Publications by authors named "Larissa M Bomfim"

8 Publications

  • Page 1 of 1

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

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

Ruthenium Complexes Containing Heterocyclic Thioamidates Trigger Caspase-Mediated Apoptosis Through MAPK Signaling in Human Hepatocellular Carcinoma Cells.

Front Oncol 2019 9;9:562. Epub 2019 Jul 9.

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

Herein, ruthenium complexes containing heterocyclic thioamidates [Ru(mmi)(bipy)(dppb)]PF (), [Ru(tzdt)(bipy)(dppb)]PF (), [Ru(dmp)(bipy)(dppb)]PF () and [Ru(mpca)(bipy)(dppb)]PF () were investigated for their cellular and molecular effects in cancer cell lines. Complexes and were the most potent of the four compounds against a panel of different cancer cell lines in monolayer cultures and showed potent cytotoxicity in a 3D model of multicellular spheroids that formed from human hepatocellular carcinoma HepG2 cells. In addition, both complexes were able to bind to DNA in a calf thymus DNA model. Compared to the controls, a reduction in cell proliferation, phosphatidylserine externalization, internucleosomal DNA fragmentation, and the loss of the mitochondrial transmembrane potential were observed in HepG2 cells that were treated with these complexes. Additionally, coincubation with a pan-caspase inhibitor (Z-VAD(OMe)-FMK) reduced the levels of apoptosis that were induced by these compounds compared to those in the negative controls, indicating that cell death through apoptosis occurred via a caspase-dependent pathway. Moreover, these complexes also induced the phosphorylation of ERK1/2, and coincubation with an MEK inhibitor (U0126), which is known to inhibit the activation of ERK1/2, but not JNK/SAPK and p38 MAPK inhibitors, reduced the complexes-induced apoptosis compared to that in the negative controls, indicating that the induction of apoptotic cell death occurred through ERK1/2 signaling in HepG2 cells. On the other hand, no increase in oxidative stress was observed in HepG2 cells treated with the complexes, and the complexes-induced apoptosis was not reduced with coincubation with the antioxidant N-acetylcysteine or a p53 inhibitor compared to that in the negative controls, indicating that apoptosis occurred via oxidative stress- and p53-independent pathways. Finally, these complexes also reduced the growth of HepG2 cells that were engrafted in C.B-17 SCID mice compared to that in the negative controls. These results indicated that these complexes are novel anticancer drug candidates for liver cancer treatment.
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http://dx.doi.org/10.3389/fonc.2019.00562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629894PMC
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

Cytotoxic potential of selected medicinal plants in northeast Brazil.

BMC Complement Altern Med 2016 Jul 8;16:199. Epub 2016 Jul 8.

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

Background: Great biodiversity is a highlight of Brazilian flora. In contrast, the therapeutic potentialities of most species used in folk medicine remain unknown. Several of these species are commonly used to treat cancer. In this study, we investigated the cytotoxic activity of 18 plants from 16 families that are found in the northeast region of Brazil.

Methods: The following species were studied: Byrsonima sericea DC. (Malpighiaceae), Cupania impressinervia Acev. Rodr. var. (revoluta) Radlk (Sapindaceae), Duranta repens Linn. (Verbenaceae), Helicostylis tomentosa (Poepp. & Endl) Rusby (Moraceae), Himatanthus bracteatus (A.DC.) Woodson (Apocynaceae), Ipomoea purga (Wender.) Hayne (Convolvulaceae), Ixora coccinea Linn. (Rubiaceae), Mabea piriri Aubl. (Euphorbiaceae), Miconia minutiflora (Melastomataceae), Momordica charantia L. (Cucurbitaceae), Ocotea glomerata (Nees) Mez (Lauraceae), Ocotea longifolia Kunth (Oreodaphne opifera Mart. Nees) (Lauraceae), Pavonia fruticosa (Mill.) Fawc. & Rendle (Malvaceae), Psychotria capitata Ruiz & Pav. (Rubiaceae), Schefflera morototoni (Aubl.) Maguire, Steyerm. & Frodin (Araliaceae), Solanum paludosum Moric. (Solanaceae), Xylopia frutescens Aubl. (Annonaceae) and Zanthoxylum rhoifolium Lam. (Rutaceae). Their dried leaves, stems, flowers or fruits were submitted to different solvent extractions, resulting in 55 extracts. After incubating for 72 h, the cytotoxicity of each extract was tested against tumor cell lines using the alamar blue assay.

Results: The B. sericea, D. repens, H. bracteatus, I. purga, I. coccinea, M. piriri, O. longifolia and P. capitata extracts demonstrated the most potent cytotoxic activity. The chloroform soluble fractions of D. repens flowers and the hexane extract of I. coccinea flowers led to the isolation of quercetin and a mixture of α- and β-amyrin, respectively, and quercetin showed moderate cytotoxic activity.

Conclusion: The B. sericea, D. repens, H. bracteatus, I. purga, I. coccinea, M. piriri, O. longifolia and P. capitata plants were identified as having potent cytotoxic effects. Further investigations are required to determine the mechanisms of cytotoxicity exhibited and their in vivo activities. This work reinforces the need to understand the therapeutics potentialities of Brazilian medicinal plants.
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http://dx.doi.org/10.1186/s12906-016-1166-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4938922PMC
July 2016

Antitumour Activity of the Microencapsulation of Annona vepretorum Essential Oil.

Basic Clin Pharmacol Toxicol 2016 Mar 6;118(3):208-13. Epub 2015 Oct 6.

Gonçalo Moniz Research Center, Oswaldo Cruz Foundation (CPqGM-FIOCRUZ/BA), Salvador, Brazil.

Annona vepretorum Mart. (Annonaceae), popularly known as 'bruteira', has nutritional and medicinal uses. This study investigated the chemical composition and antitumour potential of the essential oil of A. vepretorum leaf alone and complexed with β-cyclodextrin in a microencapsulation. The essential oil was obtained by hydrodistillation using a Clevenger-type apparatus and analysed using GC-MS and GC-FID. In vitro cytotoxicity of the essential oil and some of its major constituents in tumour cell lines from different histotypes was evaluated using the alamar blue assay. Furthermore, the in vivo efficacy of essential oil was demonstrated in mice inoculated with B16-F10 mouse melanoma. The essential oil included bicyclogermacrene (35.71%), spathulenol (18.89%), (E)-β-ocimene (12.46%), α-phellandrene (8.08%), o-cymene (6.24%), germacrene D (3.27%) and α-pinene (2.18%) as major constituents. The essential oil and spathulenol exhibited promising cytotoxicity. In vivo tumour growth was inhibited by the treatment with the essential oil (inhibition of 34.46%). Importantly, microencapsulation of the essential oil increased in vivo tumour growth inhibition (inhibition of 62.66%).
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http://dx.doi.org/10.1111/bcpt.12488DOI Listing
March 2016

Antitumor Properties of the Essential Oil From the Leaves of Duguetia gardneriana.

Planta Med 2015 Jul 30;81(10):798-803. Epub 2015 Jun 30.

Gonçalo Moniz Research Center, Oswaldo Cruz Foundation (Fiocruz), Salvador, Bahia, Brazil.

Duguetia gardneriana, popularly known in the Brazilian northeast as "jaquinha", is a species belonging to the family Annonaceae. The aim of this work was to assess the chemical composition and antitumor properties of the essential oil from the leaves of D. gardneriana in experimental models. The chemical composition of the essential oil was analyzed via gas chromatography-flame ionization detector and gas chromatography-mass spectrometry. In vitro cytotoxic activity was determined in cultured tumor cells, and in vivo antitumor activity was assessed in B16-F10-bearing mice. The identified compounds were β-bisabolene (80.99%), elemicin (8.04%), germacrene D (4.15%), and cyperene (2.82%). The essential oil exhibited a cytotoxic effect, with IC50 values of 16.89, 19.16, 13.08, and 19.33 µg/mL being obtained for B16-F10, HepG2, HL-60, and K562 cell lines, respectively. On the other hand, β-bisabolene was inactive in all of the tested tumor cell lines (showing IC50 values greater than 25 µg/mL). The in vivo analysis revealed tumor growth inhibition rates of 5.37-37.52% at doses of 40 and 80 mg/kg/day, respectively. Herein, the essential oil from the leaves of D. gardneriana presented β-bisabolene as the major constituent and showed cytotoxic and antitumor potential.
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http://dx.doi.org/10.1055/s-0035-1546130DOI Listing
July 2015

ent-Kaurane diterpenes from the stem bark of Annona vepretorum (Annonaceae) and cytotoxic evaluation.

Bioorg Med Chem Lett 2014 Aug 11;24(15):3315-20. Epub 2014 Jun 11.

Gonçalo Moniz Research Center, Oswaldo Cruz Foundation (Fiocruz), Rua Waldemar Falcão, 121, Candeal, 40296-710 Salvador, Bahia, Brazil. Electronic address:

This work describes a novel ent-kaurane diterpene, ent-3β-hydroxy-kaur-16-en-19-al along with five known ent-kaurane diterpenes, ent-3β,19-dihydroxy-kaur-16-eno, ent-3β-hydroxy-kaur-16-eno, ent-3β-acetoxy-kaur-16-eno, ent-3β-hydroxy-kaurenoic acid and kaurenoic acid, as well as caryophyllene oxide, humulene epoxide II, β-sitosterol, stigmasterol and campesterol from the stem bark of Annona vepretorum Mart. (Annonaceae). Cytotoxic activities towards tumor B16-F10, HepG2, K562 and HL60 and non-tumor PBMC cell lines were evaluated for ent-kaurane diterpenes. Among them, ent-3β-hydroxy-kaur-16-en-19-al was the most active compound with higher cytotoxic effect over K562 cell line (IC50 of 2.49 μg/mL) and lower over B16-F10 cell line (IC50 of 21.02 μg/mL).
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http://dx.doi.org/10.1016/j.bmcl.2014.06.005DOI Listing
August 2014
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