Ru(II) complexes containing coumarin hybrid ligands: synthesis and evaluation of cytotoxic and antibacterial activities

Autor: Almeida, Patr?cia Saraiva Vilas Boas de
Přispěvatelé: Neves, Amanda Porto, Kummerle, Arthur Eugen, Lima, ?urea Echevarria Aznar Neves, Silva, Gustavo Bezerra da, Vargas, Maria Domingues, Scarpellini, Marciela
Jazyk: portugalština
Rok vydání: 2019
Předmět:
Zdroj: Biblioteca Digital de Teses e Dissertações da UFRRJ
Universidade Federal Rural do Rio de Janeiro (UFRRJ)
instacron:UFRRJ
Popis: Submitted by Jorge Silva (jorgelmsilva@ufrrj.br) on 2021-11-01T17:58:52Z No. of bitstreams: 1 2019 - Patr?cia Saraiva Vilas Boas de Almeida.pdf: 10195032 bytes, checksum: 9d3b66e0e8c89792bfdc9f439bad3a1b (MD5) Made available in DSpace on 2021-11-01T17:58:52Z (GMT). No. of bitstreams: 1 2019 - Patr?cia Saraiva Vilas Boas de Almeida.pdf: 10195032 bytes, checksum: 9d3b66e0e8c89792bfdc9f439bad3a1b (MD5) Previous issue date: 2019-07-31 CAPES - Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior CNPq - Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico FAPERJ - Funda??o Carlos Chagas Filho de Amparo ? Pesquisa do Estado do Rio de Janeiro Cancer and bacterial infections are diseases that cause a large number of deaths, and despite the existing treatments, drugs being less harmful to the patients and more active against resistant cells are still needed. Coumarin derivatives and several classes of Ru(II) complexes have been studied for their potential as antimicrobial and antitumor agents. For this reason, four novel coumarin-N-acylhydrazone hybrid ligands of the type (E)-7-(diethylamino)-N'-(4-R-benzylidene)-2-oxo-2H-chromene-3-carbohydrazide (HL2: R=H; HL3: R=Cl, HL4: R=Br, HL5: R= OCH3), were obtained from condensation reactions, using one hydrazide (7-(diethylamine)-2-oxo-2H-chromone-3-carbohydrazide, HL1) and different p-substituted aldehydes. Reactions between HL2-5 and cis-[RuCl2(DMSO)4] afforded the complexes trans-cis-[RuCl2(DMSO)2(HL2-5)], C2-5 (Ru(II)-Cl-DMSO class). Concomitantly, hydrolysis of the ligand occurred, resulting in the formation of the complex trans-cis-[RuCl2(DMSO)2(HL1)] C1, containing the hydrazide as ligand. Crystal structures of HL2, HL3 and the complexes C2-5 were determined by single crystal XRD, that revealed an E to Z isomerization of the coumarin-N-acylhydrazones upon coordination. Complexes C2-5 exhibited the Ru(II) atom in a distorted octahedral geometry, where the coumarin ligand is coordinated in the keto form through the hydrazone carbonyl and the iminic nitrogen. In an attempt to synthesize a second class of complexes, containing bipyridine as auxiliary ligand and charged, ([Ru(bipy)2(HLn)]PF6 -Ru(II)-bipy class), the reaction between HL2 and cis-[Ru(bipy)2Cl2] was carried out. However, possible hydrolysis of the ligand precluded the isolation of the desired complex. A similar methodology using cumarin-?-ketoester hybrids HL6-8 yielded the complexes of the Ru(II)-bipy class, [Ru(bipy)2(HL6-8)]PF6 C6-8. The XRD analysis of C7 shows the Ru(II) ion in a distorted octahedral environment with the ligand coordinated through the deprotonated ?-ketoester portion and two bypiridines in the coordination sphere. Antiproliferative evaluation of the compounds against tumor cell lines (4T1: murine mammary carcinoma and B16-F10: murine melanoma metastatic) and a non-tumor cell line (BHK-21: hamster kidney) showed that overall, the coumarin-N-acylhydrazone and coumarin-hydrazyde hybrids HL1-5 were more active than the complexes C1-5, where the IC50 (half of the maximum inhibitory concentration) values for the ligands were found in the range of 10.6 to 50.4 ?M and between 17.7, and 97.8 ?M for the complexes. On the other hand, the coumarin-?-ketoester ligands HL6-8 were inactive (IC50 > 100 ?M), yet the complexes C6-8 presented high cytotoxicity, with IC50 values ranging from 2.0 and 12.8 ?M. For the antimicrobial assays, HL1 was the only ligand active against one gram-negative bacteria strain, however its MIC was not determined within the studied concentrations. Among the complexes, all demonstrated activity only against gram-positive bacteria strains. Within the Ru(II)-Cl-DMSO series, only C3 and C4 (R = Cl and Br) exhibited MIC at the concentrations used (40.5 and 86 ?M). On the other hand, the complexes of the Ru(II)-bipy class C6-8 presented MIC between 2.20 and 9.22 ?M. Comparing the classes of complexes, Ru(II)-bipy and Ru(II)-DMSO, the higher activities presented by the former in both biological studies was attributed to the presence of charge and of bipyridine ligands. The investigation of DNA interaction of the complexes [Ru(bipy)2(HLn)]PF6 (C6-8) are in progress. C?ncer e infec??es bacterianas s?o doen?as que causam um grande n?mero de mortes e, apesar dos tratamentos existentes, ainda se fazem necess?rios novos f?rmacos que causem menos danos aos pacientes e que sejam mais ativos ?s c?lulas resistentes. Derivados de cumarina e diversas classes de complexos de Ru(II) v?m sendo estudados quanto ao seu potencial como agentes antimicrobianos e antitumorais. Sendo assim, quatro novos ligantes h?bridos de cumarina-N-acilidrazonas do tipo (E)-(N?-4-R-benzilideno-7-(dietilamino)-2-oxo-2H-cromona-3-carboidrazida (HL2: R=H; HL3: R=Cl, HL4: R=Br, HL5: R= OCH3), foram obtidos atrav?s da condensa??o de uma hidrazida (7-(dietilamino)-2-oxo-2H-cromona-3-carboidrazida, HL1) e diferentes alde?dos p-substitu?dos. Rea??es entre HL2-5 e cis-[RuCl2(DMSO)4] resultaram em complexos trans-cis-[RuCl2(DMSO)2(HL2-5)], C2-5 (classe Ru(II)-Cl-DMSO). Concomitantemente, a hidr?lise do ligante ocorreu, resultando na forma??o do complexo trans-cis-[RuCl2(DMSO)2(HL1)] C1, contendo a hidrazida coordenada. As estruturas cristalinas dos ligantes HL2 e HL3 e dos complexos C2-5 foram determinadas por DRX, que revelaram a isomeriza??o de E para Z das cumarinas-N-acilidrazonas resultante da coordena??o. Os complexos C2-5 exibiram o ?tomo de Ru(II) em uma geometria octa?drica distorcida com o ligante coordenado na forma ceto atrav?s da carbonila da hidrazona e do nitrog?nio im?nico. Na tentativa de sintetizar uma segunda classe de complexos carregados e contendo bipiridina como ligante auxiliar ([Ru(bipy)2(HLn)]PF6 - classe Ru(II)-bipy), realizou-se a rea??o entre HL2 e cis-[Ru(bipy)2Cl2]. Por?m, a poss?vel hidr?lise do ligante impossibilitou a obten??o do complexo desejado. Uma metodologia similar utilizando h?bridos de cumarina-?-ceto?ster HL6-8 originou os complexos da classe Ru(II)-bipy, [Ru(bipy)2(HL6-8)]PF6 C6-8. A an?lise de DRX de C7 mostrou o Ru(II) em um ambiente octa?drico distorcido com o ligante coordenado pela por??o ?-ceto?ster desprotonada e duas bipiridinas na esfera de coordena??o. A avalia??o antiproliferativa dos compostos contra linhagens de c?lulas tumorais (4T1: carcinoma mam?rio murino e B16-F10: melanoma murino metast?tico) e n?o tumoral (BHK-21: rim de hamster) mostrou que, de uma maneira geral, os ligantes h?bridos cumarina-N-acilidrazona e cumarina-hidrazida HL1-5 foram mais ativos que seus complexos C1-5, cujos valores de IC50 (metade da concentra??o inibit?ria m?xima) foram encontrados na faixa de 10,6 a 50,4 ?M para os ligantes e entre 17,7 e 97,8 ?M para os complexos. Por outro lado, os ligantes cumarina-?-ceto?ster HL6-8 foram inativos (IC50 > 100 ?M), mas os complexos C6-8 apresentaram alta citotoxicidade, com valores de IC50 entre 2,0 e 12,8 ?M. Para o teste antibacteriano, HL1 foi o ?nico ligante ativo frente a uma cepa de bact?ria gram-negativa, por?m seu MIC n?o foi determinado nas concentra??es estudadas. Todos os complexos demostraram atividade somente frente a cepas de bact?rias gram positivas. Para os complexos Ru(II)-Cl-DMSO, somente C3 e C4 (R = Cl e Br) apresentaram MIC nas concentra??es utilizadas (40,5 e 86 ?M). Por outro lado, os complexos Ru(II)-bipy C6-8 apresentaram MIC entre 2,20-9,22 ?M. A maior atividade apresentada pelos derivados Ru(II)-bipy em ambos os testes biol?gicos, comparada aos complexos Ru(II)-DMSO, foi atribu?da ? presen?a de carga no complexo e aos ligantes bipiridina. Estudos de intera??o com DNA dos complexos [Ru(bipy)2(HL6-8)]PF6 (C6-8) est?o em andamento.
Databáze: OpenAIRE
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