Letícia Veras Costa Lotufo

Cytotoxic guanidine alkaloids from Pterogyne nitens.

As part of a bioprospecting program aimed at the discovery of potential anticancer drugs, two new guanidine-type alkaloids, nitensidines D and E (1, 2), and the known pterogynine (3), pterogynidine (4), and galegine (5), were isolated from the leaves of Pterogyne nitens. The structures of 1 and 2 were established on the basis of spectroscopic data interpretation. These compounds were tested against a small panel of human cancer cell lines. Compound 2 exhibited cytotoxicity for HL-60 (human myeloblastic leukemia) and SF-245 (human glioblastoma) cells.

Cytotoxicity of δ-tocotrienols from Kielmeyera coriacea against cancer cell lines.

In the search for new anti-cancer compounds, Brazilian Cerrado plant species have been investigated. The hexane root bark extract of Kielmeyera coriacea lead to a mixture of δ-tocotrienol (1) and its dimer (2). The structures of both compounds 1 and 2 were established based on detailed 1D and 2D NMR and EI-MS analyses. The cytotoxicity of the mixture was tested against four human tumor cell lines in the following cultures: MDA-MB-435 (melanoma), HCT-8 (colon), HL-60 (leukemia), and SF-295 (glioblastoma), and displayed IC(50) values ranging from 8.08 to 23.58μg/mL. Additional assays were performed in order to investigate the mechanism of action of the mixture (1+2) against the human leukemia cell line HL-60. The results suggested that the mixture suppressed leukemia growth and reduced cell survival, triggering both apoptosis and necrosis, depending on the concentration.

Evaluation of mutagenic effects of formocresol: detection of DNA-protein cross-links and micronucleus in mouse bone marrow.

OBJECTIVE The genotoxic potential of formocresol was assessed by comet assay on human peripheral blood lymphocytes and in vivo micronucleus in mice. STUDY DESIGN Peripheral blood lymphocytes, obtained from healthy donors, were exposed directly with different dilutions of formocresol for 45 minutes at 37 degrees C. To verify the possibility of formocresol to induce DNA-protein cross-links, treated lymphocytes were incubated with proteinase K. Micronucleus test was performed on male Swiss mice treated with several dilutions of formocresol by single intraperitoneal injection. After treatment, bone marrow was sampled 24 and 48 hours after formocresol administration. RESULTS Formocresol did not produce detectable DNA damage as evaluated by comet assay. However, after proteinase K exposure, a dose-dependent increase of DNA migration was observed. Formocresol induced a significant increase in micronucleus frequencies at the highest dilution only at 24 hours after administration. CONCLUSION Formocresol induced DNA-protein cross-links and an increased frequency of micronucleus.

Discovery of Phthalimides as Immunomodulatory and Antitumor Drug Prototypes

Modulation of the immune system is an emerging concept in the control of tumor growth. While there are many mechanisms that underlie the role the immune system plays in tumor cells, minimizing metastasis by attenuating the expression of pro-angiogenic cytokines, or up-regulating the expression of endothelial factors that are crucial for the angiogenic process in metastasis and alternatively enhancing the antitumor immunity mediated by interferon-g and interleukin-2 are the most significant features identified to date. 3] In view of this, the discovery of small immunomodulating agents is a task that is currently receiving much attention. Among the anticancer and immunomodulatory drug candidates that have entered into clinical trials, the majority are analogues of thalidomide (Thl, 1), such as lenalidomide (Revlimid, CC-5013) and ACTIMID (CC-4047). Studies of structure–activity relationships (SARs) in the analogues and metabolites of Thl have shown that phthalimide is an essential pharmacophoric fragment. Following this line of research, phthalimide has commonly been employed in the design of potential anti-inflammatory, immunomodulatory, antiangiogenic, and antitumor drug candidates. Given this promising outlook, the strategy of molecular hybridization using phthalimide as a pharmacophoric fragment has figured prominently in recent research and has given rise to many successful outcomes. As an example, potent and selective histone deacetylase (HDAC) inhibitors have been designed by hybridizing two distinct structural domains: phthalimide and the hydroxamic acid subunit. This has led to the identification of various SARs and the discovery of a new potent hybrid lead compound, (E)-3-(1oxo-2-(1,2-diphenylethyl)isoindolin-6-yl)-N-hydroxyacrylamide, which has been described as having selective toxicity against tumor cells. On the other hand, the thiosemicarbazones have figured prominently in the vast number of structural subunits used to design anticancer agents. Some well-known mechanisms involving thiosemicarbazones involve the inhibition of ribonucleotide reductase, alteration of DNA structure, and the chelation of endogenous metals. An example of this versatility was recently reported by Gottesman and co-workers, who used the molecular hybridization of the b-isatin scaffold and thiosemicarbazones. It was clearly demonstrated that the insertion of a thiosemicarbazone subunit into optimal templates leads to an improvement in the anticancer properties of b-isatins, paving the way for the discovery of potent and selective anticancer compounds such as the lead compound 1-(5’-fluoroisatin)-4-(4’-methoxyphenyl)-3thiosemicarbazone (2 ; IC50 = 5.2 mm against multidrug-resistant cells that express P-glycoprotein). Because of this unique pharmacological profile, the attachment of thiosemicarbazones has been employed both in the design of ligands for further complexation with transition metals and during the processes of hit-to-lead or lead-todrug conversions. Bearing in mind the molecular pharmacophores outlined above and structural requirements, we describe herein the design, synthesis, and pharmacological evaluation of 11 new potential antitumor and immunomodulatory agents. To establish an appropriate set of SARs, we first prepared phthalimides containing the thiosemicarbazide 2 b or thiosemicarbazone 4 subunits. An attempt was then made to synthesize two bioisosteres of 2 b : the semicarbazide 2 a and aminoguanidine 2 c derivatives, in addition to the analogues of 2 b containing N-methyl or N-phenyl substituents. Subsequently, a short series of phthalimides bearing the thiazolin-4-one ring (compounds 3 a–d) was also investigated, for reasons of the bioisosteric relationship present between thiazolin-4-ones and thiosemicarbazones and the significant number of thiazolin-4-ones that are active against multidrug-resistant cancer cells, as in the case of the lead compound 3. Our design incorporated the molecular hybridization approach suggested by the structural features of prototypes 1–3 in addition to molecular bioisosterism (Figure 1). The compound series 2 a–f was first prepared by using microwave irradiation, in view of a recent report in which the reaction of N-(hydroxymethyl)phthalimide with arylamines using microwave heating under normal conditions rapidly furnishes [a] S. M. T. Cavalcanti, L. C. D. CoÞlho, Dr. M. Z. Hernandes, Prof. A. C. L. Leite, Dr. V. M. O. Souza Department of Pharmaceutical Sciences Centre for Health Science, Federal University of Pernambuco (UFPE) 50740-520 Recife, PE (Brazil) Fax: (+ 55) 081-2126-8510 E-mail : ana.leite@pq.cnpq.br [b] Dr. C. Pessoa, P. M. P. Ferreira, Dr. L. V. C. Lotufo, Prof. M. O. de Moraes Department of Physiology and Pharmacology Centre for Health Science, Federal University of Cear 60430-270 Fortaleza, CE (Brazil) [c] Dr. C. A. De Simone Department of Physics and Informatics Institute of Physics, University of S1⁄4o Paulo 13560-970 S1⁄4o Carlos, SP (Brazil) [d] Dr. V. M. A. Costa, Dr. V. M. O. Souza Laboratory of Immunopathology Keiso-Asami (LIKA) Department of Parasitology, UFPE 50740-520 Recife, PE (Brazil) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cmdc.200900525.

Constituintes químicos de Parmotrema lichexanthonicum Eliasaro & Adler: isolamento, modificações estruturais e avaliação das atividades antibiótica e citotóxica

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.

Synthesis and Antitumoral Evaluation of 7-chloro-4-quinolinylhydrazones Derivatives

A series of twenty-one 7-chloro-4-quinolinylhydrazones derivatives (3a-u) have been synthesized and evaluated for their cytotoxic potential against three cancer cell lines using MTT assay. The compounds 3b, 3e, 3f, 3h, 3j, 3n, 3r and 3u displayed more than 90% of growth inhibition (GI) and they were selected for in vitro anticancer activities evaluation against four human cancer cell lines. These results were expressed as the concentrations that induce 50% inhibition of cell growth (IC50) in μg/mL. Considering that, compounds 3b, 3e, 3h, 3n, 3r and 3u exhibited good cytotoxic activity against at least three cancer cell lines (0.7967-4.200 μg/mL). In general, we observed that the presence of electron-withdrawing groups in the benzene ring is important for the anticancer activity in this series, such as fluorine (3h), chlorine (3b) amd bromine (3e) groups in meta position and nitro group (3r) in para position. These derivatives could be considered interesting start points to develop a new anticancer drug and confirm the potential of chloroquine derivatives as lead compounds in anticancer drug discovery.

1-(7-Chloroquinolin-4-yl)-2-[(1H-pyrrol-2-yl)methylene]hydrazine: a potent compound against cancer

Heteroaromatic derivatives (3a–f) have been synthesized and evaluated for their activity against four cancer cell lines. Among the studied compounds, 1-(7-Chloroquinolin-4-yl)-2-[(1H-pyrrol-2-yl)methylene]hydrazine (3e) exhibited an excellent cytotoxic activity against the referred lines, and especially on melanoma cells (MDAMB-435). In this case, compound 3e is four times more active than the standard substance Doxorubicin. Together with other results from our group, 7-chloro-4-quinolinylhydrazones derived from chloroquine could be considered a relevant finding toward the rational design of new leads for antitumor compounds.