv |
Bioinorgânica Paládio Produtos naturais Citotoxicidade Curcumina |
dc.subject.cnpq.fl_str_mv |
CIENCIAS EXATAS E DA TERRA::QUIMICA |
description |
This thesis details the synthesis, characterization and evaluation of antitumor activity of twelve monocationic PdII/phosphine complexes featuring ligands derived from products natural. The complexes were categorized in three Series: Series A; complexes with the general formula [Pd(cur)(P-P)]PF6, where cur=curcumin, PF6=hexafluorophosphate and P-P= PPh3=triphenylphosphine (A1), dppe=1,2-bis(diphenylphosphine)ethane (A2), dppp= 1,3-bis(diphenylphosphine)propane (A3), dppb=1,4'-bis(diphenylphosphine)butane (A4) and dppf=1,1'-bis(diphenylphosphine)ferrocene (A5); Series B, complexes with the general formula [Pd(dppe)(O-O)]PF6, where O-O= lau=lausone (B1), lap=lapachol (B2), lpm=3-styryl-lausone (B3) and ali=alizarin (B4); Series C, complexes of the type [Pd(P-P)(lap)]PF6, where P-P= dppp (C1), dppb (C2) and dppf (C3). Their characterization involves elemental analysis, molar conductivity, absorption spectroscopy in the infrared region, 1D and 2D nuclear magnetic resonance (31P{1H}, 1H and 13C{1H}), mass spectrometry and single-crystal X-ray diffraction. Stability assessment in biological relevant solvents, using UV-vis absorption spectroscopy, revealed instability on Series A, due to the self-oxidation of curcumin, as previously reported, while the Series B and C complexes were stable. The antitumor activity was evaluated in variety of cell lines, such as breast (MDA-MB-237, MCF-7 and SKBR-3), lung (A549), prostate (DU-145), ovarian (A2780 and A2780cis) and non-tumor cells of the breast (MCF-10A) and lung (MRC-5), varying the number of lines in each Series. Series A complexes showed low IC50 in several of the tumor lines tested, including some cell lines which the activity is superior to curcumin and cisplatin. The [Pd(cur)(PPh3)2]PF6 stands out in tumor lines MDA-MB-231 (5,0 ± 0,2 M), A2780 (0,5 ± 0,1 M) and A2780cis (1,4 ± 0,4 M) than the other complexes in the series, with the highest selectivity index displayed for the A2780 lineage (≥40). Series B systematically demonstrates the effects of naphthoquinones and anthraquinone coordination to Pd on IC50 values, highlighting the lapachol complex (B2) as the most active in of tumor cells tested, especially for A2780 (IC50 3.5 ± 0,1 µM, SI ≥ 11.4). In series C, C3 complex stands out presenting IC50 1.1 ± 0.2 M and SI ≥ 36.4 in A2780cis. In general, complexes A1, B2 and C3 were able to inhibit colony formation and induce morphological changes in tumor lines. Furthermore, the A1, B2, and C3 complexes promoted a cycle cell arrest in the Sub-G1 phase, which represents the fraction of dead cells with fragmented DNA. The flow cytometry assay with Annexin-V and 7-AAD showed that the complexes induce cell death by apoptosis. The complexes demonstrated weak and reversible interactions with the minor groove of DNA, without affecting its secondary and tertiary structures. Interaction assays with HSA were performed, revealing moderate to strong interactions with the complexes. The possible mechanism of death for the complexes is by inducing the formation of ROS in cells, as demonstrated for the A1 complex in A2780cis cells. |
publishDate |
2023 |
dc.date.issued.fl_str_mv |
2023-11-29 |
dc.date.accessioned.fl_str_mv |
2024-02-09T18:46:44Z |
dc.date.available.fl_str_mv |
2024-02-09T18:46:44Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
DUTRA, Jocely de Lucena. Complexos fosfínicos de Pd(II) com produtos naturais: síntese, caracterização, avaliação da citotoxicidade e interação com biomoléculas. 2023. Tese (Doutorado em Química) – Universidade Federal de São Carlos, São Carlos, 2023. Disponível em: https://repositorio.ufscar.br/handle/ufscar/19261. |
dc.identifier.uri.fl_str_mv |
https://repositorio.ufscar.br/handle/ufscar/19261 |
identifier_str_mv |
DUTRA, Jocely de Lucena. Complexos fosfínicos de Pd(II) com produtos naturais: síntese, caracterização, avaliação da citotoxicidade e interação com biomoléculas. 2023. Tese (Doutorado em Química) – Universidade Federal de São Carlos, São Carlos, 2023. Disponível em: https://repositorio.ufscar.br/handle/ufscar/19261. |
url |
https://repositorio.ufscar.br/handle/ufscar/19261 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
Attribution-NonCommercial-NoDerivs 3.0 Brazil http://creativecommons.org/licenses/by-nc-nd/3.0/br/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivs 3.0 Brazil http://creativecommons.org/licenses/by-nc-nd/3.0/br/ |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal de São Carlos Câmpus São Carlos |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Química - PPGQ |
dc.publisher.initials.fl_str_mv |
UFSCar |
publisher.none.fl_str_mv |
Universidade Federal de São Carlos Câmpus São Carlos |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UFSCAR instname:Universidade Federal de São Carlos (UFSCAR) instacron:UFSCAR |
instname_str |
Universidade Federal de São Carlos (UFSCAR) |
instacron_str |
UFSCAR |
institution |
UFSCAR |
reponame_str |
Repositório Institucional da UFSCAR |
collection |
Repositório Institucional da UFSCAR |
bitstream.url.fl_str_mv |
https://repositorio.ufscar.br/bitstream/ufscar/19261/3/TESE%20Jocely%20de%20Lucena%20Dutra_final.pdf https://repositorio.ufscar.br/bitstream/ufscar/19261/4/license_rdf https://repositorio.ufscar.br/bitstream/ufscar/19261/5/TESE%20Jocely%20de%20Lucena%20Dutra_final.pdf.txt |
bitstream.checksum.fl_str_mv |
392e72c08a5b373add652e70c788f8cb f337d95da1fce0a22c77480e5e9a7aec 377b99f2049a7729340b8153ed51b3b7 |
bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 MD5 |
repository.name.fl_str_mv |
Repositório Institucional da UFSCAR - Universidade Federal de São Carlos (UFSCAR) |
repository.mail.fl_str_mv |
|
_version_ |
1802136431982804992 |