Publications by authors named "Rodrigo S Correa"

49 Publications

Ruthenium (II)/allopurinol complex inhibits breast cancer progression via multiple targets.

J Biol Inorg Chem 2021 Apr 10. Epub 2021 Apr 10.

Laboratório de Genética Molecular E Citogenética Humana, sala 213, Departamento de Genética, Instituto de Ciências Biológicas I, Campus Samambaia, Universidade Federal de Goiás, Avenida Esperança, s/n, Cx Postal: 131, Goiânia, Goiás, CEP 74690-900, Brazil.

Metal complexes based on ruthenium have established excellent activity with less toxicity and great selectivity for tumor cells. This study aims to assess the anticancer potential of ruthenium(II)/allopurinol complexes called [RuCl(allo)(PPh)] (1) and [RuCl(allo)(dppb)] (2), where allo means allopurinol, PPh is triphenylphosphine and dppb, 1,4-bis(diphenylphosphino)butane. The complexes were synthesized and characterized by elemental analysis, IR, UV-Vis and NMR spectroscopies, cyclic voltammetry, molar conductance measurements, as well as the X-ray crystallographic analysis of complex 2. The antitumor effects of compounds were determined by cytotoxic activity and cellular and molecular responses to cell death mechanisms. Complex 2 showed good antitumor profile prospects because in addition to its cytotoxicity, it causes cell cycle arrest, induction of DNA damage, morphological and biochemical alterations in the cells. Moreover, complex 2 induces cell death by p53-mediated apoptosis, caspase activation, increased Beclin-1 levels and decreased ROS levels. Therefore, complex 2 can be considered a suitable compound in antitumor treatment due to its cytotoxic mechanism.
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http://dx.doi.org/10.1007/s00775-021-01862-yDOI Listing
April 2021

Ruthenium complexes show promise when submitted to toxicological safety tests using alternative methodologies.

Eur J Med Chem 2021 Apr 15;216:113262. Epub 2021 Feb 15.

Instituto de Ciências Biológicas, Universidade Federal de Goiás (UFG), CEP 74045-155, Goiânia, GO, Brazil. Electronic address:

The number of cancer cases continues to increase worldwide, and unfortunately the main systemic treatments available have numerous of side effects. Ruthenium complexes have shown to be promising chemotherapeutic agents, since they present low toxicity and are more selective for tumor tissues. We report the synthesis, characterization and biological properties of two new ruthenium (II) complexes containing Lapachol and Lawsone as ligands: (1) [Ru(Law)(dppb)(phen)]PF and (2) [Ru(Lap)(dppb)(phen)]PF, where Law = Lawsone, Lap = Lapachol, dppb = 1,4-bis(diphenylphosphine)butane and phen = 1,10-phenanthroline. The ability of the complexes (1) and (2) to interact with CT-DNA (Calf Thymus) was investigated, and the results indicate that the complexes have shown a weak interaction with this macromolecule. Complexes (1) and (2) showed a moderate interaction with BSA, via a spontaneous process with the involvement of van der Waals and hydrogen bond interactions. Both complexes were tested against human lung cancer cell lines, chronic human myeloid leukemia, murine melanoma and human cervical and non-tumoral murine fibroblast adenocarcinoma, human lung fibroblasts and monkey kidney epithelia. The potential for cytotoxicity was tested out using the MTT assay and the neutral red test, to calculate inhibitory concentrations (IC50) and selectivity indices (IS). Both complexes showed a higher selectivity index of 1.17 and 10.91, respectively, for the HeLa tumor line. Studies of toxicological evaluation, using the micronucleus test and the comet assay against non-tumor cells, as well as an assessment of the potential for acute toxicity and neurotoxicity in zebrafish (Danio rerio). In the in vitro micronucleus test, complex (1) showed the least genotoxic potential, and in the in vitro comet assay both compounds had revealed a genotoxic potential at 0.5 and 1.0 mg L, with no difference between 24 h and 48 h exposure times. In the acute toxicity tests on zebrafish embryos, complex (1) showed sublethal effects such as decreased blood circulation and heartbeat rate, which were less pronounced than with complex (2). In contrast to complex 2, which caused lethality even before 48h, complex (1) did not cause the death of the embryos at concentrations up to (2.0 mg L). Complex (2) also lead to a delay in the embryo. Cell based in vitro methods thus proved able to provide specific toxicological data, allowing a significant reduction in ∖animal experimentation. Given that in vitro tests cannot completely replace animal tests, the use of less advanced developmental stages such as zebrafish embryos, which - at least in the European Union - are not regarded protected, could be shown to be an excellent alternative for testing with, e.g., mammals.
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http://dx.doi.org/10.1016/j.ejmech.2021.113262DOI Listing
April 2021

Assessment of the biological potential of diaryltriazene-derived triazene compounds.

Sci Rep 2021 Jan 28;11(1):2541. Epub 2021 Jan 28.

Electrochemistry and Biotechnology Laboratory (EBL), University of CEUMA (UNICEUMA), São Luís, MA, 65.065-470, Brazil.

In the present study, novel, 1,3-diaryltriazene-derived triazene compounds were synthesized and tested. Triazenes are versatile and belong to a group of alkylating agents with interesting physicochemical properties and proven biological activities. This study describes the synthesis, molecular and crystalline structure, biological activity evaluation, and antifungal and antimicrobial potentials of 1,3-bis(X-methoxy-Y-nitrophenyl)triazenes [X = 2 and 5; Y = 4 and 5]. The antimicrobial and antifungal activities of the compounds were tested by evaluating the sensitivity of bacteria (American Type Culture Collection, ATCC) and clinical isolates to their solutions using standardized microbiological assays, cytotoxicity evaluation, and ecotoxicity tests. The antimicrobial potentials of triazenes were determined according to their minimum inhibitory concentrations (MICs); these compounds were active against gram-positive and gram-negative bacteria, with low MIC values. The most surprising result was obtained for T3 having the effective MIC of 9.937 µg/mL and antifungal activity against Candida albicans ATCC 90028, C. parapsilosis ATCC 22019, and C. tropicallis IC. To the best of our knowledge, this study is the first to report promising activities of triazene compounds against yeast and filamentous fungi. The results showed the potential utility of triazenes as agents affecting selected resistant bacterial and fungal strains.
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http://dx.doi.org/10.1038/s41598-021-81823-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844262PMC
January 2021

A novel ruthenium(ii) gallic acid complex disrupts the actin cytoskeleton and inhibits migration, invasion and adhesion of triple negative breast tumor cells.

Dalton Trans 2021 Jan 11;50(1):323-335. Epub 2020 Dec 11.

Departamento de Química, Universidade Federal de São Carlos - UFSCar, Rodovia Washington Luís Km 235, CP 676, 13561-901, São Carlos, SP, Brazil.

This work describes the synthesis of three new ruthenium(ii) complexes with gallic acid and derivatives of the general formula [Ru(L)(dppb)(bipy)]PF, where L = gallate (GAC), benzoate (BAC), and esterified-gallate (EGA), bipy = 2,2'-bipyridine and dppb = 1,4-bis(diphenylphosphino)butane. The complexes were characterized by elemental analysis, molar conductivity, NMR, cyclic voltammetry, UV-vis and IR spectroscopy, and two of them by X-ray crystallography. Cell viability assays show promising results, indicating higher cytotoxicity of the complexes in MDA-MB-231 cells, a triple-negative breast cancer (TNBC) cell line, compared with the hormone-dependent MCF-7 cell line. Studies in vitro with the MDA-MB-231 cell line showed that only Ru(BAC) and Ru(GAC) interacted with BSA. Besides that, the Ru(GAC) complex, which has a polyphenolic acid, interacted in an apo-Tf structure and function dependent manner and it was able to inhibit the formation of reactive oxygen species. Ru(GAC) was able to cause damage to the cellular cytoskeleton leading to inhibition of some cellular processes of TNBC cells, such as invasion, migration, and adhesion.
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http://dx.doi.org/10.1039/d0dt03490hDOI Listing
January 2021

Lapachol in the Design of a New Ruthenium(II)-Diphosphine Complex as a Promising Anticancer Metallodrug.

J Inorg Biochem 2021 Jan 23;214:111289. Epub 2020 Oct 23.

Departamento de Química, Universidade Federal de São Carlos (UFSCar), CP 676, CEP 13565-905 São Carlos, SP, Brazil. Electronic address:

The preparation of two new Ru(II)/diphosphine complexes containing Lapachol (Lap) and Lawsone (Law): (1) [Ru(Lap)(dppm)]PF and (2) [Ru(Law)(dppm)]PF, where dppm = bis(diphenylphosphino)methane, is reported here. The complexes were synthetized and fully characterized by elemental analyses, molar conductivity, UV-Vis, IR, P{H}, H and C NMR, and the crystal structure of the complex (1) was determined by X-ray diffraction. Complexes (1) and (2) showed high in vitro cytotoxicity against four cancer cells (MDA-MB-231, MCF-7, A549 and DU-145), with IC values in the micromolar range (0.03 to 2.70 μM). Importantly, complexes (1) and (2) were more active than the cisplatin, the drug used as a reference in the cytotoxic assays. Moreover, complex (1) showed high selectivity to triple-negative breast cancer cells (MDA-MB-231). Studies of the mechanism of action in MDA-MB-231 cancer cells showed that complex (1) inhibits cell migration, colony formation, and induces cell cycle arrest and apoptosis by activation of the mitochondrial pathway through the loss of mitochondrial membrane potential (ΔΨm). Furthermore, complex (1) induces ROS (Reactive Oxygen Species) generation in MDA-MB-231 cells, which can cause DNA damage. Finally, complexes (1) and (2) interact with DNA by minor grooves and show a moderate interaction with BSA (Bovine Serum Albumin), with the involvement of hydrophobic interactions. Essentially, Ru(II)/diphosphine-naphthoquinone complexes have remarkable cytotoxic effects with high selectivity to triple-negative breast cancer (MDA-MB-231) and could be promising anticancer candidates for cancer treatment. SYNOPSIS: The naphthoquinones Lapachol and Lawsone can form new ruthenium compounds with promising anticancer properties.
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http://dx.doi.org/10.1016/j.jinorgbio.2020.111289DOI Listing
January 2021

Ru(II)/diclofenac-based complexes: DNA, BSA interaction and their anticancer evaluation against lung and breast tumor cells.

Dalton Trans 2020 Sep;49(36):12643-12652

Departamento de Química, ICEB, Universidade Federal de Ouro Preto (UFOP), CEP 35400-000, Ouro Preto, MG, Brazil.

Ruthenium(ii) diclofenac-based complexes of the general formula [Ru(dicl)(P-P)(bpy)]PF6 [dicl = diclofenac, bpy = 2,2'-bipyridine, and P-P = 1,4'-bis(diphenylphosphino)butane (dppb) (1), 1,2'-bis(diphenylphosphino)ethane (dppe) (2), 1,3'-bis(diphenylphosphino)propane (dppp) (3) and 1,1'-bis(diphenylphosphino)ferrocene (dppf) (4)] are synthesized. The complexes (1-4) are characterized by elemental analyses, infrared, NMR, and UV-vis spectroscopy and (3) and (4) are characterized by single crystal X-ray diffraction. The DNA binding of complexes (1-4), studied by circular dichroism (CD) and Hoechst 33 258 staining assay, indicates their binding with the minor grooves. The complexes interact with BSA with binding constants (Kb) in the range of 2.5 × 103-5.5 × 104 M-1. The complexes exhibit high cytotoxicity against the tumor cell lines A549, MDA-MB-231, and MCF-7 with IC50 values ranging from 0.56 to 15.28 μM. The complexes are more selective for the hormone-dependent MCF-7 breast tumor cell line and complex (1) is the most potent one. The study demonstrates the anticancer activity of ruthenium(ii)/diclofenac-based complexes.
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http://dx.doi.org/10.1039/d0dt01591aDOI Listing
September 2020

On the Cytotoxicity of Chiral Ruthenium Complexes Containing Sulfur Amino Acids Against Breast Tumor Cells (MDA-231 and MCF-7).

Anticancer Agents Med Chem 2020 Aug 24. Epub 2020 Aug 24.

Departamento de Química, Universidade Federal de São Carlos - UFSCar, São Carlos, SP. Brazil.

Background: Breast cancer is one of the most common types among women. Its incidence progressively increases with age, especially after age 50. Platinum compounds are not efficient in the treatment of breast cancer, highlighting the use of other metals for the development of new chemotherapeutic agents.

Objective: This paper aims to obtain three new ruthenium compounds that incorporate sulfur amino acids in their structures and to investigate their cytotoxic activity in breast tumor cell lines.

Methods: Complexes with general formula [Ru(AA)(dppb)(bipy)] (complexes 1 and 2) or [Ru(AA)(dppb)(bipy)]PF6 (complex 3), where AA = L-cysteinate (1), D-penicillaminate (2), and L-deoxyalliinate (3), dppb = 1,4- bis(diphenylphosphino)butane and 2,2´-bipyridine, were obtained from the cis-[RuCl2(dppb)(bipy)] precursor. The cytotoxicity of the complexes on MDA-MB-231 (triple negative human breast cancer); MCF-7 (double positive human breast cancer) and V79 (hamster lung fibroblast) were performed by the MTT (4,5-dimethylthiazol-2-yl-2,5- diphenyltetrazolium bromide) method. The control agent was the cisplatin, which is a commercially available drug for cancer treatment.

Results: In complexes (1) and (2), the ligands are coordinated to the metal center by nitrogen and sulfur atoms, while in complex (3) coordination is through the oxygen and nitrogen atoms. These suggestions are based on the infrared and 31P{1H} NMR data. For complexes (1) and (2), their X-ray structures were determined confirming this suggestion. The three complexes are stable in a mixture of DMSO (80 %) and biological medium (20 %) for at least 48 h and presented cytotoxicity against the MDA-MB-231 and MCF-7 tumor cells with reasonable selectivity indexes.

Conclusion: Our work demonstrated that ruthenium complexes containing sulfur amino acids, bipyridines and bisphosphines showed cytotoxicity against the MDA-MB-231 and MCF-7 cancer cell lines, in vitro, and that they interact weakly with the DNA (Deoxyribonucleic Acid) and the HSA (Human Serum Albumin) biomolecules.

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http://dx.doi.org/10.2174/1871520620666200824114816DOI Listing
August 2020

Ru(II)-Naphthoquinone complexes with high selectivity for triple-negative breast cancer.

Dalton Trans 2020 Nov;49(45):16193-16203

Departamento de Química, Universidade Federal de São Carlos - UFSCar, Rodovia Washington Luiz, KM 235 CP 676, CEP 13561-901, São Carlos, SP, Brazil.

Six new ruthenium(ii) complexes with lapachol (Lap) and lawsone (Law) with the general formula [Ru(L)(P-P)(bipy)]PF6, where L = Lap or Law, P-P = 1,2'-bis(diphenylphosphino)ethane (dppe), 1,4'-bis(diphenylphosphino)butane (dppb), 1,1'-bis(diphenylphosphino)ferrocene (dppf) and bipy = 2,2'-bipyridine, were synthesized, fully characterized by elemental analysis, molar conductivity, NMR, cyclic voltammetry, UV-vis, IR spectroscopies and three of them by X-ray crystallography. All six complexes were active against breast (MCF-7 and MDA-MB-231) and prostate (DU-145) cancer cell lines with lower IC50 values than cisplatin. Complex [Ru(Lap)(dppe)(bipy)]PF6 (1a) showed significant selectivity for MDA-MB-231, a model of triple-negative breast cancer (TNBC), as compared to the "normal-like" human breast epithelial cell line, MCF-10A. Complex (1a) inhibited TNBC colony formation and induced loss of cellular adhesion. Furthermore, the complex (1a) induced mitochondrial dysfunction and generation of ROS, as is involved in the apoptotic cell death pathway. Preferential cellular uptake of complex (1a) was observed in MDA-MB-231 cells compared to MCF-10A cells, consistent with the observed selectivity for tumorigenic vs. non-tumorigenic cells. Taken together, these results indicate that ruthenium complexes containing lapachol and lawsone as ligands are promising candidates as chemotherapeutic agents.
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http://dx.doi.org/10.1039/d0dt01091jDOI Listing
November 2020

Nucleobase Derivatives as Building Blocks to Form Ru(II)-Based Complexes with High Cytotoxicity.

ACS Omega 2020 Jan 3;5(1):122-130. Epub 2020 Jan 3.

Departamento de Química, Instituto de Ciências Exatas e Biológicas-Campus Morro do Cruzeiro, Universidade Federal de Ouro Preto-UFOP, CEP 35400-000 Ouro Preto, MG, Brazil.

Two new Ru(II)-based complexes containing 2-thiouracil derivatives, known as 2-thiouracil (2TU) and 6-methyl-2-thiouracil (6m2TU), were synthesized using [RuCl(PPh)(bipy)] as a precursor. The obtained compounds with a general formula [Ru(2TU)(PPh)(bipy)]PF () and [Ru(6m2TU)(PPh)(bipy)]PF () were characterized by analytical techniques such as NMR, UV-vis, and IR spectroscopies, elementary analysis, mass spectrometry, and single-crystal X-ray diffraction. Moreover, the investigation of the complexes-DNA interaction were carried out using spectrophotometric titrations and showed that the complexes present a weak interaction with this biomolecule. The compounds were evaluated against HL-60, K-562, HepG2, and B16-F10 cancer cells and against noncancer cells (PBMCs). The results of the biological assay revealed that complex is more promising than complex . Finally, the present study suggests that complexes and causes cell death by apoptosis, significantly increasing the percentage of apoptotic HL-60 cells, in which the compounds altered the cell cycle, reducing the cells in G/G, G/M, and S phases.
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http://dx.doi.org/10.1021/acsomega.9b01921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963899PMC
January 2020

Non-mutagenic Ru(ii) complexes: cytotoxicity, topoisomerase IB inhibition, DNA and HSA binding.

Dalton Trans 2019 Oct;48(39):14885-14897

Dipartimentodi Biologia, UniversitàTorVergatadi Roma, 00133 Rome, Italy.

Herein we discuss five ruthenium(ii) complexes with good cytotoxicity against cancer cells. These complexes are named [Ru(tzdt)(bipy)(dppb)]PF6 (1), [Ru(mmi)(bipy)(dppb)]PF6 (2), [Ru(dmp)(bipy)(dppb)]PF6 (3), [Ru(mpca)(bipy)(dppb)]PF6 (4) and [Ru(2mq)(bipy)(dppb)]PF6 (5), where tzdt = 1,3-thiazolidine-2-thione, mmi = mercapto-1-methyl-imidazole, dmp = 4,6-diamino-2-mercaptopyrimidine, mpca = 6-mercaptopyridine-3-carboxylic acid, 2mq = 2-mercapto-4(3H)-quinazolinone, bipy = 2,2'-bipyridine and dppb = 1,4-bis(diphenylphosphino)butane. In vitro cell culture experiments revealed significant cytotoxic activity for 1-5 against MDA-MB-231, MCF-7, A549, DU-145 and HepG2 tumor cells, higher than that for the standard anticancer drug cisplatin. Compound/DNA interaction studies were carried out showing that 1-5 interact with DNA by electrostatic force of attraction or by hydrogen bonding. Moreover, the complexes interact, moderately and spontaneously, with human serum albumin (HSA) through the hydrophobic region. The five complexes are able to inhibit the DNA supercoiled relaxation mediated by human topoisomerase IB (TopIB), and complex 1 is found to be the most efficient TopIB inhibitor among the five compounds. The inhibitory effect and analysis of different steps of the TopIB catalytic cycle indicate that complex 1 inhibits the cleavage reaction impeding the binding of the enzyme to DNA and has no effect on the religation step. Complexes 1, 2 and 3 did not show mutagenic activity when they were evaluated by the cytokinesis-block micronucleus cytome assay in HepG2 cells and the Ames test in the presence and absence of mouse liver S9 metabolic activation. Therefore, it is necessary to perform further in-depth analysis of the therapeutic potential of these promising ruthenium complexes as anticancer drugs.
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http://dx.doi.org/10.1039/c9dt01905gDOI Listing
October 2019

Ruthenium(II) complexes with 6-methyl-2-thiouracil selectively reduce cell proliferation, cause DNA double-strand break and trigger caspase-mediated apoptosis through JNK/p38 pathways in human acute promyelocytic leukemia cells.

Sci Rep 2019 08 7;9(1):11483. Epub 2019 Aug 7.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, Brazil.

Ruthenium(II) complexes with 6-methyl-2-thiouracil cis-[Ru(6m2tu)(PPh)] (1) and [Ru(6m2tu)(dppb)] (2) (where PPhtriphenylphosphine; dppb = 1,4-bis(diphenylphosphino)butane; and 6m2tu = 6-methyl-2-thiouracil) are potent cytotoxic agents and able to bind DNA. The aim of this study was to evaluate in vitro cellular underlying mechanism and in vivo effectiveness of these ruthenium(II) complexes in human acute promyelocytic leukemia HL-60 cells. Both complexes displayed potent and selective cytotoxicity in myeloid leukemia cell lines, and were detected into HL-60 cells. Reduction of the cell proliferation and augmented phosphatidylserine externalization, caspase-3, -8 and -9 activation and loss of mitochondrial transmembrane potential were observed in HL-60 cells treated with both complexes. Cotreatment with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, reduced Ru(II) complexes-induced apoptosis. In addition, both metal complexes induced phosphorylation of histone H2AX (S139), JNK2 (T183/Y185) and p38α (T180/Y182), and cotreatment with JNK/SAPK and p38 MAPK inhibitors reduced complexes-induced apoptosis, indicating DNA double-strand break and activation of caspase-mediated apoptosis through JNK/p38 pathways. Complex 1 also reduced HL-60 cell growth in xenograft model. Overall, the outcome indicated the ruthenium(II) complexes with 6-methyl-2-thiouracil as a novel promising antileukemic drug candidates.
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http://dx.doi.org/10.1038/s41598-019-47914-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686011PMC
August 2019

Ru(II)-thymine complex causes DNA damage and apoptotic cell death in human colon carcinoma HCT116 cells mediated by JNK/p38/ERK1/2 via a p53-independent signaling.

Sci Rep 2019 07 31;9(1):11094. Epub 2019 Jul 31.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil.

Ru(II)-thymine complex [Ru(PPh)(Thy)(bipy)]PF (where PPh = triphenylphosphine, Thy = thyminate and bipy = 2,2'-bipyridine) is a potent cytotoxic agent with ability to bind to DNA, inducing caspase-mediated apoptosis in leukemia cells. In this study, we investigated the mechanism underlying the cell death induction by Ru(II)-thymine complex in human colon carcinoma HCT116 cells, as well as its effect in xenograft tumor model. The Ru(II)-thymine complex increased significantly the percentage of apoptotic HCT116 cells. Co-treatment with a JNK/SAPK inhibitor, p38 MAPK inhibitor and MEK inhibitor, which inhibit the activation of ERK1/2, caused a marked reduction of the percentage of complex-induced apoptotic cells. Moreover, the Ru(II)-thymine complex induced an increase in phospho-JNK2 (T183/Y185), phospho-p38α (T180/Y182) and phospho-ERK1 (T202/Y204) levels in HCT116 cells. Treatment with the Ru(II)-thymine complex increased significantly the phospho-histone H2AX (S139) expression, a DNA damage marker. The expression of phospho-p53 (S15) and MDM2 were not changed, and the co-treatment with a p53 inhibitor (cyclic pifithrin-α) did not reduce the complex-induced apoptosis in HCT116 cells, indicating that the Ru(II)-thymine complex induces DNA damage-mediated apoptosis by JNK/p38/ERK1/2 via a p53-independent signaling. The Ru(II)-thymine complex (1 and 2 mg/kg/day) also inhibited HCT116 cell growth in a xenograft model, reducing the tumor mass at 32.6-40.1%. Altogether, indicate that the Ru(II)-thymine complex is a promising anti-colon cancer drug candidate.
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http://dx.doi.org/10.1038/s41598-019-47539-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668648PMC
July 2019

Ru(II) complexes containing uracil nucleobase analogs with cytotoxicity against tumor cells.

J Inorg Biochem 2019 09 9;198:110751. Epub 2019 Jun 9.

Departamento de Química, Universidade Federal de São Carlos - UFSCar, Rodovia Washington Luiz, KM 235 CP 676, CEP 13561-901 São Carlos, SP, Brazil; Instituto de Química, Universidade Federal de Goiás - UFG, CEP 74690-900 Goiânia, GO, Brazil. Electronic address:

We report on chemistry and cytotoxic studies of four new ruthenium (II) complexes containing uracil derivatives. All compounds are neutral, presenting the formula [Ru(PPh)(2TU)] (1), [Ru(PPh)(6m2TU)] (2), [Ru(dppb)(2TU)] (3) and [Ru(dppb)(6m2TU)] (4), where PPh = triphenylphosphine; dppb = 1,4-bis(diphenylphosphino)butane, 2TU = 2-thiouracil and 6m2TU = 6-methyl-2-thiouracil. They were characterized using NMR, UV-vis and IR spectroscopies, microanalytical analysis and mass spectrometry. Furthermore, the crystal structures of 1-4 were determined by single-crystal X-ray diffraction. The coordination of 2-thiouracil derivatives with ruthenium increases regions able to carry out hydrogen bonds with the biological targets, such as DNA. We evaluated the interaction of the complexes with DNA by UV/Vis spectrophotometric titration, and as a result, the values of DNA-binding constants are in the range of 0.8-1.8 × 10 M. Moreover, the interaction of the complexes with BSA was investigated. In vitro, activities against B16-F10 (mouse melanoma), HepG2 (human hepatocellular carcinoma), HL-60 (human promyelocytic leukemia) and K562 (human chronic myelocytic leukemia) and non-tumor cells: PBMC (human peripheral blood mononuclear cells activated with concanavalin A - human lymphoblast) were carried out. Cytotoxicity assays revealed that complexes (2) and (4) present biological activity against tumor cells comparable with oxaliplatin, the reference platinum drug, revealing that they are promising molecules for developing new antitumor compounds.
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http://dx.doi.org/10.1016/j.jinorgbio.2019.110751DOI Listing
September 2019

Ru(II)-Thymine Complex Causes Cell Growth Inhibition and Induction of Caspase-Mediated Apoptosis in Human Promyelocytic Leukemia HL-60 Cells.

Int J Mol Sci 2018 May 30;19(6). Epub 2018 May 30.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Rua Waldemar Falcão, 121, Candeal, Salvador 40296-710, Bahia, Brazil.

Ruthenium-based compounds represent a class of potential antineoplastic drugs. Recently, we designed, synthesized, and identified the Ru(II)-thymine complex [Ru(PPh₃)₂(Thy)(bipy)]PF₆ (where PPh = triphenylphosphine, Thy = thymine and bipy = 2,2'-bipyridine) as a potent cytotoxic agent with the ability to bind to DNA and human and bovine serum albumins. In this study, the underlying cytotoxic mechanism of the [Ru(PPh₃)₂(Thy)(bipy)]PF₆ complex was assessed. This complex displayed potent cytotoxicity in different cancer cell lines; the morphology that is associated with apoptotic cell death, increased internucleosomal DNA fragmentation without cell membrane permeability, loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization, and caspase-3 activation were observed in human promyelocytic leukemia HL-60 cells that were treated with the complex. Moreover, pretreatment of HL-60 cells with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, partially reduced the apoptosis that was induced by the complex, indicating that the apoptotic cell death occurred through a caspase-mediated pathway. In conclusion, the [Ru(PPh₃)₂(Thy)(bipy)]PF₆ complex displays potent cytotoxicity to different cancer cells and induces caspase-mediated apoptosis in HL-60 cells.
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http://dx.doi.org/10.3390/ijms19061609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032384PMC
May 2018

Cytotoxic activity and structural features of Ru(II)/phosphine/amino acid complexes.

J Inorg Biochem 2018 05 23;182:48-60. Epub 2017 Dec 23.

Departamento de Química, Universidade Federal de São Carlos, C.P. 676, CEP 13565-905 São Carlos, (SP), Brazil.

Thirteen new ruthenium amino acid complexes were synthesized and characterized. They were obtained by the reaction of α-amino acids (AA) with [RuCl(P-P)(N-N)], where P-P=1,4-bis(diphenylphosphino)butane (dppb) or 1,3-bis(diphenylphosphino)propane (dppp) and N-N=4,4'-dimethyl-2,2'-bipyridine (4'-Mebipy), 5,5'-dimethyl-2,2'-bipyridine (5'-Mebipy) or 4,4'-Methoxy-2-2'-bipyridine (4'-MeObipy). This afforded a family of complexes formulated as [Ru(AA-H)(P-P)(N-N)]PF, where AA=glycine (Gly), L-alanine (Ala), L-valine (Val), L-tyrosine (Tyr), L-tryptophan (Trp), L-histidine (His) and L-methionine (Met). All compounds were characterized by elemental analysis, spectroscopic and electrochemical techniques. The [Ru(AA-H)(P-P)(N-N)]PF complexes are octahedral (the AA-H ligand binding involves N-amine and O-carboxylate), diamagnetic (low-spin d, S=0) and present bands due to electronic transitions in the visible region. H, C{H} and P{H} NMR spectra of the complexes indicate the presence of C symmetry, and the identification of diastereoisomers. In vitro cytotoxicity assays of the compounds and cisplatin were carried out using MDA-MB-231 (human breast) tumor cell line and a non-tumor breast cell line (MCF-10A). Most complexes present promising results with IC values comparable with the reference drug cisplatin and high selectivity indexes were found for the complexes containing L-Trp. The binding of two Ru-precursors of the type [RuCl(dppb)(NN)] (N-N=4'-MeObipy or 4'-Mebipy) to the blood transporter protein human serum albumin (HSA) was evaluated by fluorescence and circular dichroism spectroscopy. Both complexes bind HSA, probably in the hydrophobic pocket near Trp214, and the Ru-complex containing 4'-MeObipy shows higher affinity for HSA than the 4'-Mebipy one.
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http://dx.doi.org/10.1016/j.jinorgbio.2017.12.010DOI Listing
May 2018

A ruthenium-based 5-fluorouracil complex with enhanced cytotoxicity and apoptosis induction action in HCT116 cells.

Sci Rep 2018 01 10;8(1):288. Epub 2018 Jan 10.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil.

Combination of multifunctionalities into one compound is a rational strategy in medicinal chemical design, and have often been used with metallodrug-based compounds. In the present study, we synthesized a novel ruthenium-based 5-fluorouracil complex [Ru(5-FU)(PPh)(bipy)]PF (PPh = triphenylphosphine; and bipy = 2,2'-bipyridine) with enhanced cytotoxicity in different cancer cells, and assessed its apoptosis induction action in human colon carcinoma HCT116 cells. The complex was characterized by infrared, cyclic voltammetry, molar conductance measurements, elemental analysis, NMR experiments and X-ray crystallographic analysis. In both 2D and 3D cell culture models, the complex presented cytotoxicity to cancer cells more potent than 5-FU. A typical morphology of apoptotic cell death, increased internucleosomal DNA fragmentation, without cell membrane permeability, loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization and caspase-3 activation were observed in complex-treated HCT116 cells. Moreover, the pre-treatment with Z-DEVD-FMK, a caspase-3 inhibitor, reduced the apoptosis induced by the complex, indicating cell death by apoptosis through caspase-dependent and mitochondrial intrinsic pathways. The complex failed to induce reactive oxygen species production and DNA intercalation. In conclusion, the novel complex displays enhanced cytotoxicity to different cancer cells, and is able to induce caspase-mediated apoptosis in HCT116 cells.
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http://dx.doi.org/10.1038/s41598-017-18639-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762908PMC
January 2018

Ru/Fe bimetallic complexes: Synthesis, characterization, cytotoxicity and study of their interactions with DNA/HSA and human topoisomerase IB.

Arch Biochem Biophys 2017 12 28;636:28-41. Epub 2017 Oct 28.

Department of Biology, University of Rome Tor Vergata, 00133, Rome, Italy. Electronic address:

Three ruthenium/iron-based compounds, 1: [Ru(MIm)(bipy)(dppf)]PF (MIm = 2-mercapto-1-methylimidazole anion), 2: [RuCl(Im)(bipy)(dppf)]PF (Im = imidazole), and 3: [Ru(tzdt)(bipy)(dppf)]PF (tzdt = 1,3-thiazolidine-2-thione anion) (dppf = 1,1'-bis(diphenylphosphine)ferrocene and bipy = 2,2'-bipyridine), were synthesized, and characterized by elemental analyses, conductivity, UV/Vis, IR, H, C and P{1H} NMR spectroscopies, and by electrochemical technique. The complex 3 was also characterized by single-crystal X-ray. The three ruthenium(II) complexes show cytotoxicity against DU-145 (prostate carcinoma cells) and A549 (lung carcinoma cells) tumor cells. The free ligands do not exhibit any cytotoxic activity, such as evident by the IC values higher than 200 μM. UV/Vis and viscosity experiments showed that the complexes interact weakly with the DNA molecule, via electrostatic forces. The interaction of the complexes 1-3 with the HSA is moderate, with K values in range of 10-10 M, presenting a static mechanism of interaction stabilized by hydrophobic. Complexes 2 and 3 showed high affinity for the FA7 HSA site as evidenced by fluorescence spectroscopy and molecular docking. Complexes 1-3 were tested as potential human Topoisomerase IB inhibitors by analysing the different steps of the enzyme catalytic cycle. The results indicate that all compounds efficiently inhibit the DNA relaxation and the cleavage reaction, in which the effect increases upon pre-incubation. Complexes 1 and 2 are also able to slow down the religation reaction.
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http://dx.doi.org/10.1016/j.abb.2017.10.015DOI Listing
December 2017

Cytotoxicity and anti-tumor effects of new ruthenium complexes on triple negative breast cancer cells.

PLoS One 2017 12;12(9):e0183275. Epub 2017 Sep 12.

Departmento de Gerontologia, Universidade Federal de São Carlos, São Carlos, São Paulo, Brazil.

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype. The high rate of metastasis associated to the fact that these cells frequently display multidrug resistance, make the treatment of metastatic disease difficult. Development of antitumor metal-based drugs was started with the discovery of cisplatin, however, the severe side effects represent a limitation for its clinical use. Ruthenium (Ru) complexes with different ligands have been successfully studied as prospective antitumor drugs. In this work, we demonstrated the activity of a series of biphosphine bipyridine Ru complexes (1) [Ru(SO4)(dppb)(bipy)], (2) [Ru(CO3)(dppb)(bipy)], (3) [Ru(C2O4)(dppb)(bipy)] and (4) [Ru(CH3CO2)(dppb)(bipy)]PF6 [where dppb = 1,4-bis(diphenylphosphino)butane and bipy = 2,2'-bipyridine], on proliferation of TNBC (MDA-MB-231), estrogen-dependent breast tumor cells (MCF-7) and a non-tumor breast cell line (MCF-10A). Complex (4) was most effective among the complexes and was selected to be further investigated on effects on tumor cell adhesion, migration, invasion and in apoptosis. Moreover, DNA and HSA binding properties of this complex were also investigated. Results show that complex (4) was more efficient inhibiting proliferation of MDA-MB-231 cells over non-tumor cells. In addition, complex (4) was able to inhibit MDA-MB231 cells adhesion, migration and invasion and to induce apoptosis and inhibit MMP-9 secretion in TNBC cells. Complex (4) should be further investigated in vivo in order to stablish its potential to improve breast cancer treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183275PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595280PMC
October 2017

Selective Ru(II)/lawsone complexes inhibiting tumor cell growth by apoptosis.

J Inorg Biochem 2017 11 26;176:66-76. Epub 2017 Aug 26.

Departamento de Química, Universidade Federal de São Carlos, CP 676, CEP 13565-905, São Carlos, SP, Brazil. Electronic address:

New Ru(II) complexes with lawsone (law) characterized as trans-[Ru(law)(PPh)(N-N)]PF, where PPh means triphenylphosphine and N-N is 2,2'-bipyridine (1), 4,4'-dimethyl-2,2'-bipyridine (2), 4,4'-dimethoxy-2,2'-bipyridine (3), 1,10-phenanthroline (4) or 4,7-diphenyl-1,10-phenanthroline (5), induce apoptosis in tumor cells. Cytotoxicity of the complexes against the tumor cell lines DU-145 (prostate cancer cells), MCF-7 (breast cancer cells), A549 (lung cancer cells) and lung non-tumor cell line MRC-5 demonstrated promising IC values, lower than those found for the cisplatin, a drug used as a reference. Due to the high cytotoxic activity and selectivity against A549 cells line, complex (5) was selected for detailed assays. The complex (5) inhibits cells migration in concentrations in a nanomolar range, inducing tumor cell death by apoptosis, as confirmed by flow cytometry experiments. Furthermore, the antiproliferative activity of complex (5) on A549 tumor cells is attributed to a cell cycle arrest at the Sub G1 phase, followed by a decrease in the number of cells at the S phase. In addition, the interaction of the complexes (1-5) with CT-DNA was evaluated by circular dichroism, in which no changes in the secondary structure of DNA were observed, suggesting a weak interaction of the complexes with the biomolecule. On the other hand, complexes (1-5) showed a higher interaction with human serum albumin (HSA) by non-covalent van der Waals forces and hydrogen bonding, resulting in static quenching.
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http://dx.doi.org/10.1016/j.jinorgbio.2017.08.019DOI Listing
November 2017

Copper(I)-Phosphine Polypyridyl Complexes: Synthesis, Characterization, DNA/HSA Binding Study, and Antiproliferative Activity.

Inorg Chem 2017 Apr 14;56(7):3781-3793. Epub 2017 Mar 14.

Diretoria de Metrologia Aplicada às Ciências da Vida, Instituto Nacional de Metrologia, Qualidade e Tecnologia , CEP 25250-020 Xerém, RJ, Brazil.

A series of copper(I)-phosphine polypyridyl complexes have been investigated as potential antitumor agents. The complexes [Cu(PPh)dpq]NO (2), [Cu(PPh)dppz]NO (3), [Cu(PPh)dppa]NO (4), and [Cu(PPh)dppme]NO (5) were synthesized by the reaction of [Cu(PPh)NO] with the respective planar ligand under mild conditions. These copper complexes were fully characterized by elemental analysis, molar conductivity, FAB-MS, and NMR, UV-vis, and IR spectroscopies. Interactions between these copper(I)-phosphine polypyridyl complexes and DNA have been investigated using various spectroscopic techniques and analytical methods, such as UV-vis titrations, thermal denaturation, circular dichroism, viscosity measurements, gel electrophoresis, and competitive fluorescent intercalator displacement assays. The results of our studies suggest that these copper(I) complexes interact with DNA in an intercalative way. Furthermore, their high protein binding affinities toward human serum albumin were determined by fluorescence studies. Additionally, cytotoxicity analyses of all complexes against several tumor cell lines (human breast, MCF-7; human lung, A549; and human prostate, DU-145) and non-tumor cell lines (Chinese hamster lung, V79-4; and human lung, MRC-5) were performed. The results revealed that copper(I)-phosphine polypyridyl complexes are more cytotoxic than the corresponding planar ligand and also showed to be more active than cisplatin. A good correlation was observed between the cytostatic activity and lipophilicity of the copper(I) complexes studied here.
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http://dx.doi.org/10.1021/acs.inorgchem.6b02419DOI Listing
April 2017

Understanding the conformational changes and molecular structure of furoyl thioureas upon substitution.

Spectrochim Acta A Mol Biomol Spectrosc 2017 Apr 28;176:8-17. Epub 2016 Dec 28.

CEQUINOR (UNLP-CONICET, CCT La Plata), Departamento de Química, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, C.C. 962 (1900), La Plata, Argentina. Electronic address:

1-Acyl thioureas [RC(O)NHC(S)NRR] are shown to display conformational flexibility depending on the degree of substitution at the nitrogen atom. The conformational landscape and structural features for two closely related thioureas having R=2-furoyl have been studied. The un-substituted 2-furoyl thiourea (I) and its dimethyl analogue, i.e. 1-(2-furoyl)-3,3-dimethyl thiourea (II), have been synthesized and fully characterized by spectroscopic (FT-IR, H and C NMR) and elemental analysis. According to single crystal X-ray diffraction analysis, compounds I and II crystallize in the monoclinic space group P21/c. In the compound I, the trans-cis geometry of the almost planar thiourea unit is stabilized by intramolecular NH⋯OC hydrogen bond between the H atom of the cis thioamide and the carbonyl O atom. In compound II, however, the acyl thiourea group is non-planar, in good agreement with the potential energy curve computed at the B3LYP/6-31+G(d,p) level of approximation. Centrosymmetric dimers generated by intermolecular NH⋯SC hydrogen bond forming R(8) motif are present in the crystals. Intermolecular interactions have been rationalized in terms of topological partitions of the electron distributions and Hirshfeld surface analysis, which showed the occurrence of S⋯H, O⋯H and H⋯H contacts that display an important role to crystal packing stabilization of both thiourea derivatives.
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http://dx.doi.org/10.1016/j.saa.2016.12.038DOI Listing
April 2017

Ruthenium(II) complexes of 1,3-thiazolidine-2-thione: Cytotoxicity against tumor cells and anti-Trypanosoma cruzi activity enhanced upon combination with benznidazole.

J Inorg Biochem 2016 Mar 2;156:153-63. Epub 2016 Jan 2.

Departamento de Química, Universidade Federal de São Carlos, CP 676, CEP 13565-905 São Carlos, SP, Brazil. Electronic address:

Three new mixed and mononuclear Ru(II) complexes containing 1,3-thiazolidine-2-thione (tzdtH) were synthesized and characterized by spectroscopic analysis, molar conductivity, cyclic voltammetry, high-resolution electrospray ionization mass spectra and X-ray diffraction. The complexes presented unique stereochemistry and the proposed formulae are: [Ru(tzdt)(bipy)(dppb)]PF6 (1), cis-[Ru(tzdt)2(PPh3)2] (2) and trans-[Ru(tzdt)(PPh3)2(bipy)]PF6 (3), where dppb=1,4-bis(diphenylphosphino)butane and bipy=2,2'-bipyridine. These complexes demonstrated strong cytotoxicity against cancer cell lines when compared to cisplatin. Specifically, complex 2 was the most potent cytotoxic agent against MCF-7 breast cells, while complexes 1 and 3 were more active in DU-145 prostate cells. Binding of complexes to ctDNA was determined by UV-vis titration and viscosity measurements and revealed binding constant (Kb) values in range of 1.0-4.9×10(3)M(-1), which are characteristic of compounds possessing weak affinity to ctDNA. In addition, these complexes presented antiparasitic activity against Trypanosoma cruzi. Specifically, complex 3 demonstrated strong potency, moderate selectivity index and acted in synergism with the approved antiparasitic drug, benznidazole. Additionally, complex 3 caused parasite cell death through a necrotic process. In conclusion, we demonstrated that Ru(II) complexes have powerful pharmacological activity, while the metal-free tzdtH does not provoke the same outcome.
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http://dx.doi.org/10.1016/j.jinorgbio.2015.12.024DOI Listing
March 2016

Inhibition of human DNA topoisomerase IB by nonmutagenic ruthenium(II)-based compounds with antitumoral activity.

Metallomics 2016 Feb;8(2):179-92

Departamento de Química, Universidade Federal de São Carlos, CP 676, CEP 13565-905, São Carlos, SP, Brazil.

Herein we synthesized two new ruthenium(II) compounds [Ru(pySH)(bipy)(dppb)]PF6 (1) and [Ru(HSpym)(bipy)(dppb)]PF6 (2) that are analogs to an antitumor agent recently described, [Ru(SpymMe2)(bipy)(dppb)]PF6 (3), where [(Spy) = 2-mercaptopyridine anion; (Spym) = 2-mercaptopyrimidine anion and (SpymMe2) = 4,6-dimethyl-2-mercaptopyrimidine anion]. In vitro cell culture experiments revealed significant anti-proliferative activity for 1-3 against HepG2 and MDA-MB-231 tumor cells, higher than the standard anti-cancer drugs doxorubicin and cisplatin. No mutagenicity is detected when compounds are evaluated by cytokinesis-blocked micronucleus cytome and Ames test in the presence and absence of S9 metabolic activation from rat liver. Interaction studies show that compounds 1-3 can bind to DNA through electrostatic interactions and to albumin through hydrophobic interactions. The three compounds are able to inhibit the DNA supercoiled relaxation mediated by human topoisomerase IB (Top1). Compound 3 is the most efficient Top1 inhibitor and the inhibitory effect is enhanced upon pre-incubation with the enzyme. Analysis of different steps of Top1 catalytic cycle indicates that 3 inhibits the cleavage reaction impeding the binding of the enzyme to DNA and slows down the religation reaction. Molecular docking shows that 3 preferentially binds closer to the residues of the active site when Top1 is free and lies on the DNA groove downstream of the cleavage site in the Top1-DNA complex. Thus, 3 can be considered in further studies for a possible use as an anticancer agent.
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http://dx.doi.org/10.1039/c5mt00227cDOI Listing
February 2016

Iron-mediated stabilization of soil carbon amplifies the benefits of ecological restoration in degraded lands.

Ecol Appl 2015 Jul;25(5):1226-34

Recent observations across a 14-year restoration chronosequence have shown an unexpected accumulation of soil organic carbon in strip-mined areas of central Brazil. This was attributed to the rapid plant colonization that followed the incorporation of biosolids into exposed regoliths, but the specific mechanisms involved in the stabilization of carbon inputs from the vegetation remained unclear. Using isotopic and elemental analyses, we tested the hypothesis that plant-derived carbon accumulation was triggered by the formation of iron-coordinated complexes, stabilized into physically protected (occluded) soil fractions. Confirming this hypothesis, we identified a fast formation of microaggregates shortly after the application of iron-rich biosolids, which was characterized by a strong association between pyrophosphate-extractable iron and plant-derived organic matter. The formation of microaggregates preceded the development of macroaggregates, which drastically increased soil carbon content (-140 Mg C/ha) a few years after restoration. Consistent with previous theoretical work, iron-coordinated organic complexes served as nuclei for aggregate formation, reflecting the synergistic effect of biological, chemical, and physical mechanisms of carbon stabilization in developing soils. Nevertheless, iron was not the only factor affecting soil carbon content. The highest carbon accumulation was observed during the period of highest plant diversity (> 30 species; years 3-6), declining significantly with the exclusion of native species by invasive grasses (years 9-14). Furthermore, the increasing dominance of invasive grasses was associated with a steady decline in the concentration of soil nitrogen and phosphorus per unit of accumulated carbon. These results demonstrate the importance of interdependent ecological and biogeochemical processes, and the role of soil-plant interactions in determining the success of restoration efforts. In contrast with previous but unsuccessful attempts to restore mined areas through nutrient application alone, iron-mediated stabilization of vegetation inputs favored the regeneration of a barren stable state that had persisted for over five decades since disturbance. The effectiveness of coupled organic matter and iron "fertilization," combined with management of invasive species, has the possibility to enhance terrestrial carbon sequestration and accelerate the restoration of degraded lands, while addressing important challenges associated with urban waste disposal.
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http://dx.doi.org/10.1890/14-2151.1DOI Listing
July 2015

Ru(II)-based complexes with N-(acyl)-N',N'-(disubstituted)thiourea ligands: Synthesis, characterization, BSA- and DNA-binding studies of new cytotoxic agents against lung and prostate tumour cells.

J Inorg Biochem 2015 Sep 22;150:63-71. Epub 2015 Apr 22.

Departamento de Química, Universidade Federal de São Carlos, UFSCar, Rodovia Washington Luís KM 235, CP 676, 13561-901, São Carlos, SP, Brazil. Electronic address:

Four ruthenium(II)-based complexes with N-(acyl)-N',N'-(disubstituted)thiourea derivatives (Th) were obtained. The compounds, with the general formula trans-[Ru(PPh3)2(Th)(bipy)]PF6, interact with bovine serum albumin (BSA) and DNA. BSA-binding constants, which were in the range of 3.3-6.5×10(4) M(-1), and the thermodynamic parameters (ΔG, ΔH and ΔS), suggest spontaneous interactions with this protein by electrostatic forces due to the positive charge of the complexes. Also, binding constant by spectrophotometric DNA titration (Kb = 0.8-1.8×10(4) M(-1)) and viscosity studies indicate weak interactions between the complexes and DNA. Cytotoxicity assays against DU-145 (prostate cancer) and A549 (lung cancer) tumour cells revealed that the complexes are more active in tumour cells than in normal (L929) cells, and that they present high cytotoxicity (low IC50 values) compared with the reference metallodrug, cisplatin.
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http://dx.doi.org/10.1016/j.jinorgbio.2015.04.008DOI Listing
September 2015

Antiparasitic activities of novel ruthenium/lapachol complexes.

J Inorg Biochem 2014 Jul 27;136:33-9. Epub 2014 Mar 27.

Departamento de Química, Universidade Federal de São Carlos, CP 676, CEP 13565-905, São Carlos (SP), Brazil. Electronic address:

The present study describes the synthesis, characterization, antileishmanial and antiplasmodial activities of novel diimine/(2,2'-bipyridine (bipy), 1,10-phenanthroline (phen), 4,4'-methylbipyridine (Me-bipy) and 4,4'-methoxybipyridine (MeO-bipy)/phosphine/ruthenium(II) complexes containing lapachol (Lap, 2-hydroxy-3-(3-33 methyl-2-buthenyl)-1,4-naphthoquinone) as bidentate ligand. The [Ru(Lap)(PPh3)2(bipy)]PF6 (1), [Ru(Lap)(PPh3)2(Me-bipy)]PF6 (2), [Ru(Lap)(PPh3)2(MeO-bipy)]PF6(3) and[Ru(Lap)(PPh3)2(phen)]PF6 (4) complexes, PPh3=triphenylphospine, were synthesized from the reactions of cis-[RuCl2(PPh3)2(X-bipy)] or cis-[RuCl2(PPh3)2(phen)], with lapachol. The [RuCl2(Lap)(dppb)] (5) [dppb=1,4-bis(diphenylphosphine)butane] was synthesized from the mer-[RuCl3(dppb)(H2O)] complex. The complexes were characterized by elemental analysis, molar conductivity, infrared and UV-vis spectroscopy, (31)P{(1)H} and (1)H NMR, and cyclic voltammetry. The Ru(III) complex, [RuCl2(Lap)(dppb)], was also characterized by the EPR technique. The structure of the complexes [Ru(Lap)(PPh3)2(bipy)]PF6 and [RuCl2(Lap)(dppb)] was elucidated by X-ray diffraction. The evaluation of the antiparasitic activities of the complexes against Leishmania amazonensis and Plasmodium falciparum demonstrated that lapachol-ruthenium complexes are more potent than the free lapachol. The [RuCl2(Lap)(dppb)] complex is the most potent and selective antiparasitic compound among the five new ruthenium complexes studied in this work, exhibiting an activity comparable to the reference drugs.
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http://dx.doi.org/10.1016/j.jinorgbio.2014.03.009DOI Listing
July 2014

Unprecedented carbon accumulation in mined soils: the synergistic effect of resource input and plant species invasion.

Ecol Appl 2013 Sep;23(6):1345-56

Department of Land, Air, and Water Resources, University of California, Biogeochemistry and Nutrient Cycling Laboratory, One Shields Avenue, Davis, California 95616-8627, USA.

Opencast mining causes severe impacts on natural environments, often resulting in permanent damage to soils and vegetation. In the present study we use a 14-year restoration chronosequence to investigate how resource input and spontaneous plant colonization promote the revegetation and reconstruction of mined soils in central Brazil. Using a multi-proxy approach, combining vegetation surveys with the analysis of plant and soil isotopic abundances (delta13C and delta15N) and chemical and physical fractionation of organic matter in soil profiles, we show that: (1) after several decades without vegetation cover, the input of nutrient-rich biosolids into exposed regoliths prompted the establishment of a diverse plant community (> 30 species); (2) the synergistic effect of resource input and plant colonization yielded unprecedented increases in soil carbon, accumulating as chemically stable compounds in occluded physical fractions and reaching much higher levels than observed in undisturbed ecosystems; and (3) invasive grasses progressively excluded native species, limiting nutrient availability, but contributing more than 65% of the total accumulated soil organic carbon. These results show that soil-plant feedbacks regulate the amount of available resources, determining successional trajectories and alternative stable equilibria in degraded areas undergoing restoration. External inputs promote plant colonization, soil formation, and carbon sequestration, at the cost of excluding native species. The introduction of native woody species would suppress invasive grasses and increase nutrient availability, bringing the system closer to its original state. However, it is difficult to predict whether soil carbon levels could be maintained without the exotic grass cover. We discuss theoretical and practical implications of these findings, describing how the combination of resource manipulation and management of invasive species could be used to optimize restoration strategies, counteracting soil degradation while maintaining species diversity.
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http://dx.doi.org/10.1890/12-1957.1DOI Listing
September 2013

Unprecedented carbon accumulation in mined soils: the synergistic effect of resource input and plant species invasion.

Ecol Appl 2013 Sep;23(6):1345-56

Department of Land, Air, and Water Resources, University of California, Biogeochemistry and Nutrient Cycling Laboratory, One Shields Avenue, Davis, California 95616-8627, USA.

Opencast mining causes severe impacts on natural environments, often resulting in permanent damage to soils and vegetation. In the present study we use a 14-year restoration chronosequence to investigate how resource input and spontaneous plant colonization promote the revegetation and reconstruction of mined soils in central Brazil. Using a multi-proxy approach, combining vegetation surveys with the analysis of plant and soil isotopic abundances (delta13C and delta15N) and chemical and physical fractionation of organic matter in soil profiles, we show that: (1) after several decades without vegetation cover, the input of nutrient-rich biosolids into exposed regoliths prompted the establishment of a diverse plant community (> 30 species); (2) the synergistic effect of resource input and plant colonization yielded unprecedented increases in soil carbon, accumulating as chemically stable compounds in occluded physical fractions and reaching much higher levels than observed in undisturbed ecosystems; and (3) invasive grasses progressively excluded native species, limiting nutrient availability, but contributing more than 65% of the total accumulated soil organic carbon. These results show that soil-plant feedbacks regulate the amount of available resources, determining successional trajectories and alternative stable equilibria in degraded areas undergoing restoration. External inputs promote plant colonization, soil formation, and carbon sequestration, at the cost of excluding native species. The introduction of native woody species would suppress invasive grasses and increase nutrient availability, bringing the system closer to its original state. However, it is difficult to predict whether soil carbon levels could be maintained without the exotic grass cover. We discuss theoretical and practical implications of these findings, describing how the combination of resource manipulation and management of invasive species could be used to optimize restoration strategies, counteracting soil degradation while maintaining species diversity.
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http://dx.doi.org/10.1890/12-1957.1DOI Listing
September 2013

2,4,6-Trinitro-phenyl 4-methyl-benzoate.

Acta Crystallogr Sect E Struct Rep Online 2012 Nov 13;68(Pt 11):o3107. Epub 2012 Oct 13.

Departamento de Química - Facultad de Ciencias, Universidad del Valle, Apartado 25360, Santiago de Cali, Colombia.

In the title compound, C(14)H(9)N(3)O(8), the benzene rings form a dihedral angle of 69.02 (5)°. The central ester group is rotated by 25.86 (9)° relative to the p-tolyl group. In the crystal, the mol-ecules are linked by C-H⋯O inter-actions into helical chains along [010].
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http://dx.doi.org/10.1107/S1600536812041773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3515213PMC
November 2012

Probing the relationships between molecular conformation and intermolecular contacts in N,N-dibenzyl-N'-(furan-2-carbonyl)thiourea.

Acta Crystallogr C 2012 Jan 9;68(Pt 1):o19-22. Epub 2011 Dec 9.

Departamento de Química Inorgánica, Facultad de Química, Universidad de la Habana, Habana 10400, Cuba.

In the crystal structure of the title compound, C(20)H(18)N(2)O(2)S, molecules are linked by bifurcated C-H···O hydrogen-bond interactions, giving rise to chains whose links are composed of alternating centrosymmetrically disposed pairs of molecules and characterized by R(2)(2)(10) and R(2)(2)(20) hydrogen-bonding motifs. Also, N-H···S hydrogen bonds form infinite zigzag chains along the [010] direction, which exhibit the C(4) motif. Hirshfeld surface and fingerprint plots were used to explore the intermolecular interactions in the crystal structure. This analysis confirms the important role of C-H···O hydrogen bonds in the molecular conformation and in the crystal structure, providing a potentially useful tool for a full understanding of the intermolecular interactions in acylthiourea derivatives.
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http://dx.doi.org/10.1107/S0108270111052620DOI Listing
January 2012