Publications by authors named "Fernando R Pavan"

58 Publications

Design, synthesis and antibacterial activity of chalcones against MSSA and MRSA planktonic cells and biofilms.

Bioorg Chem 2021 Aug 31;116:105279. Epub 2021 Aug 31.

Laboratory of Antibiotics and Chemotherapeutics, Department of Chemistry and Environmental Sciences, Institute of Biosciences, Humanities and Exact Sciences, São Paulo State University, São José do Rio Preto, SP, Brazil. Electronic address:

Staphylococcus aureus is the one of the most successful modern pathogens. The same bacterium that lives as a skin and mucosal commensal can be transmitted in health-care and community-settings and causes severe infections. Thus, there is a great challenge for a discovery of novel anti-Staphylococcus aureus compounds, which should act against resistant strains. Herein, we designed and synthesized a series of 17 chalcones, substituted by amino group on ring A, which were evaluated against methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus MRSA planktonic cells. The antibacterial potency was improved by substituents on ring B, which were designed according to Topliss' manual method. 4-bromo-3'-aminochalcone (5f) was the most active, demonstrating minimum inhibitory concentration (MIC) values of 1.9 μg mL and 7.8 µg mL against MSSA and MRSA, respectively. The association of 5f with vancomycin demonstrated synergistic effect against MSSA and MRSA, with Fractional Inhibitory Concentration Index (FICI) values of 0.4 and 0.3, respectively. Subinhibitory concentration of 5f inhibited the MSSA and MRSA adhesion to human keratinocytes. Chalcone 5f was able to reduce MSSA and MRSA biofilm formation, as well as acts on preformed biofilm in concentration-dependent mode. Scanning electron microscopy analyses confirmed severe perturbations caused by 5f on MSSA and MRSA biofilm architecture. The acute toxicity assay, using Galleria mellonella larvae, indicated a low toxic effect of 5f after 72 h, displaying lethality of 20% and 30% at 7.8 μg mL and 78.0 μg mL, respectively. In addition, the antibacterial activity spectrum of 5f indicated action against planktonic cells of Enterococcus faecalis (MIC = 7.8 μg mL), Acinetobacter baumannii (MIC = 15.6 μg mL) and Mycobacterium tuberculosis (MIC = 5.7 μg mL). Altogether, these results open new avenues for 5f as an anti-Staphylococcus aureus agent, with potential applications as antibacterial drug, adjunct of antibiotics and medical devices coating.
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http://dx.doi.org/10.1016/j.bioorg.2021.105279DOI Listing
August 2021

A Novel Ruthenium(II) Complex With Lapachol Induces G2/M Phase Arrest Through Aurora-B Kinase Down-Regulation and ROS-Mediated Apoptosis in Human Prostate Adenocarcinoma Cells.

Front Oncol 2021 24;11:682968. Epub 2021 Jun 24.

School of Pharmaceutical Sciences, São Paulo State University, Araraquara, Brazil.

Lapachol is a well-studied natural product that has been receiving great interest due to its anticancer properties that target oxidative stress. In the present work, two novel lapachol-containing ruthenium(II) complexes [Ru(Lap)(dppm)(bipy)]PF () and [Ru(Lap)(dppm)(phen)]PF () [Lap = lapachol, dppm = 1,1'-bis(diphosphino)methane, bipy = 2,2'-bipyridine, phen = 1,10-phenantroline] were synthesized, fully characterized, and investigated for their cellular and molecular responses on cancer cell lines. We found that both complexes exhibited a potent cytotoxic effect in a panel of cancer cell lines in monolayer cultures, as well as in a 3D model of multicellular spheroids formed from DU-145 human prostate adenocarcinoma cells. Furthermore, the complex () suppressed the colony formation, induced G2/M-phase arrest, and downregulated Aurora-B. The mechanism studies suggest that complex () stimulate the overproduction of reactive oxygen species (ROS) and triggers caspase-dependent apoptosis as a result of changes in expression of several genes related to cell proliferation and caspase-3 and -9 activation. Interestingly, we found that N-acetyl-L-cysteine, a ROS scavenger, suppressed the generation of intracellular ROS induced by complex (), and decreased its cytotoxicity, indicating that ROS-mediated DNA damage leads the DU-145 cells into apoptosis. Overall, we highlighted that coordination of lapachol to phosphinic ruthenium(II) compounds considerably improves the antiproliferative activities of resulting complexes granting attractive selectivity to human prostate adenocarcinoma cells. The DNA damage response to ROS seems to be involved in the induction of caspase-mediated cell death that plays an important role in the complexes' cytotoxicity. Upon further investigations, this novel class of lapachol-containing ruthenium(II) complexes might indicate promising chemotherapeutic agents for prostate cancer therapy.
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http://dx.doi.org/10.3389/fonc.2021.682968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264259PMC
June 2021

Antibacterial activity of a new monocarbonyl analog of curcumin MAC 4 is associated with divisome disruption.

Bioorg Chem 2021 04 27;109:104668. Epub 2021 Jan 27.

Department of Chemistry and Environmental Sciences, Institute of Biosciences, Humanities and Exact Sciences, São Paulo State University (Unesp), São José do Rio Preto, 15054-000, SP, Brazil. Electronic address:

Curcumin (CUR) is a symmetrical dicarbonyl compound with antibacterial activity. On the other hand, pharmacokinetic and chemical stability limitations hinder its therapeutic application. Monocarbonyl analogs of curcumin (MACs) have been shown to overcome these barriers. We synthesized and investigated the antibacterial activity of a series of unsymmetrical MACs derived from acetone against Mycobacterium tuberculosis and Gram-negative and Gram-positive species. Phenolic MACs 4, 6 and 8 showed a broad spectrum and potent activity, mainly against M. tuberculosis, Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus (MRSA), with MIC (minimum inhibitory concentration) values ranging from 0.9 to 15.6 µg/mL. The investigation regarding toxicity on human lung cells (MRC-5 and A549 lines) revealed MAC 4 was more selective than MACs 6 and 8, with SI (selectivity index) values ranging from 5.4 to 15.6. In addition, MAC 4 did not demonstrate genotoxic effects on A549 cells and it was more stable than CUR in phosphate buffer (pH 7.4) for 24 h at 37 °C. Fluorescence and phase contrast microscopies indicated that MAC 4 has the ability to disrupt the divisome of Bacillus subtilis without damaging its cytoplasmic membrane. However, biochemical investigations demonstrated that MAC 4 did not affect the GTPase activity of B. subtilis FtsZ, which is the main constituent of the bacterial divisome. These results corroborated that MAC 4 is a promising antitubercular and antibacterial agent.
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http://dx.doi.org/10.1016/j.bioorg.2021.104668DOI Listing
April 2021

Differential miRNA Expression in Human Macrophage-Like Cells Infected with Yeasts Cultured in Planktonic and Biofilm Forms.

J Fungi (Basel) 2021 Jan 18;7(1). Epub 2021 Jan 18.

School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, São Paulo 14800-903, Brazil.

affects healthy and immunocompromised individuals, sometimes causing a severe disease. This fungus has two morphotypes, the mycelial (infective) and the yeast (parasitic) phases. MicroRNAs (miRNAs) are small RNAs involved in the regulation of several cellular processes, and their differential expression has been associated with many disease states. To investigate miRNA expression in host cells during infection, we studied the changes in the miRNA profiles of differentiated human macrophages infected with yeasts from two fungal strains with different virulence, EH-315 (high virulence) and 60I (low virulence) grown in planktonic cultures, and EH-315 grown in biofilm form. MiRNA profiles were evaluated by means of reverse transcription-quantitative polymerase chain reaction using a commercial human miRNome panel. The target genes of the differentially expressed miRNAs and their corresponding signaling pathways were predicted using bioinformatics analyses. Here, we confirmed biofilm structures were present in the EH-315 culture whose conditions facilitated producing insoluble exopolysaccharide and intracellular polysaccharides. In infected macrophages, bioinformatics analyses revealed especially increased (hsa-miR-99b-3p) or decreased (hsa-miR-342-3p) miRNAs expression levels in response to infection with biofilms or both growth forms of yeasts, respectively. The results of miRNAs suggested that infection by can affect important biological pathways of the host cell, targeting two genes: one encoding a protein that is important in the cortical cytoskeleton; the other, a protein involved in the formation of stress granules. Expressed miRNAs in the host's response could be proposed as new therapeutic and/or diagnostic tools for histoplasmosis.
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http://dx.doi.org/10.3390/jof7010060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830537PMC
January 2021

Benzofuroxan Derivatives as Potent Agents against Multidrug-Resistant Mycobacterium tuberculosis.

ChemMedChem 2021 Apr 9;16(8):1268-1282. Epub 2021 Feb 9.

School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara Jaú Highway KM 01, 14800903, Araraquara, Brazil.

Tuberculosis (TB) is currently the leading cause of death related to infectious diseases worldwide, as reported by the World Health Organization. Moreover, the increasing number of multidrug-resistant tuberculosis (MDR-TB) cases has alarmed health agencies, warranting extensive efforts to discover novel drugs that are effective and also safe. In this study, 23 new compounds were synthesized and evaluated in vitro against the drug-resistant strains of M. tuberculosis. The compound 6-((3-fluoro-4-thiomorpholinophenyl)carbamoyl)benzo[c][1,2,5]oxadiazole 1-N-oxide (5 b) was particularly remarkable in this regard as it demonstrated MIC values below 0.28 μM against all the MDR strains evaluated, thus suggesting that this compound might have a different mechanism of action. Benzofuroxans are an attractive new class of anti-TB agents, exemplified by compound 5 b, with excellent potency against the replicating and drug-resistant strains of M. tuberculosis.
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http://dx.doi.org/10.1002/cmdc.202000899DOI Listing
April 2021

Antimicrobial and antitumor activity of S-methyl dithiocarbazate Schiff base zinc(II) complexes.

J Inorg Biochem 2021 03 13;216:111331. Epub 2020 Dec 13.

Centro de Química Estrutural and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal. Electronic address:

Schiff bases (SB) obtained from S-methyl dithiocarbazate and aromatic aldehydes: salicylaldehyde (HL), o-vanillin (HL), pyridoxal (HL) and 2,6-diformyl-4-methylphenol (HL), and their corresponding Zn(II)-complexes (1-4), are synthesized. All compounds are characterized by elemental analyses, infrared, UV-Vis, nuclear magnetic resonance spectroscopy and mass spectrometry. The structures of HL and [Zn(L)(HO)(DMF)] (1a) (DMF = dimethylformamide) are solved by single crystal X-ray diffraction. The SB coordinates the metal center through the O, N and S atoms. The radical scavenging activity is tested using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, with all ligand precursors showing IC values ~40 μM. Cytotoxicity studies with several tumor cell lines (PC-3, MCF-7 and Caco-2) as well as a non-tumoral cell line (NHDF) are reported. Interestingly, 1 has relevant and selective antiproliferative effect against Caco-2 cells (IC = 9.1 μM). Their antimicrobial activity is evaluated in five bacterial strains (Klebsiella pneumoniae, Acinetobacter baumannii, Listeria monocytogenes, Pseudomonas aeruginosa and Staphylococcus aureus) and two yeast strains (Candida albicans and Candida tropicalis) with some compounds showing bacteriostatic and fungicidal activity. The minimal inhibitory concentration (MIC) of HL against Mycobacterium tuberculosis is also reported, with HL and HL showing very high activity (MIC < 0.6 μg/mL). The ability of the compounds to bind bovine serum albumin (BSA) and DNA is evaluated for HL and [Zn(L)(CHCOO)] (4), both showing high binding constants to BSA (ca. 10 M) and ability to bind DNA. Overall, the reported compounds show relevant antitumor and antimicrobial properties, our data indicating they may be promising compounds in several fields of medicinal chemistry.
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http://dx.doi.org/10.1016/j.jinorgbio.2020.111331DOI Listing
March 2021

Antibacterial activities and antiproliferative assays over a tumor cells panel of a silver complex with 4-aminobenzoic acid: Studies in vitro of sustained release using bacterial cellulose membranes as support.

J Inorg Biochem 2020 11 6;212:111247. Epub 2020 Sep 6.

University of Araraquara - UNIARA, 14801-320 Araraquara, São Paulo, Brazil. Electronic address:

The aims of this work were to evaluate the antibacterial and antiproliferative potential in vitro of the metal complex with 4-aminobenzoic acid (Ag-pABA) and a drug delivery system based on bacterial cellulose (BC-Ag-pABA). The Ag-pABA complex was characterized by elemental analysis, high resolution mass spectrometry and single-crystal X-ray diffraction techniques, which indicated a 1:2 metal/pABA composition plus a nitrate ion coordinated to silver by the oxygen atom, with the coordination formula [Ag (CHNO)(NO)]. The coordination of pABA to the silver ion occurred by the nitrogen atom. The in vitro antibacterial activity of the complex evaluated by minimum inhibitory concentration assays demonstrated the effective growth inhibitory activity against Gram-positive, Gram-negative biofilm producers and acid-alcohol resistant Bacillus. The antiproliferative activities against a panel of eight tumor cells demonstrated the activity of the complex with a significant selectivity index (SI). The DNA interaction capacity and the Ames Test indicated the absence of mutagenicity. The BC-Ag-pABA composite showed an effective capacity of sustained release of Ag-pABA. The observed results validate further studies on its mechanisms of action and the conditions that mediate the in vivo biological effects using animal models to confirm its safety and effectiveness for treatment of skin and soft tissues infected by bacterial pathogens, urinary tract infections and cancer.
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http://dx.doi.org/10.1016/j.jinorgbio.2020.111247DOI Listing
November 2020

Cytotoxic and apoptotic effects of ternary silver(i) complexes bearing 2-formylpyridine thiosemicarbazones and 1,10-phenanthroline.

Dalton Trans 2020 Apr;49(16):5264-5275

Department of General and Inorganic Chemistry, Department of Analytical Chemistry, UNESP - São Paulo State University, Institute of Chemistry, CEP 14800-060 Araraquara, SP, Brazil.

New silver(i) compounds containing 2-formylpyridine-N(4)-R-thiosemicarbazones and 1,10-phenanthroline (phen) were synthesized and characterized by spectroscopic techniques (IR and NMR), elemental analysis, ESI-MS and molar conductance measurements. In these complexes, both phen and thiosemicarbazone ligands are coordinated in a chelating bidentate fashion. Compounds 1-3 not only showed good in vitro antiproliferative activity against human lung (A549) and breast tumor cells (MDA-MB-231 and MCF-7), with IC50 values ranging from 1.49 to 20.90 μM, but were also demonstrated to be less toxic towards human breast non-tumor cells (MCF-10A). Cellular uptake studies indicated that compounds 1-3 were taken up by the MDA-MB-231 cells in 6 hours. Cell death assays in the MDA-MB-231 cells were conducted with compound 1 aiming to evaluate its effects on cell morphology, induction of apoptosis, the cell cycle, reactive oxygen species (ROS) formation and mitochondrial membrane potential (Δψm). Compound 1 caused morphological changes, such as cell shrinkage and rounding, increased the sub-G1 phase population, and induced apoptotic cell death, ROS formation and loss of mitochondrial membrane potential (Δψm). DNA binding results revealed that 1 interacted with the ct-DNA minor groove. Complexes 1-3 also exhibited good in vitro activity against M. tuberculosis H37Rv, with MIC values ranging from 3.37 to 4.65 μM.
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http://dx.doi.org/10.1039/d0dt00253dDOI Listing
April 2020

Experimental data on novel Fe(III)-complexes containing phenanthroline derivatives for their anticancer properties.

Data Brief 2019 Dec 27;27:104548. Epub 2019 Sep 27.

Koc University Research Center for Translational Medicine (KUTTAM), Sariyer, Istanbul, Turkey.

This dataset is related to the research article entitled "May iron(III) complexes containing phenanthroline derivatives as ligands be prospective anticancer agents?" [1]. It includes the characterization by UV-Vis absorption spectroscopy and magnetic techniques of a group of mixed ligand Fe(III) complexes bearing a tripodal aminophenolate ligand L, HL = ,-bis(2-hydroxy-3,5-dimethylbenzyl)--(2-pyridylmethyl)amine, and different aromatic bases (NN = 2,2'-bipyridine [Fe(L)(bipy)]PF (), 1,10-phenanthroline [Fe(L)(phen)]PF (), or a phenanthroline derivative co-ligand: [Fe(L)(amphen)]NO (), [Fe(L)(amphen)]PF (), [Fe(L)(Clphen)]PF (), [Fe(L)(epoxyphen)]PF () (where amphen = 1,10-phenanthroline-5-amine, epoxyphen = 5,6-epoxy-5,6-dihydro-1,10-phenanthroline, Clphen = 5-chloro-1,10-phenanthroline), as well as [Fe(L)(EtOH)]NO (), [Fe(phen)Cl] () and [Fe(amphen)Cl] (). Data on their hydrolytic stability in physiological buffers is shown, as well as on their interaction with DNA by spectroscopic tools. Additionally, the anticancer efficacy and the cellular death mechanisms activated in response to these drugs in HeLa, H1299 and MDA-MB-231 cells are provided.
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http://dx.doi.org/10.1016/j.dib.2019.104548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817691PMC
December 2019

Bactericidal effect of pyridine-2-thiol 1-oxide sodium salt and its complex with iron against resistant clinical isolates of Mycobacterium tuberculosis.

J Antibiot (Tokyo) 2020 02 16;73(2):120-124. Epub 2019 Oct 16.

Department of Biological Sciences, Faculty of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, SP, Brazil.

The objective of this study was to determine the activity of pyridine-2-thiol 1-oxide sodium salt (Na mpo) and its complex with iron [Fe(mpo)] against Mycobacterium tuberculosis. The compounds were tested against a standard strain of M. tuberculosis HRv (ATCC 27294), with minimal inhibitory concentrations (MIC) of 7.20 and 1.07 μM to Na mpo and [Fe(mpo)], respectively, and against three clinical isolates with different genotypic profiles, with MIC values ranging from 0.74 to 6.52 and 0.30 to 2.25 μM to Na mpo and [Fe(mpo)], respectively. [Fe(mpo)] was more effective against susceptible strains but both compounds were effective in inhibiting MDR and XDR-TB clinical strains. The profile activity was determined through the methodology of a time-kill curve against standard and clinical strains of M. tuberculosis. Time-kill studies indicated that Na mpo had an early bactericidal activity against HRv and clinical isolates, with sterilizing effects observed in 5 and 7 days, respectively, at its MIC. The anti MDR and XDR-M. tuberculosis activity and bactericidal effect of Na mpo and [Fe(mpo)] demonstrate their potential as new compounds for the treatment of tuberculosis.
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http://dx.doi.org/10.1038/s41429-019-0243-3DOI Listing
February 2020

A Novel Antifungal System With Potential for Prolonged Delivery of Histatin 5 to Limit Growth of .

Front Microbiol 2019 30;10:1667. Epub 2019 Jul 30.

Department of Biochemistry and Chemical Technology, Institute of Chemistry, UNESP - São Paulo State University, Araraquara, Brazil.

Currently 75-88% of fungal infections are caused by species, and is the main microorganism that causes these infections, especially oral candidiasis. An option for treatment involves the use of the antifungal peptide Histatin 5 (Hst 5), which is naturally found in human saliva but undergoes rapid degradation when present in the oral cavity, its site of action. For this reason, it is important to develop a way of applying this peptide to the oral lesions, which promotes the gradual release of the peptide. In the present study, we have evaluated the development of liposomes of different lipid compositions, loaded with the peptide as a way to promote its release slowly and gradually, preserving its antifungal potential. For this, the peptide 0WHistatin 5, an analog of the peptide Hst 5, was synthesized, which contains the amino acid tryptophan in its sequence. The solid phase synthesis method was used, followed by cleavage and purification. The liposomes were produced by thin film hydration technique in three different lipid compositions, F1, F2, and F3 and were submitted to an extrusion and sonication process to standardize the size and study the best technique for their production. The liposomes were characterized by dynamic light scattering, and tests were performed to determine the encapsulation efficiency, release kinetics, stability, and evaluation of antifungal activity. The extruded liposomes presented average size in the range of 100 nm, while sonicated liposomes presented a smaller size in the range of 80 nm. The encapsulation efficiency was higher for the sonicated liposomes, being 34.5% for F1. The sonicated F3 presented better stability when stored for 60 days at 4°C. The liposomes showed the ability to release the peptide for the total time of 96 h, with the first peak after 5 h, and a further increase of the released after 30 h. Time-kill assay showed that the liposomes were able to control yeast growth for 72 h. The data suggest that the liposomes loaded with 0WHistatin 5 maintained the action of the peptide and were able to limit the growth of , being a suitable system for use in the treatment of oral candidiasis.
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http://dx.doi.org/10.3389/fmicb.2019.01667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683761PMC
July 2019

Antibacterial activity of 3,3'-dihydroxycurcumin (DHC) is associated with membrane perturbation.

Bioorg Chem 2019 09 7;90:103031. Epub 2019 Jun 7.

Department of Chemistry and Environmental Sciences, Institute of Biosciences, Humanities and Exact Sciences, São Paulo State University (Unesp), São José do Rio Preto 15054-000, Brazil. Electronic address:

Curcumin is a plant diphenylheptanoid and has been investigated for its antibacterial activity. However, the therapeutic uses of this compound are limited due to its chemical instability. In this work, we evaluated the antimicrobial activity of diphenylheptanoids derived from curcumin against Gram-positive and Gram-negative bacteria, and also against Mycobacterium tuberculosis in terms of MIC (Minimum Inhibitory Concentration) and MBC (Minimum Bactericidal Concentration) values. 3,3'-Dihydroxycurcumin (DHC) displayed activity against Enterococcus faecalis, Staphylococcus aureus and M. tuberculosis, demonstrating MIC values of 78 and 156 µg/mL. In addition, DHC was more stable than curcumin in acetate buffer (pH 5.0) and phosphate buffer (pH 7.4) for 24 h at 37 °C. We proposed that membrane and the cell division protein FtsZ could be the targets for DHC due to that fact that curcumin exhibits this mode of antibacterial action. Fluorescence microscopy of Bacillus subtilis stained with SYTO9 and propidium iodide fluorophores indicated that DHC has the ability to perturb the bacterial membrane. On the other hand, DHC showed a weak inhibition of the GTPase activity of B. subtilis FtsZ. Toxicity assay using human cells indicated that DHC has moderate capacity to reduce viability of liver cells (HepG2 line) and lung cells (MRC-5 and A549 lines) when compared with doxorubicin. Alkaline comet assay indicated that DHC was not able to induce DNA damage in A549 cell line. These results indicated that DHC is promising compound with antibacterial and antitubercular activities.
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http://dx.doi.org/10.1016/j.bioorg.2019.103031DOI Listing
September 2019

May iron(III) complexes containing phenanthroline derivatives as ligands be prospective anticancer agents?

Eur J Med Chem 2019 Aug 13;176:492-512. Epub 2019 May 13.

Koc University Research Center for Translational Medicine (KUTTAM), Sariyer, Istanbul, Turkey; Koc University, Medical School, Sariyer, Istanbul, Turkey. Electronic address:

We report the design, synthesis and biological studies on a group of mixed ligand Fe(III) complexes as anti-cancer drug candidates, namely their interaction with DNA, cytotoxicity and mechanism(s) of action. The aim is to obtain stable, efficient and selective Fe-complexes to be used as anti-cancer agents with less damaging side effects than previously reported compounds. Five ternary Fe(III) complexes bearing a tripodal aminophenolate ligand L, HL = N,N-bis(2-hydroxy-3,5-dimethylbenzyl)-N-(2-pyridylmethyl)amine, and different aromatic bases NN = 2,2'-bipyridine [Fe(L)(bipy)]PF (1), 1,10-phenanthroline [Fe(L)(phen)]PF (2), or a phenanthroline derivative co-ligand: [Fe(L)(amphen)]NO (3), [Fe(L)(amphen)]PF (3a), [Fe(L)(Clphen)]PF (4), [Fe(L)(epoxyphen)]PF (5) (where amphen = 1,10-phenanthroline-5-amine, epoxyphen = 5,6-epoxy-5,6-dihydro-1,10-phenanthroline, Clphen = 5-chloro-1,10-phenanthroline) and the [Fe(L)(EtOH)]NO (6) complex are synthesized. The compounds are characterized in the solid state and in solution by elemental analysis, ESI-MS, magnetic susceptibility measurements and FTIR, UV-Vis, H and C NMR and fluorescence spectroscopies. [Fe(phen)Cl] and [Fe(amphen)Cl] were also prepared for comparison purposes. Spectroscopic binding studies indicate groove binding as the main interaction for most complexes with DNA, and for those containing amphen a B- to Z-DNA conformational change is proposed to occur. As determined via MTT analysis all compounds 1-6 are cytotoxic against a panel of three different cell lines (HeLa, H1299, MDA-MB-231). For selected compounds with promising cytotoxic activity, apoptosis was evaluated using cell and DNA morphology, TUNEL, Annexin V/7AAD staining and caspase3/7 activity. The compounds induce oxidative DNA damage on plasmid DNA and in cell culture as assessed by 8-oxo-Guanine and γH2AX staining. Comet assay confirmed the presence of genomic damage. There is also increased reactive oxygen species formation following drug treatment, which may be the relevant mechanism of action, thus differing from that normally assumed for cisplatin. The Fe(III)-complexes were also tested against strains of M. Tuberculosis (MTb), complex 2 depicting higher anti-MTb activity than several known second line drugs. Hence, these initial studies show prospective anti-cancer and anti-MTb activity granting promise for further studies.
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http://dx.doi.org/10.1016/j.ejmech.2019.04.070DOI Listing
August 2019

New ternary iron(iii) aminobisphenolate hydroxyquinoline complexes as potential therapeutic agents.

Dalton Trans 2019 Jun 24;48(24):8702-8716. Epub 2019 May 24.

Koc University, School of Medicine, Sariyer, Istanbul, Turkey.

In the quest for therapeutic iron-based metallodrugs, two new mixed-ligand iron(iii) complexes bearing the tripodal aminobisphenolate ligand N,N-bis(3,5-dimethyl-2-hydroxybenzyl)-N-(2-pyridylmethyl)amine (HL) and hydroxyquinoline co-ligands, 8-hydroxyquinoline (8HQ) or 5-chloro-8-hydroxyquinoline (Cl8HQ), are synthesized, fully characterized and formulated as [Fe(L)(8HQ)] (1) and [Fe(L)(Cl8HQ)] (2), respectively. These high-spin Fe(iii) complexes are stable in aqueous solution in the presence of equimolar amounts of Bovine Serum Albumin (BSA), which indicates a likely binding interaction with the protein. In fact, binding constant log values at pH 7.4 for HSA of 5.08 and 6.35 were obtained for 1 and 2, respectively. Compounds 1 and 2 are cytotoxic against both human triple-negative breast adenocarcinoma (MDA-MB-231) and human cervical carcinoma (HeLa) cancer cells, and the activity is significantly improved by inclusion of the co-ligands 8HQ and Cl8HQ to the precursor complex Fe(L). Moreover, 1 and 2 are more active than 8HQ and Cl8HQ, particularly at lower incubation times tested, 24 and 48 h. Cells treated with the complexes display typical features of apoptosis as assessed by cellular morphology, DNA condensation and TUNEL analysis. COMET assays show that both drug candidates induce genomic damage in both cell lines. The complexes exhibit DNA cleavage activity and DNA damage that may be related to their ability to generate ROS. Overall, data supports that 1 and 2 are both active anticancer drug candidates within the low micromolar range. This is particularly interesting in the case of the breast MDA-MB-231 line, a model for triple-negative breast cancer that is an aggressive form of breast cancer, highly invasive and with limited treatment options and very poor prognosis. Furthermore, both complexes exhibited good anti-Mycobacterium tuberculosis activity, suggesting that 1 and 2 might have a wide spectrum of biological activity and justify further research.
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http://dx.doi.org/10.1039/c9dt01193eDOI Listing
June 2019

Modulatory effects of verapamil in rifampicin activity against Mycobacterium tuberculosis.

Future Microbiol 2019 02 16;14:185-194. Epub 2019 Jan 16.

Department of Biological Sciences, School of Pharmaceutical Sciences, Paulista State University, Araraquara, Sao Paulo, Brazil.

Aim: To evaluate modulatory effect of verapamil (VP) in rifampicin (RIF) activity and its effect in efflux pumps (EPs) transcript levels in Mycobacterium tuberculosis.

Materials & Methods: RIF and VP minimal inhibitory concentration, combinatory effect and detection of mutations were determined in 16 isolates. EPs transcript levels were determined in four isolates by real-time PCR after exposure to drugs.

Results: VP showed good combinatory effect among RIF-resistant isolates. This effect was also observed in the relative transcript levels of EPs, mainly after 72 h of exposure, depending on the EP gene, genotype and the resistance profile of the isolate.

Conclusion: Additional regulatory mechanisms in the EP activities, as well as, interactions with other drug-specific resistance mechanisms need further investigation in M. tuberculosis.
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http://dx.doi.org/10.2217/fmb-2018-0277DOI Listing
February 2019

A Nanostructured Lipid System to Improve the Oral Bioavailability of Ruthenium(II) Complexes for the Treatment of Infections Caused by .

Front Microbiol 2018 6;9:2930. Epub 2018 Dec 6.

School of Pharmaceutical Sciences, Universidade Estadual Paulista, Araraquara, Brazil.

Tuberculosis (TB) is an infectious, airborne disease caused by the bacterium that mainly affects the lungs. Fortunately, tuberculosis is a curable disease, and in recent years, death rates for this disease have decreased. However, the existence of antibiotic-resistant strains and the occurrence of co-infections with human immunodeficiency virus (HIV), have led to increased mortality in recent years. Another area of concern is that one-third of the world's population is currently infected with in its latent state, serving as a potential reservoir for active TB. In an effort to address the failure of current TB drugs, greater attention is being given to the importance of bioinorganic chemistry as an ally in new research into the development of anti-TB drugs. Ruthenium (Ru) is a chemical element that can mimic iron (Fe) in the body. In previous studies involving the following heteroleptic Ru complexes, [Ru(pic)(dppb)(bipy)]PF (SCAR1), [Ru(pic)(dppb)(Me-bipy)]PF (SCAR2), [Ru(pic)(dppb)(phen)]PF (SCAR4), -[Ru(pic)(dppe)]PF (SCAR5), and [Ru(pic)(dppe)(phen)]PF (SCAR7), we observed excellent anti-TB activity, moderate cell-toxicity, and a lack of oral bioavailability in an model of these complexes. Therefore, the objective of this study was to evaluate the toxicity and oral bioavailability of these complexes by loading them into a nanostructured lipid system. The nanostructured lipid system was generated using different ratios of surfactant (soybean phosphatidylcholine, Eumulgin, and sodium oleate), aqueous phase (phosphate buffer with a concentration of 1X and pH 7.4), and oil (cholesterol) to generate a system for the incorporation of Ru(II) compounds. The anti-TB activity of the compounds was determined using a microdilution assay with Resazurin (REMA) against strains of s HRv and clinical isolates resistant. Cytotoxicity assay using J774.A1 cells (ATCC TIB-67) and intra-macrophage activity were performed. The oral bioavailability assay was used to analyze blood collected from female BALB/C mice. Plasma collected from the same mice was analyzed via inductively coupled plasma mass spectrometry (ICP-MS) to quantify the number of Ru ions. The complexes loaded into the nanostructured lipid system maintained activity and toxicity was found to be reduced compared with the compounds that were not loaded. The complexes showed intra-macrophagic activity and were orally bioavailable.
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http://dx.doi.org/10.3389/fmicb.2018.02930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291527PMC
December 2018

Determination of in vitro absorption in Caco-2 monolayers of anticancer Ru(II)-based complexes acting as dual human topoisomerase and PARP inhibitors.

Biometals 2019 02 30;32(1):89-100. Epub 2018 Nov 30.

Center of Exact Sciences and Technology, Federal University of São Carlos, São Carlos, SP, 13565-905, Brazil.

Due to their unique and versatile biochemical properties, ruthenium-based compounds have emerged as promising anticancer agents. Previous studies showed that three ruthenium(II) compounds: [Ru(pySH)(bipy)(dppb)]PF (1), [Ru(HSpym)(bipy)(dppb)]PF (2) and Ru[(SpymMe)(bipy)(dppb)]PF (3) presented anticancer properties higher than doxorubicin and cisplatin and acted as human topoisomerase IB (Topo I) inhibitors. Here, we focused our studies on in vitro intestinal permeability and anticancer mechanisms of these three complexes. Caco-2 permeation studies showed that 1 did not permeate the monolayer of intestinal cells, suggesting a lack of absorption on oral administration, while 2 and 3 permeated the cells after 60 and 120 min, respectively. Complexes 2 and 3 fully inhibited Topo II relaxation activity at 125 µM. In previously studies, 3 was the most potent inhibitor of Topo I, here, we concluded that it is a dual topoisomerase inhibitor. Moreover, it presented selectivity to cancer cells when evaluated by clonogenic assay. Thus, 3 was selected to gene expression assay front MDA-MB-231 cells from triple-negative breast cancer (TNBC), which represents the highly aggressive subgroup of breast cancers with poor prognosis. The analyses revealed changes of 27 out of 84 sought target genes. PARP1 and PARP2 were 5.29 and 1.83 times down-regulated after treatment with 3, respectively. PARPs have been attractive antitumor drug targets, considering PARP inhibition could suppress DNA damage repair and sensitize tumor cells to DNA damage agents. Recent advances in DNA repair studies have shown that an approach that causes cell lethality using synthetic PARP-inhibiting drugs has produced promising results in TNBC.
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http://dx.doi.org/10.1007/s10534-018-0160-0DOI Listing
February 2019

Sulfonamide-containing copper(II) metallonucleases: Correlations with in vitro antimycobacterial and antiproliferative activities.

J Inorg Biochem 2018 10 21;187:85-96. Epub 2018 Jul 21.

Institute of Chemistry, University of Campinas, UNICAMP, 13083-970 Campinas, SP, Brazil. Electronic address:

The bis-(1,10-phenanthroline)copper(I) complex, [Cu(I)(phen)], was the first copper-based artificial nuclease reported in the literature. The biological and ligand-like properties of sulfonamides make them good candidates for fine-tuning the reactivity of the [Cu(phen)] motif with biomolecules. In this context, we developed three novel copper(II) complexes containing the sulfonamides sulfameter (smtrH) and sulfadimethoxine (sdmxH) and (N^N)-bidentate ligands (2,2'-biyridine or 1,10-phenantroline). The compounds were characterized by chemical and spectroscopic techniques and single-crystal X-ray crystallography. When targeting plasmid DNA, the phen-containing compounds [Cu(smtr)(phen)] (1) and [Cu(sdmx)(phen)] (2) demonstrated nuclease activity even in the absence of reducing agents. Addition of ascorbic acid resulted in a complete cleavage of DNA by 1 and 2 at concentrations higher than 10 μM. Experiments designed to evaluate the copper intermediates involved in the nuclease effect after reaction with ascorbic acid identified at least the [Cu(I)(N^N)], [Cu(I)(sulfa)(N^N)] and [Cu(I)(sulfa)] species. The compounds interact with DNA via groove binding and intercalation as verified by fluorescence spectroscopy, circular dichroism (CD) and molecular docking. The magnitude and preferred mode of binding are dependent on the nature of both N^N ligand and the sulfonamide. The potent nuclease activity of compounds 1 and 2 are well correlated with their antiproliferative and anti-M. tuberculosis profiles. The results presented here demonstrated the potential for further development of copper(II)-sulfonamide-(N^N) complexes as multipurpose metallodrugs.
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http://dx.doi.org/10.1016/j.jinorgbio.2018.07.011DOI Listing
October 2018

New heterobimetallic ferrocenyl derivatives: Evaluation of their potential as prospective agents against trypanosomatid parasites and Mycobacterium tuberculosis.

J Inorg Biochem 2018 10 23;187:73-84. Epub 2018 Jul 23.

Área Química Inorgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay. Electronic address:

Searching for prospective agents against infectious diseases, four new ferrocenyl derivatives, [M(L)(dppf)4](PF), with M = Pd(II) or Pt(II), dppf = 1,1'-bis(dipheny1phosphino) ferrocene and HL = tropolone (HTrop) or hinokitiol (HHino), were synthesized and characterized. Complexes and ligands were evaluated against the bloodstream form of T. brucei, L. infantum amastigotes, M. tuberculosis (MTB) sensitive strain and MTB clinical isolates. Complexes showed a significant increase of the anti-T. brucei activity with respect to the free ligands (>28- and >46-fold for Trop and 6- and 22-fold for Hino coordinated to Pt-dppf and Pd-dppf, respectively), yielding IC values < 5 μM. The complexes proved to be more potent than the antitrypanosomal drug Nifurtimox. The new ferrocenyl derivatives were more selective towards the parasite than the free ligands. The Pt compounds were less toxic on J774 murine macrophages (mammalian cell model), than the Pd ones, showing selectivity index values (SI = IC murine macrophage/ICT. brucei) up to 23. Generation of the {M-dppf} compounds lead to a slightly positive impact on the anti-leishmanial potency. Although the ferrocenyl derivatives were more active on sensitive MTB than the free ligands (MIC = 9.88-14.73 μM), they showed low selectivity towards the pathogen. Related to the mechanism of action, the antiparasitic effect cannot be ascribed to an interference of the compounds with the thiol-redox homeostasis of the pathogen. Fluorescence measurements pointed at DNA as a probable target of the new compounds. [Pt(Trop)(dppf)](PF) and [Pt(Hino)(dppf)](PF) could be considered prospective anti-T. brucei agents that deserve further research.
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http://dx.doi.org/10.1016/j.jinorgbio.2018.07.013DOI Listing
October 2018

Unprecedented Antitubercular Activitiy of Manganese(II) Complexes Containing 1,10-Phenanthroline and Dicarboxylate Ligands: Increased Activity, Superior Selectivity, and Lower Toxicity in Comparison to Their Copper(II) Analogs.

Front Microbiol 2018 2;9:1432. Epub 2018 Jul 2.

Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, São Paulo, Brazil.

is the etiologic agent of tuberculosis. The demand for new chemotherapeutics with unique mechanisms of action to treat (multi)resistant strains is an urgent need. The objective of this work was to test the effect of manganese(II) and copper(II) phenanthroline/dicarboxylate complexes against . The water-soluble Mn(II) complexes, [Mn(oda)(phen)(HO)][Mn(oda)(phen)(oda)]·4HO () and {[Mn(3,6,9-tdda)(phen)]·3HO·EtOH}n () (odaH = octanedioic acid, phen = 1,10-phenanthroline, tddaH = 3,6,9-trioxaundecanedioic acid), and water-insoluble complexes, [Mn(ph)(phen)(HO)] (), [Mn(ph)(phen)(HO)]·4HO (), [Mn(isoph)(phen)]·4HO (), {[Mn(phen)(HO)]}(isoph)(phen)·12HO () and [Mn(tereph)(phen)]·5HO () (phH = phthalic acid, isophH = isophthalic acid, terephH = terephthalic acid), robustly inhibited the viability of strains, H37Rv and CDC1551. The water-soluble Cu(II) analog of (), [Cu(oda)(phen)](ClO)·2.76HO·EtOH (), was significantly less effective against both strains. Whilst () retarded H37Rv growth much better than its soluble Cu(II) equivalent, {[Cu(3,6,9-tdda)(phen)]·3HO·EtOH}n (), both were equally efficient against CDC1551. VERO and A549 mammalian cells were highly tolerant to the Mn(II) complexes, culminating in high selectivity index (SI) values. Significantly, studies using larvae indicated that the metal complexes were minimally toxic to the larvae. The Mn(II) complexes presented low MICs and high SI values (up to 1347), indicating their auspicious potential as novel antitubercular lead agents.
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http://dx.doi.org/10.3389/fmicb.2018.01432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036174PMC
July 2018

Dual-protected amino acid derivatives as new antitubercular agents.

Chem Biol Drug Des 2018 08 31;92(2):1576-1580. Epub 2018 May 31.

Department of Chemistry, Federal University of Juiz de Fora, Minas Gerais, Brazil.

Tuberculosis is an infectious disease with high incidence and growing drug-resistant rates. In an attempt to develop new antitubercular agents, 35 compounds were synthesized, most of them bearing a carbamate and enantiopure amino acid moiety. These compounds had their activity evaluated toward a Mycobacterium tuberculosis strain (ATCC 27294) and cytotoxicity against fibroblast MRC-5 cells (ATCC CCL-171). Three of the prepared derivatives presented a good antimicrobial inhibition and two of them a moderate cytotoxicity. The lipophilicity seems to play a vital role in the cell growth activity, with best results for the derivatives with a higher logP.
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http://dx.doi.org/10.1111/cbdd.13315DOI Listing
August 2018

Three new platinum complexes containing fluoroquinolones and DMSO: Cytotoxicity and evaluation against drug-resistant tuberculosis.

J Inorg Biochem 2018 06 16;183:77-83. Epub 2018 Mar 16.

Instituto de Química, Universidade Federal de Uberlândia, Campus Santa Mônica, Uberlândia, MG, Brazil. Electronic address:

This work describes the synthesis, characterization and biological evaluation of three platinum complexes of the type [Pt(DMSO)(L)Cl]Cl, in which L represents a fluoroquinolone, namely, ciprofloxacin (cpl), ofloxacin (ofl), or sparfloxacin (spf). The new complexes were characterized by elemental analysis, high-resolution mass spectrometry (HRESIMS) and H, C and Pt NMR (nuclear magnetic resonance). The spectral data suggest that the fluoroquinolones act as bidentate ligands coordinated to Pt(II) through the nitrogen atoms of the piperazine ring. Microbiological assays against wild type Mycobacterium tuberculosis (ATCC 27294) showed that all complexes have been very potent, exhibiting antitubercular potency at concentrations <2 μM, although none of the complexes presented higher potency than established anti-TB drugs. As to the resistant strains, the complex with sparfloxacin, [Pt(DMSO)(spf)Cl]Cl exhibited the best potential against most Mycobacterium tuberculosis clinical isolates. The cytotoxicity of these compounds was also evaluated in three breast cell lines: MCF-10 (a healthy cell), MCF-7 (a hormone responsive cancer cell) and MDA-MB-231 (triple negative breast cancer cell). In both tumor cell lines, [Pt(DMSO)(spf)Cl]Cl was more active and more selective than cisplatin. Flow cytometry analysis revealed that [Pt(DMSO)(spf)Cl]Cl induced late apoptotic cell death in MDA-MB-231 cells.
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http://dx.doi.org/10.1016/j.jinorgbio.2018.03.010DOI Listing
June 2018

Antibacterial and Antitubercular Activities of Cinnamylideneacetophenones.

Molecules 2017 Oct 10;22(10). Epub 2017 Oct 10.

Laboratory of Green and Medicinal Chemistry, Department of Chemistry and Environmental Sciences, Institute of Biosciences, Humanities and Exact Sciences, São Paulo State University (Unesp), São José do Rio Preto, SP 15054-000, Brazil.

Cinnamaldehyde is a natural product with broad spectrum of antibacterial activity. In this work, it was used as a template for design and synthesis of a series of 17 cinnamylideneacetophenones. Phenolic compounds and exhibited MIC (minimum inhibitory concentration) and MBC (minimum bactericidal concentration) values of 77.9 to 312 µM against , , and Compounds , , , and presented potent effects against (57.2 µM ≤ MIC ≤ 70.9 µM). Hydrophilic effects caused by substituents on ring B increased antibacterial activity against Gram-positive species. Thus, log were calculated by using high-performance liquid chromatography-photodiode array detection (HPLC-PDA) analyses, and cinnamylideneacetophenones presented values ranging from 2.5 to 4.1. In addition, the effects of and were evaluated on pulmonary cells, indicating their moderate toxicity (46.3 µM ≤ IC ≤ 96.7 µM) when compared with doxorubicin. Bioactive compounds were subjected to in silico prediction of pharmacokinetic properties, and did not violate Lipinski's and Veber's rules, corroborating their potential bioavailability by an oral route.
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http://dx.doi.org/10.3390/molecules22101685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151560PMC
October 2017

Bis(diphenylphosphino)amines-containing ruthenium cymene complexes as potential anti-Mycobacterium tuberculosis agents.

J Inorg Biochem 2017 08 9;173:134-140. Epub 2017 Apr 9.

Departamento de Química, Universidade Federal do Paraná, Centro Politécnico, CP 19081, CEP 81531-980 Curitiba, PR, Brazil. Electronic address:

Several ruthenium complexes have been investigated regarding anti-Mycobacterium tuberculosis (anti-MTb) activity, with some diphosphine-containing ruthenium complexes comparable to first and second line drugs. However, to the best of our knowledge, there is no PNP-containing ruthenium complexes applied as metallodrugs. Thus, this study focused on the synthesis, characterization and anti-MTb activity of a new series of coordination compounds with general formula [RuCl(η-p-cymene)(PNP)]X (R=CHPy (Py=pyridine)-[1a], CHPh (Ph=phenyl)-[1b], Ph-[1c] and p-tol (p-tol=p-tolyl)-[1d]; X=PF or BF). The complexes were fully characterized by NMR (H, P{H}), vibrational spectroscopy (FTIR), ESI-MS, molar conductance, elemental analysis and X-ray diffraction studies. The molecular structures of [1a]PF, [1c]BF and [1d]PF were determined and confirm the spectroscopic and ESI-MS data. The complexes were used in anti-MTb trials, and the preliminary results are presented. The complexes are promising anti-MTb agents with MIC (Minimum Inhibitory Concentration of compounds required to inhibit the growth of 90% of MTb) values comparable with the Ethambutol, the reference drug used in this work, and complex [1a]BF presented the highest selectivity index.
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http://dx.doi.org/10.1016/j.jinorgbio.2017.04.008DOI Listing
August 2017

Novel copper(II) complexes with hydrazides and heterocyclic bases: Synthesis, structure and biological studies.

J Inorg Biochem 2017 07 26;172:138-146. Epub 2017 Apr 26.

Instituto de Química, Universidade Federal de Uberlândia, Uberlândia, MG, Brazil. Electronic address:

Five new copper(II) complexes of the type [Cu(NO)(NN)(ClO)], in which NO=4-fluorophenoxyacetic acid hydrazide (4-FH) or 4-nitrobenzoic hydrazide (4-NH) and NN=1,10-phenanthroline (phen), 4-4'-dimethoxy-2-2'-bipyridine (dmb) or 2,2-bipyridine (bipy) were synthesized and characterized using various spectroscopic methods. The X-ray structural analysis of one representative compound indicates that the geometry around the copper ion is distorted octahedron, in which the ion is coordinated to hydrazide via the terminal nitrogen and the carbonyl oxygen, and to heterocyclic bases via their two nitrogen atoms. Two perchlorate anions occupy the apical positions, completing the coordination sphere. The cytotoxic activity of compounds was investigated in three tumor cell lines (K562, MDA-MB-231 and MCF-7). Concerning K562 cell line, the complexes with 1,10-phenanthroline exhibit high cytotoxic activity and are more active than carboplatin, free ligands and [Cu(phen)]. Considering the cytotoxicity results, further investigations for the compounds [Cu(4-FH)(phen)(ClO)] I and [Cu(4-NH)(phen)(ClO)]∙HO III were performed. Flow cytometric analysis revealed that these complexes induce apoptotic cell death in MDA-MB-231 cell line and bind to DNA with K values of 4.38×10 and 2.62×10, respectively. These compounds were also evaluated against wild type Mycobacterium tuberculosis (ATCC 27294) and exhibited antimycobacterial activity, displayed MIC values lower than those of the corresponding free ligands.
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http://dx.doi.org/10.1016/j.jinorgbio.2017.04.024DOI Listing
July 2017

Nanostructured lipid carriers for incorporation of copper(II) complexes to be used against .

Drug Des Devel Ther 2017 20;11:909-921. Epub 2017 Mar 20.

Department of Drugs and Medicines, Faculdade de Ciências Farmacêuticas, UNESP - Univ Estadual Paulista, Campus Araraquara, Araraquara, SP, Brazil.

Tuberculosis (TB) is a disease caused by . Cessation of treatment before the recommended conclusion may lead to the emergence of multidrug-resistant strains. The aim of this study was to develop nanostructured lipid carriers (NLCs) for use in the treatment of . The NLCs comprised the following lipid phase: 2.07% polyoxyethylene 40 stearate, 2.05% caprylic/capric triglyceride, and 0.88% polyoxyl 40 hydrogenated castor oil; the following aqueous phase: 3.50% poloxamer 407 (F1-F6), and 0.50% cetyltrimethylammonium bromide (F7-F12); and incorporated the copper(II) complexes [CuCl(INH)]·HO (1), [Cu(NCS)(INH)]·5HO (2), and [Cu(NCO)(INH)]·4HO (3) to form compounds F11.1, F11.2, and F11.3, respectively. The mean diameter of F11, F11.1, F11.2, and F11.3 ranged from 111.27±21.86 to 134.25±22.72 nm, 90.27±12.97 to 116.46±9.17 nm, 112.4±10.22 to 149.3±15.82 nm, and 78.65±6.00 to 122.00±8.70 nm, respectively. The polydispersity index values for the NLCs ranged from 0.13±0.01 to 0.30±0.09. The NLCs showed significant changes in zeta potential, except for F11.2, with F11, F11.1, F11.2, and F11.3 ranging from 18.87±4.04 to 23.25±1.13 mV, 17.03±1.77 to 21.42±1.87 mV, 20.51±1.88 to 22.60±3.44 mV, and 17.80±1.96 to 25.25±7.78 mV, respectively. Atomic force microscopy confirmed the formation of nanoscale spherical particle dispersions by the NLCs. Differential scanning calorimetry determined the melting points of the constituents of the NLCs. The in vitro activity of copper(II) complex-loaded NLCs against HR showed an improvement in the anti-TB activity of 55.4, 27.1, and 41.1 times the activity for complexes 1, 2, and 3, respectively. An in vivo acute toxicity study of complex-loaded NLCs demonstrated their reduced toxicity. The results suggest that NLCs may be a powerful tool to optimize the activity of copper(II) complexes against .
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http://dx.doi.org/10.2147/DDDT.S127048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367736PMC
May 2017

Human topoisomerase inhibition and DNA/BSA binding of Ru(II)-SCAR complexes as potential anticancer candidates for oral application.

Biometals 2017 06 16;30(3):321-334. Epub 2017 Mar 16.

School of Pharmaceutical Sciences, São Paulo State University, Araraquara, 14800-903, Brazil.

Three ruthenium(II) phosphine/diimine/picolinate complexes were selected aimed at investigating anticancer activity against several cancer cell lines and the capacity of inhibiting the supercoiled DNA relaxation mediated by human topoisomerase IB (Top 1). The structure-lipophilicity relationship in membrane permeability using the Caco-2 cells have also been evaluated in this study. SCAR 5 was found to present 45 times more cytotoxicity against breast cancer cell when compared to cisplatin. SCAR 4 and 5 were both found to be capable of inhibiting the supercoiled DNA relaxation mediated by Top 1. Interaction studies showed that SCAR 4 and 5 can bind to DNA through electrostatic interactions while SCAR 6 is able to bind covalently to DNA. The complexes SCAR were found to interact differently with bovine serum albumin (BSA) suggesting hydrophobic interactions with albumin. The permeability of all complexes was seen to be dependent on their lipophilicity. SCAR 4 and 5 exhibited high membrane permeability (P  > 10 × 10 cm·s) in the presence of BSA. The complexes may pass through Caco-2 monolayer via passive diffusion mechanism and our results suggest that lipophilicity and interaction with BSA may influence the complexes permeation. In conclusion, we demonstrated that complexes have powerful pharmacological activity, with different results for each complex depending on the combination of their ligands.
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http://dx.doi.org/10.1007/s10534-017-0008-zDOI Listing
June 2017

Synthesis and SAR evaluation of novel thioridazine derivatives active against drug-resistant tuberculosis.

Eur J Med Chem 2017 Feb 23;127:147-158. Epub 2016 Dec 23.

Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London, SE1 9NH, United Kingdom. Electronic address:

The neuroleptic drug thioridazine has been recently repositioned as possible anti-tubercular drug. Thioridazine showed anti-tubercular activity against drug resistant mycobacteria but it is endowed with adverse side effects. A small library of thioridazine derivatives has been designed through the replacement of the piperidine and phenothiazine moieties, with the aim to improve the anti-tubercular activity and to reduce the cytotoxic effects. Among the resulting compounds, the indole derivative 12e showed an antimycobacterial activity significantly better than thioridazine and a cytotoxicity 15-fold lower.
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http://dx.doi.org/10.1016/j.ejmech.2016.12.042DOI Listing
February 2017
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