Palladium(II) complexes containing C,N- and N,S-donors ligands: synthesis, characterization, cytotoxicity and study of interaction with biomolecules

Autor: Zanetti, Renan Diego
Přispěvatelé: Universidade Estadual Paulista (Unesp), Godoy Netto, Adelino Vieira de [UNESP]
Jazyk: portugalština
Rok vydání: 2022
Předmět:
Zdroj: Repositório Institucional da UNESP
Universidade Estadual Paulista (UNESP)
instacron:UNESP
ISSN: 7170-5007
Popis: Submitted by Renan Diego Zanetti (renan.zanetti@unesp.br) on 2022-10-07T12:02:44Z No. of bitstreams: 1 Tese - Renan D. Zanetti.pdf: 8548821 bytes, checksum: d1026f588a029900e1e59c0bcbb3840d (MD5) Approved for entry into archive by Ana Carolina Gonçalves Bet null (abet@iq.unesp.br) on 2022-10-07T17:16:28Z (GMT) No. of bitstreams: 1 zanetti_rd_dr_araiq_int.pdf: 8456642 bytes, checksum: 8f0e71705007fbd1e44e0def347a4e0e (MD5) Made available in DSpace on 2022-10-07T17:16:28Z (GMT). No. of bitstreams: 1 zanetti_rd_dr_araiq_int.pdf: 8456642 bytes, checksum: 8f0e71705007fbd1e44e0def347a4e0e (MD5) Previous issue date: 2022-09-16 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) O câncer representa o conjunto de doenças que mais causa morte em todo mundo, sendo os casos relacionados apenas ao trato respiratório aparecendo como a sexta principal causa de morte, em 2019, segundo a OMS. Dentre as diversas formas de tratamento disponíveis, a quimioterapia é uma das mais aplicadas, tendo destaque para a cisplatina, um complexo de platina(II), que teve sua ação antitumoral descoberta na década de 70 e, desde então, tem sido aplicado com esse propósito. No entanto, o caráter tóxico somado a crescente resistência a fármacos (MDR) tem motivado a busca por novos candidatos a metalo-fármacos. Assim, complexos de paládio(II) aparecem como um candidatos promissores no design de compostos com potencial atividade antitumoral, já que possuem características estruturais semelhantes a platina(II), porém com a vantagem de geralmente não serem genotóxicos. Nesse sentido, duas séries de complexos de paládio(II) foram preparadas e reportadas neste trabalho. A primeira série compreende três complexos (R1-R3) derivados de pirazóis de fórmula geral [PdCl(nTPz)(PPh3)], {HTPz= 3,5-dimetilpirazol-1- iminotiolato (R1); MTPz= 3,5-dimetilpirazol-N-metil-1-iminotiolato (R2); FTPz= 3,5-dimetilpirazol-N-fenil-1-iminotiolato (R3); e PPh3 = trifenilfosfina. A segunda série, compreende dois complexos ciclopaladados derivados de benzilaminas de fórmula geral [Pd(C2 ,N-dmpa)(X)(lut)] {X = Cl− (RZ1) ou NNN− (RZ2)}, dmpa = N,N-dimetil-1-feniletilamina, lut = 2,6-Lutidina. Todos os complexos foram devidamente caracterizados por espectroscopia vibracional na região do IV, RMN de 1H e 13C, análise elementar e espectrometria de massas ESI/MS. Estudos de estabilidade química em solução aquosa também foram submetidos para as séries de complexos, por RMN ¹H, ³¹P, UV-Vis e condutividade molar. Ensaios in vitro de atividade antiproliferativa foram submetidos para a primeira série de complexos, frente as linhagens celulares MCF-7 (tumoral de mama) e MRC-5 (fibroblasto normal de pulmão). Os complexos foram ativos contra as células tumorais testadas, sendo o composto R2 com atividade comparável ao fármaco de referência cisplatina. Estudos de mecanismo de ação mostraram que os complexos da primeira série (R2-R3) tiveram a capacidade de inibir as enzimas catepsinas B e L, corroborados por estudos in sílico por ancoragem molecular com a enzima B. Por outro lado, os mesmos compostos não apresentaram atividade inibitória frente a enzima topoisomerase IIα, além de exibirem interações de natureza moderada com DNA. Para um dos compostos da segunda série (RZ2), a interação com DNA também foi estudada e apresentou um perfil de interação fraca com a biomolécula, porém mostrou boa capacidade de interação com a albumina de soro humano (HSA), especificamente no subdomínio II localizado no sítio I de Sudlow. Cancer represents the set of diseases that causes the most deaths worldwide, with cases related only to the respiratory tract appearing as the sixth leading cause of death in 2019, according to the WHO. Among the available forms of treatment, chemotherapy is one of the most applied, with emphasis on cisplatin, a platinum(II) complex, which had its antitumor activity discovered in the 1970s and since then has been applied with this purpose. However, the toxic character plus to the increasing drug resistance (MDR) has motivated the search for new candidates for metallodrugs. Thus, palladium(II) complexes appear as promising candidates for the design of compounds with potential antitumor activity, since they have structural characteristics similar to platinum(II), but with the advantage of not being genotoxic. In this sense, two series of palladium(II) complexes were prepared and reported in this work. The first series comprises three complexes (R1-R3) derived from pyrazoles of general formulae [PdCl(nTPz)(PPh3)], {HTPz= 3,5-dimethylpyrazole-1-iminothiolate (R1); MTPz= 3,5-dimethyl-pyrazole-N-methyl-1-iminothiolate (R2); FTPz= 3,5-dimethylpyrazole-N-phenyl-1-iminothiolate (R3); and PPh3 = triphenylphosphine. The second series comprises two cyclopallated complexes derived from benzylamines with the general formulae [Pd(C2,N-dmpa)(X)(lut)] {X = Cl− (RZ1) or NNN− (RZ2)}, dmpa = N,N-dimethyl-1-phenethylamine, lut = 2,6-Lutidine. All complexes were properly characterized by IR vibrational spectroscopy, 1H and 13C NMR, elemental analysis and ESI/MS mass spectrometry. Chemical stability studies in aqueous solution were also submitted for the series of complexes, by ¹H NMR, ³¹P, UV-Vis and molar conductivity. In vitro assays of antiproliferative activity were performed for the first series of complexes, against the cell lines MCF-7 (breast tumor) and MRC-5 (normal lung fibroblast). The complexes were active against the tested tumor cells, with the compound R2 with activity comparable to the reference drug cisplatin. Studies of the mechanism of action showed that the first series complexes (R2-R3) have had the ability to inhibit cathepsins B and L enzymes, corroborated by in silico studies by molecular docking with B enzyme. On the other hand, the same compounds do not showed inhibitory activity against topoisomerase IIα in addition to exhibiting moderate interactions with DNA. For one of the compounds of the second series (RZ2), the interaction with DNA was also studied and it showed weak interaction with the biomolecule, however it showed good ability to interact with human serum albumin (HSA), specifically in the subdomain II located at the Sudlow site I. 141023/2018-0
Databáze: OpenAIRE
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