Natural products from marine invertebrates: potential chemotherapic anti-proliferative, antibiotic and against tropical diseases agents

• Grant number: 01/03095-5
• Support Opportunities: Research Projects - Thematic Grants
• Start date: March 01, 2002
• End date: August 31, 2006
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Roberto Gomes de Souza Berlinck
• Grantee: Roberto Gomes de Souza Berlinck
• Host Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil

Abstract

Brazil is blessed with a great biodiversity, that constitutes one of the most important sources of biologically active compounds, even if it has been largely underexplored. Such as the Amazon and Atlantic rainforests, the Brazilian marine fauna remains practically unexplored towards the search of new biologically active natural products. Considering that marine organisms have shown to be one of the most promising sources of new bioactive compounds for the treatment of different human diseases, the 8.000 km of the Brazilian coastline represents a great potential for the finding of new pharmacologically active molecular leads. The proposal of this project is the isolation of biologically active substances from marine invertebrate crude extracts, which display activity in different bioassays: anti-proliferative against cancer cell lines, antibiotic activity against drug-resistant bacteria, as well as enzyme inhibition on enzymes that regulate the metabolic pathway of tropical diseases vectors (Chagas disease and Leishmaniasis). Cancer is a growing public health problem whose estimated worldwide new incidences are over six million cases per year, being considered the second causa mortis factor all over the world. In Brazil it is estimated that one hundred thousand people die of cancer per year. All around the world the financial costs of cancer are immense, both to the individual and to society as a whole. Treatment of breast, lung, and prostate cancers account for over half of the direct medical costs. Therefore, it is of seminal importance to provide new drug leads that may be developed into new cancer medicines, aiming to diminish the incidence of cancer mortalities. Natural products extracts continue to be the most promising source of new drug leads for cancer. They contain an exceptional diversity of chemotypes, suitable for high throughtput screening and further development by combinatorial synthesis, molecular modeling and structure versus activity studies. The first goal of this project is to undertake a comprehensive screening of extracts from Brazilian marine organisms in new bioassays relevant to cancer. We believe that this project has excellent potential for the discovery of new bioactive substances that will prove to be useful leads for the development of pharmaceutical agents effective in the treatment of different types of human solid tumors. The enormous success of the early antibiotics left society and the scientific community unprepared for the emergence of antibiotic resistance bacteria. This resistance, has spread rapidly and left physicians with little resource for the treatment of common infections. The infections caused by Staphylococcus aureus are currently a considerable problem. Even vancomycin, which was the last resort for the treatment of infections by methillicin-resistant S. aureus, has rendered recently innefective. Clearly, the recent emergence and clinical significance of drug-resistant bacterial infection has created an urgent need for the rapid and continued development of new classes of antibiotics that can keep pace with the changing face of bacterial antibiotic susceptibility.A second aim of this project is to evaluate a large number of crude extracts obtained from marine invertebrates against several different strains of antibiotic resistant S. aureus. Active extracts will be subjected to fractionation in order to isolate the active antibiotics and evaluate the antibiotic potency of pUle compounds against antibiotic resistant Staphylococcus aureus. Tropical diseases, such as malaria, Leishmaniasis and Chagas diseases, are a major health problems in developing countries such as India, China, African countries and Brazil, affecting over five hundred million people all over the world. Only a few natural and synthetic compounds have proven to be effective in treatment for such diseases. Moreover, frequently the parasites acquire resistance to the used medicines. Such is the case of quinine derivatives for the treatment of malaria. The third aim of this project is to evaluate the crude extracts in different enzyme-based bioassays, using enzymes that participate in tropical diseases parasite's metabolic pathways. This is a new approach for the discovery of new leads that mar be useful for the development of new drugs for the treatment of tropical diseases. Active extracts will be selected for isolation and purification studies based on their activity profile. Isolation steps will include crude extracts screening, dereplication, isolation and bioactive pure compounds identification. The isolation will be bioassay and spectroscopically monitored. Pure compounds will be evaluated on the originally active bioassay. Pure compounds with promising activity profile will be subjected to a detailed bioactivity study, including mechanism-of-action, with specific methods used for each bioassay. Potently and selectively active structurally novel compounds will be patented. (AU)

Scientific publications

(6)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

OLIVEIRA, JAINE H. H. L. DE; GRUBE, ACHIM; KOCK, MATTHIAS; BERLINCK, ROBERTO GOMES DE SOUZA; MACEDO, MARIO L.; FERREIRA, ANTONIO G.; HAJDU, EDUARDO. Ingenamine G and cyclostellettamines G-I, K, and L from the new Brazilian species of marine sponge Pachychalina sp. Journal of Natural Products, v. 67, n. 10, p. 1685-1689, Oct. 2004. (01/03095-5)

SIMONE P. DE LIRA; MIRNA H. R. SELEGHIM; DAVID E. WILLIAMS; FREDERIC MARION; PAMELA HAMILL; FRANÇOIS JEAN; RAYMOND J. ANDERSEN; EDUARDO HAJDU; ROBERTO G. S. BERLINCK. A SARS-coronovirus 3CL protease inhibitor isolated from the marine sponge Axinella cf. corrugata: structure elucidation and synthesis. Journal of the Brazilian Chemical Society, v. 18, n. 2, p. 440-443, 2007-04-00. (01/03095-5)

ANA CLAUDIA GRANATO; JAINE H. H. L. DE OLIVEIRA; MIRNA H. R. SELEGHIM; ROBERTO G. S. BERLINCK; MARIO L. MACEDO; ANTONIO G. FERREIRA; ROSANA M. DA ROCHA; EDUARDO HAJDU; SOLANGE PEIXINHO; CLAUDIA O. PESSOA; et al. Produtos naturais da ascídia Botrylloides giganteum, das esponjas Verongula gigantea, Ircinia felix, Cliona delitrix e do nudibrânquio Tambja eliora, da costa do Brasil. Química Nova, v. 28, n. 2, p. 192-198, 2005-03-00. (96/04316-5, 01/03095-5)

TATIANA O. DE LIRA; ROBERTO G. S. BERLINCK; GISLENE G. F. NASCIMENTO; EDUARDO HAJDU. Further dibromotyrosine-derived metabolites from the marine sponge Aplysina caissara. Journal of the Brazilian Chemical Society, v. 17, n. 7, p. 1233-1240, 2006-12-00. (01/03095-5)

DE OLIVEIRA‚ J.H.; SELEGHIM‚ M.H.; TIMM‚ C.; GRUBE‚ A.; KÖCK‚ M.; NASCIMENTO‚ G.G.; MARTINS‚ A.C.; SILVA‚ E.G.; DE SOUZA‚ A.O.; MINARINI‚ P.R.; et al. Antimicrobial and antimycobacterial activity of cyclostellettamine alkaloids from sponge Pachychalina sp.. MARINE DRUGS, v. 4, n. 1, p. 1-8, 2006. (01/03095-5)

MIRIAM H. KOSSUGA; SIMONE P. DE LIRA; ANDRÉA M. NASCIMENTO; MARIA TERESA P. GAMBARDELLA; ROBERTO G. S. BERLINCK; YOHANDRA R. TORRES; GISLENE G. F. NASCIMENTO; ELI F. PIMENTA; MARCIO SILVA; OTÁVIO H. THIEMANN; et al. Isolamento e atividades biológicas de produtos naturais das esponjas monanchora arbuscula, aplysina sp. petromica ciocalyptoides e topsentia ophiraphidites, da ascídia didemnum ligulum e do octocoral carijoa riisei. Química Nova, v. 30, n. 5, p. 1194-1202, 2007-10-00. (96/04316-5, 01/03095-5)

Filed patent(s) as a result of this research project