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A new trachylobane diterpene ent-trachyloban-18,19-diol (1) was isolated from root bark of Croton floribundus, along with known diterpenes ent-trachyloban-19-oic acid (2), 15b-hydroxy-ent-trachyloban-19-oic acid (3), ent-trachyloban-19-ol (4), ent-kaur-16-en-19-oic acid (5), ent-kaur-16-ene-6a,19-diol (6) and ent-16a-hydroxykaur-11-en-19-oic acid (7). ent-trachyloban-18,19-diol (1) was submitted to derivatization reactions affording four new compounds (8-11). Cytotoxic activity of diterpenes 1, 3, 4, 7-11 against three human cancer cell lines was evaluated. No compounds showed cytotoxic potential with IC50 values greater than 25 mg/mL. Compound 6 was evaluated against five human cancer cell lines, showing moderate effect against three cancer cell lines, MDA-MB-435, HCT-8 and HCT-116, with IC50 values of 14.32, 13.47 and 12.1 mg/mL, respectively.

The phytochemical investigation of the ethanol extract from the aerial parts of Blainvillea rhomboidea (Asteraceae) resulted in the isolation and characterization of 8β-tigloyloxy-grazielia acid, together with the flavonoids derrone, acacetin, luteolin and luteolin 7-methyl ether, and p-(1-methyl-ethan-1-ol)-phenol. The structures of all compounds were determined by spectroscopic methods (¹H and 13C NMR and HREIMS) and comparison with published spectral data. The flavonoids luteolin and 7-O-metyl-luteolin, isolated from the active dichloromethane fraction, showed moderate cytotoxic activity.

In the present study ten 2,3-diyne-1,4-naphthoquinone derivatives (3a-j) were synthesized by Sonogashira coupling reaction between the 2,3-dibromo-1,4-naphthoquinone (2) and several functionalized terminal alkynes using a catalytic complex of palladium (II) and CuI. Alkynes are among phenylacetylene, 1-ethyl-4-methoxybenzene, 2-methyl-3-butyn-2-ol, 1-ethynyl-1-cyclohexanol, 4-pentyn-2-ol, 4-pentyn-1-ol, 1-pentyne, 1-hexyne, 1-decyne and 1-octyne. The yields of products obtained ranged 15 to 55%. The enediynes having hydroxyl groups, in their structures such as 2,3-di(3-hydroxy-3-methylbut-1-in-1-yl)-, 2,3-di[(1-hydroxycyclohexyl)ethynyl]- and 2,3-di(5-hydroxypent-1-yl)-1,4-naphthoquinone were subjected to acetylation reaction using acetic anhydride and montmorillonite clay K-10 under sonication, thereby obtaining three new enediyne derivatives (3c’, d’ and f’) with yields ranging from 56 to 71%. The compounds were all characterized by 1H NMR and 13C NMR spectra, IR and MS-LC. These compounds containing the 1,4-naphthoquinone nucleus and acetylenic substituents in the quinonoid ring form a enediyne system (Z-3-ene-1,5-diyne) highly reactive, possibly subject to Bergman cycloaromatization, with potential antitumor activity. The enediynes underwent evaluation of the cytotoxic potential against three tumor cell lines, OVCAR-8 (ovarian adenocarcinoma - human), PC-3M (metastatic prostate cancer - human), NCI-H358M (bronchoalveolar lung carcinoma - human), presenting, in general, satisfactory results for inhibition of cell growth. The compound 2,3-di(3-hydroxy-3-methylbut-1-in-yl)-1,4-naphthoquinone (3c) where said among the substances analyzed by presenting a lower IC50 (˂ 2 µg/mL) for three cell lines tested, which is characterized as a potent cytotoxic agent.

A tea made with the leaves or stem bark of Bauhinia pulchella Benth (Fabaceae) is used in the treatment of diabetes. Ethanol (EEF) and aqueous (EAF) extracts were obtained from the leaves and the antioxidant and citotoxic activities were tested, as well as quantify the content of flavonoids and phenolic compounds (TPC). EEF and EAF showed similar profiles by HPLC, with the presence of three compounds. Column chromatography reverse phase (C18) and Sephadex LH-20, followed by semi preparative HPLC-C18 of EAF resulted in three flavonoids. Their structures were identified by 1H and 13C NMR as myricitrin (1), quercitrin (2) and afzelin (3). In assay of determination of reactive substances to thiobarbituric acid (TBARS), with DPPH, ABTS and nitric oxide (NO•) free radicals, EAF showed antioxidant potential higher than the EEF. This is the first report of the occurrence of the flavonoids 1-3, in the species B. pulchella. EEF and EAF were inactive in the cytotoxicity assays. In short, the polar extracts from the leaves of B. pulchella proved to be promising sources of biomolecules phenolic, with antioxidant potential, which may, in the future, be used as chemical markers for species and validation of therapeutic use.

The genus Chamaecrista comprises more than 330 species, with only a few studies on their chemical composition and biologic activities. In this study, the phytochemical profile of leaf, stems, and fruits extracts of the C. duckeana were examined by UPLC ESI HRMS analysis to determine possibly bioactive constituents. The antioxidant activity was carried out through in vitro assay, by the sequestration of the free radical DPPH. To evaluate the cytotoxic activity of the extracts, an MTT assay was used and the IC50 was determined against HL60 and RAJI cell lines. The metabolic profiles of the botanical parts are dominated by flavonoid class, highlighting isoflavonoids such as daidzin and ononin. All these compounds are reported for the first time in C. duckeana. The extracts presented antioxidant potential, and the activity of the stems extract was higher than the standard butylated hydroxytoluene. In the cytotoxic assay, only HL60 line (leukemia) had growth inhibition over 80%. The stems presented more expressive cytotoxicity with IC50 of 137.3 (104.6-180.1) and 106.8 (96.52-118.3) μmol. L-1 for HL60 and RAJI, respectively. In conclusion, the present work provides an in-depth knowledge about the chemical profile of C. duckeana, a species rich in bioactive secondary metabolites with cytotoxic activity.

Docetaxel (DTX) is a non-selective antineoplastic agent with low solubility and a series of side effects. The technology of pH-sensitive and anti-epidermal growth factor receptor (anti-EGFR) immunoliposomes aims to increase the selective delivery of the drug in the acidic tumor environment to cells with EFGR overexpression. Thus, the study aimed to develop pH-sensitive liposomes based on DOPE (dioleoylphosphatidylethanolamine) and CHEMS (cholesteryl hemisuccinate), using a Box–Behnken factorial design. Furthermore, we aimed to conjugate the monoclonal antibody cetuximab onto liposomal surface, as well as to thoroughly characterize the nanosystems and evaluate them on prostate cancer cells. The liposomes prepared by hydration of the lipid film and optimized by the Box–Behnken factorial design showed a particle size of 107.2 ± 2.9 nm, a PDI of 0.213 ± 0.005, zeta potential of −21.9 ± 1.8 mV and an encapsulation efficiency of 88.65 ± 20.3%. Together, FTIR, DSC and DRX characterization demonstrated that the drug was properly encapsulated, with reduced drug crystallinity. Drug release was higher in acidic pH. The liposome conjugation with the anti-EGFR antibody cetuximab preserved the physicochemical characteristics and was successful. The liposome containing DTX reached an IC50 at a concentration of 65.74 nM in the PC3 cell line and 28.28 nM in the DU145 cell line. Immunoliposome, in turn, for PC3 cells reached an IC50 of 152.1 nM, and for the DU145 cell line, 12.60 nM, a considerable enhancement of cytotoxicity for the EGFR-positive cell line. Finally, the immunoliposome internalization was faster and greater than that of liposome in the DU145 cell line, with a higher EGFR overexpression. Thus, based on these results, it was possible to obtain a formulation with adequate characteristics of nanometric size, a high encapsulation of DTX and liposomes and particularly immunoliposomes containing DTX, which caused, as expected, a reduction in the viability of prostate cells, with high cellular internalization in EGFR overexpressing cells.

Objective: To evaluate genotoxicity of zinc oxide, P. A. calcium hydroxide, mineral trioxide aggregate and an iodoform paste using comet assay on human lymphocytes. Material and Methods: Two positive controls were used: methyl-methanesulfonate for the P.A. calcium hydroxide and mineral trioxide aggregate; and doxorubicin for the iodoform paste and zinc oxide. There were also two negative controls: distilled water for the P.A. calcium hydroxide and mineral trioxide aggregate; and DMSO for the iodoform paste and zinc oxide. Comets were identified using fluorescence microscopy and 100 of them were counted on each of the three slides analyzed per drug test. A damage index was established, taking into consideration the score pattern that had previously been determined from the size and intensity of the comet tail. Analysis of variance, followed by Tukey’s test, was used to compare the means of the DNA damage indices. Results: The DNA damage index observed for mineral trioxide aggregate (7.08 to 8.58) and P.A. calcium hydroxide (6.50 to 8.33), which were similar to negative control index. On the other hand, damage index for zinc oxide (104.7 to 218.50) and iodoform paste (115.7 to 210.7) were similar to positive control index. Conclusion: Iodoform paste and zinc oxide showed genotoxicity at all concentrations used.

The aim of this study was to evaluate the chemical composition, antioxidant and antibacterial activities and cytotoxicity of fractions from Selaginella convoluta, obtained by liquid–liquid extraction using hexane (Sc-Hex), chloroform (Sc-CHCl3) and ethyl acetate (Sc-AcOEt). The phenolic and flavonoid contents were measured by the Folin-Ciocalteu and aluminium chloride methods, respectively. Antioxidant activities were evaluated by using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging and β-carotene-linoleic acid bleaching test. The antibacterial effect was evaluated by the method of microdilution and the cytotoxicity analysis in HCT-116 (colon), OVCAR-8 (ovarian) and SF-295 (brain) cells were carried out for MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) test. The fractions were positive for the presence of anthracene derivatives, flavonoids, lignans, naphthoquinones, steroids and triterpenoids. The Sc-Hex and Sc-AcOEt showed good antioxidant activities. The fractions of S. convoluta demonstrated antibacterial activity and showed weak cytotoxicity. These activities were correlated with presence of phenolic compounds in active fractions.

Specimens of Leonotis nepetiflolia were obtained from cultivated and wild environments to verify their influences in chemical composition. Phytochemical analyses were conducted for the ethyl acetate phase obtained by partitioning the crude ethanol extract from the cultivated leaves of L. nepetifolia. In doing so, flavonoid 3',4',5-trimethoxy-6,7-dihidroxyflavone (cirsiliol), a chemotaxonomic marker of the family Lamiaceae, was isolated. The results reveal that all phases and extracts tested exhibited weak to moderate antimicrobial activity against the strains of bacteria tested. The evaluation of in vitrocytotoxic and antitumor activity showed that the ethyl acetate phases obtained from both wild and cultivated leaves exhibit high potential cytotoxic and antitumor (> 78.0% of inhibition) activity. The major component of these phases was identified by high-performance liquid chromatography-diode array detector and nuclear magnetic resonance analyses using both 1D and 2D methods. The results further indicate that the flavonoid cirsiliol is the agent responsible for the activity observed in these phases.

Compounds isolated from essential oils play an important role in the prevention and treatment of cancer. Monoterpenes are natural products, and the principal constituents of many essential oils. The aim of this study was to investigate the cytotoxic potential of p-menthane derivatives. Additionally, analogues of perillyl alcohol, a monoterpene with known anticancer activity, were evaluated to identify the molecular characteristics which contribute to their cytotoxicity, which was tested against OVCAR-8, HCT-116, and SF-295 human tumor cell lines, using the MTT assay. The results of this study showed that (−)-perillaldehyde 8,9-epoxide exhibited the highest percentage inhibition of cell proliferation (GI = 96.32%–99.89%). Perillyl alcohol exhibited high cytotoxic activity (90.92%–95.82%), while (+)-limonene 1,2-epoxide (GI = 58.48%–93.10%), (−)-perillaldehyde (GI = 59.28%–83.03%), and (−)-8-hydroxycarvotanacetone (GI = 61.59%–94.01%) showed intermediate activity. All of the compounds tested were less cytotoxic than perillyl alcohol, except (−)-perillaldehyde 8,9-epoxide (IC50 = 1.75–1.03 µL/mg). In general, replacement of C-C double bonds by epoxide groups in addition to the aldehyde group increases cytotoxicity. Furthermore, stereochemistry seems to play an important role in cytotoxicity. We have demonstrated the cytotoxic influence of chemical substituents on the p-menthane structure, and analogues of perillyl alcohol.

A new flavonoid, catechin-3-O-(3"-O-trans-cinnamoyl)-α-rhamnopyranoside, along with known compounds, catechin-3-O-α-rhamnopyranoside, 3-oxo-urs-12-en-28-oic acid, 2,4,6-trimethoxybenzoic acid, 2-butyl-D-fructofuranoside and 1-butyl-D-fructofuranoside, has been isolated from the stem bark of V. thyrsoidea. These compounds were assayed for inhibition of protease activity (cathepsins B and K) and against cancer cell lines. Catechin-3-O-(3"-O-trans-cinnamoyl)-α-rhamnopyranoside showed moderate inhibitory activity (IC50 = 62.02 µM) against cathepsin B while 2-butyl-D-fructofuranoside was the most potent against a strain of CNS (SF-295) and human leukemia (HL-60) with IC50 = 36.80 µM and IC50 = 25.37 µM, respectively.

Bauhinia purpurea (Fabaceae). Plants of the Bauhinia species (Fabaceae) are used in the treatment of several infections and diseases, especially diabetes. In this paper, with an aim to contribute to the knowledge of the chemistry and therapeutic potential of the Amazonian species of the genus Bauhinia, flavonoid profiles in the leaves and branches of Bauhinia purpurea collected in Manaus and São Gabriel da Cachoeira/AM were analyzed by HPLC-DAD and ESIMS. Differences in the flavonoid profiles were detected along with the presence of rutin and isoquercitrin in the leaves collected in Manaus. All samples showed antioxidant activity, however, no cytotoxic activity against cell lines MDA-MB435 (breast), HCT-8 (colon), and SF-295 (glioblastoma) could be detected.

Annona vepretorum Mart. é uma espécie endêmica do bioma Caatinga, conhecida no Nordeste do Brasil como "araticum". Neste trabalho, o conteúdo de fenóis totais foi determinado pelo método de Folin-Ciocalteu. O teor de flavonoides totais também foi medido. A atividade antioxidante dos extratos foi analisada pelos métodos do sequestro do radical DPPH e inibição da auto-oxidação do β-caroteno, e comparada com o ácido ascórbico, BHA e BHT, utilizados como compostos de referência. A análise de citotoxidade foi realizada frente a linhagens de células HCT-116, OVCAR-8 e SF-295. O efeito antibacteriano foi avaliado pelo método de microdiluição. O conteúdo de fenóis totais do extrato etanólico (Av-EtOH) foi de 76,60 ± 5,57 mg de equivalente de ácido gálico/g. O conteúdo de flavonoides foi de 194,50 ± 11,72 mg de equivalente de catequina/g para o extrato hexânico. O extrato EtOH exibiu boa atividade antioxidante (IC50 = 98,87 ± 11,24 mg/mL) no método do DPPH. Os extratos mostraram atividade citotóxica e antibacteriana contra a maior parte das células e microrganismos testados. Pesquisas adicionais serão realizadas para o isolamento e a identificação dos principais constituintes fenólicos dos extratos.

From the lichen Parmotrema lichexantonicum were isolated the depsidone salazinic acid, the xanthone lichexanthone, and the depside atranorin. The two major compounds, salazinic acid and lichexanthone, were selected for structure modifications. Salazinic acid afforded O-alkyl salazinic acids, some of them potentially cytotoxic against tumor cell lines (HCT-8, SF-295 and MDA/ MB - 435). From lichexanthone were obtained norlichexanthone, 3-O-methylnorlichexanthone, 3-O-methyl-6-O-prenylnorlichexanthone, 3,6-di-O-prenyl-norlichexanthone, 3,6-bis[(3,3-dimethyloxyran-2-il)methoxy]-1-hydroxy-8-methyl-9H-xanten-9-one and 3,6-bis[3-(dimethylamine)propoxy]-1-hydroxy-8-methyl-9H-xanten-9-one. The last compound was the most active against S. aureus.

PURPOSE: To investigate the effects of bisphosphosnate alendronate (ALD) and metotrexate (MTX) on an experimental model of Walker 256 carcinosarcoma developed in the oral cavity of rats. METHODS Walker 256 carcinosarcoma cell suspension (0,1 mL) containing 10(6) cell/mL was implanted in the alveoli of the first and second molars. The animals were divided and treated with saline, MTX, ALD, and MTX plus ALD. Later, the animals were sacrificed, the tumors were measured and the mandibles were removed for radiographic and histological analysis. RESULTS: In the control group, the radiographic images demonstrated radioluscency with poorly defined borders, and the microscopic examination revealed tumor infiltration into the peripheral and central regions of the bone. Areas of necrosis were commonly seen. In the treated groups with ALD, associated or not with MTX, the radiographic analysis revealed circumscribed tumor-induced osteolysis and various degrees of radiotransparence; while, histologically, preserved bone trabeculae with osteoid formation was observed among malignant cells. CONCLUSION: The bisphosphonate alendronate exherted an osteoprotective effect and induced bone neoformation on the Walker 256 carcinosarcoma inoculated in rat mandibles. The combination of metotrexate with bisphosphonate alendronate is more successful than treatment with the agents alone in controlling the growth of neoplastic cells and in stimulating reactive new bone. Therefore, this may be an alternative treatment to malignant lesions of maxillaries with osteolysis.OBJETIVO: Avaliar o efeito do bisfosfonato alendronato (ALD) e do metotrexato (MTX) em modelo do carcinossarcoma 256 de Walker na mandíbula de ratos. MÉTODOS: Uma suspensão de células tumorais do carcinossarcoma 256 de Walker (0,1mL), na concentração de 10(6) células/mL, foi implantada nos alvéolos de ratos previamente abertos por exodontia. Os animais foram divididos em grupos e tratados com salina, MTX, ALD e associação do MTX com ALD. Após o sacrifício, os tumores foram medidos e as mandíbulas removidas para exames radiográfico e histológico. RESULTADOS: No exame radiográfico do grupo controle foi verificada área lítica, sem evidência de reparo na região dos alvéolos, e no microscópico, infiltração óssea periférica e central, de pequenas células tumorais com diversas áreas de necrose. Nos grupos tratados com ALD, associado ou não ao MTX, a análise radiográfica mostrou redução da osteólise tumor-induzida com graus variados de radiotransparência na estrutura óssea; enquanto que, na análise histopatológica, trechos de tecido ósseo preservado, com formação de osteóide em meio a células tumorais foram observados. CONCLUSÃO: O bisfosfonato alendronato exerceu um efeito osteoprotetor e induziu neoformação óssea em mandíbulas de ratos implantadas com células de carcinossarcoma de Walker 256. A combinação do metotrexato com o bisfosfonato alendronato foi mais eficaz que o tratamento com os agentes isoladamente no controle do crescimento das células neoplásicas e na estimulação da formação óssea. Sendo assim, essa associação constitui-se uma alternativa de tratamento das neoplasias malignas dos maxilares com invasão e comprometimento ósseo.

art of our research program concentrates on the discovery of new bioactivecompounds prepared either by total synthesis or molecular transformation of compoundswith bioactivity profiles. In this work we have focused our interest on chemicaltransformations of the Diels-Alder adduct tricyclo[6.2.1.02,7]undeca-4,9-dien-3,6-dione inorder to obtain cage-like compounds and derivatives, followed by an evaluation of theirbiological activity.

OBJETIVO: Estabelecer um modelo experimental de desenvolvimento tumoral na cavidade oral de ratos, permitindo, assim, o estudo da osteólise induzida pelo tumor nos ossos do complexo maxilomandibular como também nas estruturas dentais, através da caracterização histomorfológica da reabsorção óssea e dentária. MÉTODOS: Uma suspensão de células tumorais (0,1mL) do Carcinossarcoma de Walker 256, na concentração de 10(6) células/mL foi implantado na cavidade alveolar de ratos previamente aberta por exodontia. Os animais foram observados durante 12 (doze) dias consecutivos para determinação da curva de peso corpóreo, sendo posteriormente sacrificados e as mandíbulas removidas para exames radiográfico e histológico. RESULTADOS: No exame radiográfico foi verificada área lítica, sem evidência de reparo, na região dos alvéolos. No exame microscópico foi identificada infiltração óssea, periférica e central, de pequenas células hipercromáticas e pleomórficas, com leve infiltrado inflamatório mononuclear associado e áreas de necrose. O índice de pega foi de 100%. CONCLUSÃO: O modelo animal de invasão óssea, do tumor de Walker na cavidade oral, possibilita a avaliação in vivo de drogas antitumorais e esquemas terapêuticos no tratamento do câncer bucal.PURPOSE: To estabilish an experimental model of tumor development in the oral cavity of rats, that would enable to study the tumor-induced autolysis in the maxillomandibular bone complex as well as of the dental structures, through histomorphological characterization of bone and dental resorption. METHODS: Walker 256 carcinossarcoma cell suspension (0,1 mL containing 10(6) cell/mL) was implanted in the alveoli of first and second molars. The animals were observed during twelve consecutive days and the body weigth were determined. Later, the animals were sacrificed and their mandibles removed to radiographic and hystologic analysis. RESULTS: The radiographic image demonstrated radioluscencies with poorly defined borders. Microscopic examination revealed the tumor infiltration into the peripheral and central regions of bone.The tumor was composed predominantly of small cells with hyperchromatic nuclei which were occasionally pleomorphic. Areas of necrosis were commonly seen and chronic inflammatory cell infiltration was variable. The index of tumor incidence was 100%. CONCLUSION: The animal model of bone invasion of Walker 256 tumor permits the evaluation in vivo of new chemotherapic drugs in the treatment of oral cancer.

Disruption of the epigenetic program of gene expression is a hallmark of cancer that initiates and propagates tumorigenesis. Altered DNA methylation, histone modifications and ncRNAs expression are a feature of cancer cells. The dynamic epigenetic changes during oncogenic transformation are related to tumor heterogeneity, unlimited self-renewal and multi-lineage differentiation. This stem cell-like state or the aberrant reprogramming of cancer stem cells is the major challenge in treatment and drug resistance. Given the reversible nature of epigenetic modifications, the ability to restore the cancer epigenome through the inhibition of the epigenetic modifiers is a promising therapy for cancer treatment, either as a monotherapy or in combination with other anticancer therapies, including immunotherapies. Herein, we highlighted the main epigenetic alterations, their potential as a biomarker for early diagnosis and the epigenetic therapies approved for cancer treatment.

Cirsiliol is a flavone found in many Lamiaceae species with high cytotoxic activity against tumor cell lines. Although cirsiliol is being used in cancer therapy, its pharmacological potential is limited by its low solubility and bioavailability. In this paper, a cirsiliol-β-cyclodextrin inclusion complex was developed in order to increase its solubility and bioavailability. The formation of inclusion complex was proved by scanning electron microscopy, Fourier-transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR) and solubility increment was verified through the ultraviolet-visible (UV-Vis) method. The cytotoxic effect against tumor cells (PC3, HCT-116 and HL-60 human cell lines, and S-180 murine cell line) and the antitumor activity in mice bearing sarcoma S-180 were also investigated. The inclusion complex was obtained with 71.45% of total recovery and solubility 2.1 times higher compared to the compound in its free form. This increment in solubility was responsible by a tumor growth inhibition potentiation (1.5 times greater compared to compound in its free form). In addition, this study showed that cirsiliol and its inclusion complex in β-cyclodextrin have strong antitumor potential at low doses without promoting side effects commonly observed for conventional drugs as doxorubicin.