Organometallic Complex Strongly Impairs Chikungunya Virus Entry to the Host Cells

Chikungunya fever is a disease caused by the Chikungunya virus (CHIKV) that is transmitted by the bite of the female of Aedes sp. mosquito. The symptoms include fever, muscle aches, skin rash, and severe joint pains. The disease may develop into a chronic condition and joint pain for months or years. Currently, there is no effective antiviral treatment against CHIKV infection. Treatments based on natural compounds have been widely studied, as many drugs were produced by using natural molecules and their derivatives. Alpha-phellandrene (α-Phe) is a naturally occurring organic compound that is a ligand for ruthenium, forming the organometallic complex [Ru2Cl4(p-cymene)2] (RcP). Organometallic complexes have shown promising as candidate molecules to a new generation of compounds that presented relevant biological properties, however, there is a lack of knowledge concerning the anti-CHIKV activity of these complexes. The present work evaluated the effects of the RcP and its precursors, the hydrate ruthenium(III) chloride salt (RuCl3⋅xH2O) (Ru) and α-Phe, on CHIKV infection in vitro. To this, BHK-21 cells were infected with CHIKV-nanoluciferase (CHIKV-nanoluc), a viral construct harboring the nanoluciferase reporter gene, at the presence or absence of the compounds for 16 h. Cytotoxicity and impact on infectivity were analyzed. The results demonstrated that RcP exhibited a strong therapeutic potential judged by the selective index > 40. Antiviral effects of RcP on different stages of the CHIKV replicative cycle were investigated; the results showed that it affected early stages of virus infection reducing virus replication by 77% at non-cytotoxic concentrations. Further assays demonstrated the virucidal activity of the compound that completely blocked virus infectivity. In silico molecular docking calculations suggested different binding interactions between aromatic rings of RcP and the loop of amino acids of the E2 envelope CHIKV glycoprotein mainly through hydrophobic interactions. Additionally, infrared spectroscopy spectral analysis indicated interactions of RcP with CHIKV glycoproteins. These data suggest that RcP may act on CHIKV particles, disrupting virus entry to the host cells. Therefore, RcP may represent a strong candidate for the development of anti-CHIKV drugs

Complexos contendo o ligante 2 - Mercaptopiridina derivados da série '[RUCL IND. 3(NO)(P-P)]'

Neste trabalho novos complexos nitrosilos de rutênio (II) contendo bifosfinas foram obtidos e caracterizados. A série de complexos [RuCl3(NO)(P-P)] (1) foi utilizada como precursora na obtenção de compostos do tipo [Ru(pyS)2(P-P)] (2), P-P = dppe, c-dppen, dppp e dppb e [Ru(pyS)2(NO)(η1-P-PO)]PF6 (3), P-P = dppm e dppb; pyS = 2-mercaptopiridina, em rendimentos e pureza satisfatórios. Utilizou-se as técnicas usuais para caracterização dos complexos, entre elas: espectroscopias IV, UV/vis e RMN multinuclear (1H, 13C{1H} e 31P{1H}), voltametria cíclica, voltametria de pulso diferencial e análise elementar. A maioria dos compostos forneceu monocristais adequados para estudos por difração de raios-X. Os complexos do tipo (1) foram obtidos por rotas sintéticas já estabelecidas em nossos laboratórios. O inédito fac-[RuCl3(NO)(c-dppen)] foi isolado e caracterizado, tendo inclusive a estrutura cristalográfica resolvida. Este fato permitiu a realização de interessantes comparações deste com o isômero mer-[RuCl3(NO)(dppb)]. Adicionalmente, obtevese a estrutura cristalográfica do [RuCl3(NO)(c-dppen)] e realizou-se pela primeira vez ensaios eletroquímicos para toda a série (1) e experimentos de RMN multinuclear para o mer-[RuCl3(NO)(dppb)]. Assim, aproveita-se a oportunidade para algumas discussões adicionais, importantes para o melhor entendimento da série como um todo e para fins de comparação com os complexos derivados. Os produtos isolados nas reações com a pySH mostraram ser dependentes da bifosfina utilizada, já que o mesmo procedimento foi utilizado para obtenção dos derivados (2) e (3). A série (2) acima citada, com exceção do derivado com a c-dppen que é inédito, foi obtida anteriormente na literatura por rota de síntese diferente da aqui descrita. Apresentase a caracterização e discussão dos resultados...In this work new nitrosyl complexes of ruthenium (II) containing diphosphines were obtained and characterized. The series of compounds [RuCl3(NO)(P-P)] (1) was used as the precursor to obtain compounds of the type [Ru(pyS)2(P-P)] (2), P-P = dppe, c-dppen, dppp and dppb and [Ru(pyS)2(NO)(η1-PPO)] PF6 (3), P-P = dppm and dppb; pyS = 2-mercaptopyridine, in acceptable yields and purity. Standard techniques were used for characterization of the compounds, among them: infrared, visible-UV and multinuclear NMR (1H, 13C{1H} and 31P{1H}) spectroscopies, cyclic voltammetry, pulse diferential voltammetry and elemental analysis. Most of the studied complexes supplied crystals suitable for X-ray crystal structure analysis. Compounds of type (1) were obtained by synthetic routes previously established in our laboratories. The unpublished fac-[RuCl3(NO)(dppb)] was isolated, characterized and had its crystallographic structure solved. This fact allowed interesting comparisons with the geometrical isomer mer-[RuCl3(NO)(dppb)]. In addition, the crystallographic structure of the [RuCl3(NO)(c-dppen)] was obtained and electrochemical characterization for all series (1) as well as multinuclear NMR experiments for the mer-[RuCl3(NO)(dppb)] were carried out for the first time. These studies offer us the opportunity for some additional discussions about the precursor complexes important to the comparisons with the results for the derivative compounds. The isolated products of the reactions with 2-mercaptopyridine ligand showed to be dependent on the diphosphine from the precursor, since the same procedure was used for obtaining derivatives (2) and (3). The series (2), mentioned above, was described previously in the literature, except for the c-dppen derivative, utilizing another synthetic route. The characterization and discussion ...(Complete abstract, click electronic access below

Dependence of the product on the P-P ligand in reactions of [RuCl(3)(NO)(P-P)] complexes (P-P = aromatic diphosphines) with 2-mercaptopyridine

This study presents the syntheses and characterization of 2-mercaptopyridine (pyS(-)) complexes containing ruthenium(II) with the following general formula [Ru(pyS)(2)(P-P)], P-P = (c-dppen) = cis-1,2-bis(diphenylphosphino)ethylene) (1); (dppe)=1,2-bis(diphenylphosphino)ethane (2); (dppp)=1,3-bis(diphenylphosphino)propane (3) and (dppb) = 1,4-bis(diphenylphosphino)butane (4). The complexes were synthesized from the mer- or fac-[RuCl(3)(NO)(P-P)] precursors in the presence of triethylamine in methanol solution with dependence of the product on the P-P ligand. The reaction of pyS- with a ruthenium complex containing a bulky aromatic diphosphine dppb disclosed a major product with a dangling coordinated dppbO-P, the [Ru(pyS)(2)(NO)(eta(1)-dppbO-P)]PF(6) (5). In addition, this work also presents and discusses the spectroscopic and electrochemical behavior of 1-5. and report the X-ray structures for I and S. (C) 2009 Elsevier Ltd. All rights reserved.FAPESPFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)CNPqConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)CAPESCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)FINEPFinanciadora de Estudos e Projetos (FINEP

A new nitrosyl ruthenium complex: Synthesis, chemical characterization, in vitro and in vivo antitumor activities and probable mechanism of action

This study describes the synthesis of a new ruthenium nitrosyl complex with the formula [RuCl(2)NO(BPA)] [BPA = (2-hydroxybenzyl)(2-methylpyridyl)amine ion], which was synthesized and characterized by spectroscopy, cyclic voltammetry, X-ray crystallography, and theoretical calculation data. The biological studies of this complex included in vitro cytotoxic assays, which revealed its activity against two different tumor cell lines (HeLa and Tm5), with efficacy comparable to that of cisplatin, a metal-based drug that is administered in clinical treatment. The in vivo studies showed that [RuCl2NO(BPA)] is effective in reducing tumor mass. Also, our results suggest that the mechanism of action of [RuCl(2)NO(BPA)] includes binding to DNA, causing fragmentation of this biological molecule, which leads to apoptosis. (C) 2011 Elsevier Masson SAS. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP (Sao Paulo State Research Foundation)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)CNPq (Brazilian National Research Council)Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)FAPERJ (Rio de Janeiro State Research Foundation)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)CAPES (Coordination for the Improvement of Higher Education Personnel

Influence of ligands on the fac hm D mer isomerization in [RuCl 3 (NO)(P-P)] complexes, [P-P = R 2 P(CH 2 ) n PR 2 (n = 1-3) and R 2 P(CH 2 )POR 2 , PR 2 -CH@CH-PR 2 , R = Ph and (C 6 H 11 ) 2 P-(CH 2 ) 2 -P(C 6 H 11 ) 2 ]

Abstract [RuCl 3 (NO)(P-P)], [P-P = R 2 P(CH 2 ) n PR 2 (n = 1-3) and R 2 P(CH 2 )POR 2 , PR 2 -CH@CH-PR 2 , R = Ph and (C 6 H 11 ) 2 P-(CH 2 ) 2 -P(C 6 H 11 ) 2 ] were obtained and characterized by 31 P { 1 H} NMR, IR spectroscopies and cyclic voltammetry. The structures of fac-[RuCl 3 -(NO)(P-P)], P-P = dppm (1), dppe (2), c-dppen (3) and dppp (4), mer-[RuCl 3 (NO)(dcpe)] (6a) and mer-[RuCl 3 (NO)(dppmO)] (7) have been determined by X-ray diffraction. Photochemical isomerization of fac-to mer-[RuCl 3 (NO)(P-P)] was observed under white light in a CH 2 Cl 2 solution and in solid state. The isomerization processes were followed by IR and 31 P { 1 H} spectra. The mer-[RuCl 3 ( 15 NO)-(dppb)] isomer was used for the definition of the phosphorus atoms in the structure of the complex in solution. The electrochemical study shows that the oxidation/reduction processes observed in these complexes are dependent on both the isomer (fac or mer) and the solvent. In CH 2 Cl 2 , the NO + reduction potentials are less negative for the mer-isomers than for the fac ones, while in CH 3 CN solvent these potentials are, in general, very close for both isomers

Ruthenium (II) phosphine/picolinate complexes as antimycobacterial agents

The synthesis, characterization and the anti-Mycobacterium tuberculosis (MTB) activities of three ruthenium complexes containing the 2-pyridinecarboxylic acid anion (picolinate), with formulae cis-[Ru(pic)(dppm)(2)]PF(6) (1), Cis- [Ru(pic)(dppe)(2)]PF(6) (2) and [Ru(pic)(2)(PPh(3))(2)] (3) [pic = 2-pyridinecarboxylate; dppm = bis(diphenylphosphino)methane: dppe = 1,2-bis(diphenylphosphino)ethane; PPh(3) = triphenylphosphine] are reported in this article. The complexes were characterized by elemental analysis, spectroscopic and electrochemical techniques. Their in vitro anti mycobacterial activity was determinated as the Minimum Inhibitory Concentration (MIC) for MTB cell growth, measured by the REMA method. The best MICs were found for complexes (1) and (2), with values of 0.78 and 0.26 mu g/mL, respectively. The results are comparable to or better than ""first line"" or ""second line"" drugs commonly used in the treatment of TB. (C) 2009 Elsevier Masson SAS. All rights reserved.CNPqConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)[2008/10390-2]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)[2009/06499-1]CYTED-RIIDFCMCYTED-RIIDFC

fac-[RuCl3(no)(dppb)] (I) and mer-[RuCl3(NO)(diop)] (II) complexes: Syntheses, characterization and x-ray structures

The fac-[RuCl3(NO)(dppb)] complex I has been prepared from solution of the correspondent mer isomer in refluxing methanol (dppb = 1,4-bis(diphenylphosphino)butane). The mer-[RuCl3(NO)(diop)] (II) has been obtained from the mer-[RuCl3(diop)(H2O)] by bubbling NO for 1 h in dichloromethane (diop = 2S,3S-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane). The complexes have been characterized by microanalysis, cyclic voltammetry (CV), IR and 31P{1H} NMR spectroscopies. The crystal and molecular structures of these two compounds have been determined from X-ray studies. The mer-[RuCl3(NO)(dppb)] isomer III was characterized in solution by NMR spectra (31P{1H}, 1H{31P}, 31P-1H HETCORR, COSY 1H-1H, HMQC 1H-13C and HMBC 1H-13C). © 2002 Elsevier Science Ltd. All rights reserved

Synthesis, Characterization, Cytotoxic Activity, and Interactions with CT-DNA and BSA of Cationic Ruthenium(II) Complexes Containing Dppm and Quinoline Carboxylates

The complexes cis-[Ru(quin)(dppm)2]PF6 and cis-[Ru(kynu)(dppm)2]PF6 (quin = quinaldate; kynu = kynurenate; dppm = bis(diphenylphosphino)methane) were prepared and characterized by elemental analysis, electronic, FTIR, 1H, and 31P{H1} NMR spectroscopies. Characterization data were consistent with a cis arrangement for the dppm ligands and a bidentate coordination through carboxylate oxygens of the quin and kynu anions. These complexes were not able to intercalate CT-DNA as shown by circular dichroism spectroscopy. On the other hand, bovine serum albumin (BSA) binding constants and thermodynamic parameters suggest spontaneous interactions with this protein by hydrogen bonds and van der Waals forces. Cytotoxicity assays were carried out on a panel of human cancer cell lines including HepG2, MCF-7, and MO59J and one normal cell line GM07492A. In general, the new ruthenium(II) complexes displayed a moderate to high cytotoxicity in all the assayed cell lines with IC50 ranging from 10.1 to 36 µM and were more cytotoxic than the precursor cis-[RuCl2(dppm)2]. The cis-[Ru(quin)(dppm)2]PF6 were two to three times more active than the reference metallodrug cisplatin in the MCF-7 and MO59J cell lines

Synthesis, characterization, X-ray structure and in vitro anti mycobacterial and antitumoral activities of Ru(II) phosphine/diimine complexes containing the "SpymMe(2)" ligand, SpymMe(2)=4,6-dimethyl-2-mercaptopyrimidine

The reaction of cis-[RuCl2(dppb)(N-N)], dppb = 1,4-bis(diphenylphosphino)butane, complexes with the ligand HSpymMe(2), 4,6-dimethyl-2-mercaptopyrimidine, yielded the cationic complexes [Ru(SpymMe(2))(dppb)(N-N)]PF6, N-N = bipy (1) and Me-bipy (2), bipy = 2,2'-bipyridine and Me-bipy = 4,4'dimethyl-2,2'-bipyridine, which were characterized by spectroscopic and electrochemical techniques and X-ray crystallography and elemental analysis. Additionally, preliminary in vitro tests for antimycobacterial activity against Mycobacterium tuberculosis H37Rv ATCC 27264 and antitumor activity against the MDA-MB-231 human breast tumor cell line were carried out on the new complexes and also on the precursors cis-[RuCl2(dppb)(N-N)], N-N = bipy (3) and Me-bipy (4) and the free ligands dppb, bipy, Me-bipy and SpymMe(2). The minimal inhibitory concentration (MIC) of compounds needed to kill 90% of mycobacterial cells and the IC50 values for the antitumor activity were determined. Compounds 1-4 exhibited good in vitro activity against M. tuberculosis, with MIC values ranging between 0.78 and 6.25 mu g/mL, compared to the free ligands (MIC of 25 to >50 mu g/mL) and the drugs used to treat tuberculosis. Complexes I and 2 also showed promising antitumor activity, with IC50 values of 0.46 +/- 0.02 and 0.43 +/- 0.08 mu M, respectively, against MDA-MB-231 breast tumor cells. (C) 2008 Elsevier B.V. All rights reserved.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP