Prospecting for anticancer secondary metabolites produced by phytopathogenic fungi

Author(s)

Jaqueline Moraes Bazioli

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Farmacêuticas
• Defense date: 2023-04-13

Examining board members

João Ernesto de Carvalho; Thais Petrochelli Banzato; Giovanna Barbarini Longato; Débora Barbosa Vendramini Costa; Karina Cogo Müller

• Advisor: João Ernesto de Carvalho

Abstract

Natural products are regarded as major and important sources of molecules used in chemotherapy. Herein, bioassay-guided fractionation and bioactive molecular networking were used as strategies to find candidate active molecules directly from the bioactive fraction of Epicoccum sp. Among the fungi previously studied, the crude extract of Epicoccum sp. antiproliferative exhibited in vitro activity and its active fraction was tested against the human cell line OVCAR-3 (ovarian cancer). Evaluation of the metabolic profile of the fungus Epicoccum sp. led to the isolation and characterization of the known compound epipyridone (1). Isolated from the most active fraction, epipyridone (1) presented cytotoxic activity against OVCAR-3 at 134.7 µM. These initial results regarding cytotoxicity against OVCAR-3 (human ovarian cancer cell line), never described for this compound before, indicate that further studies are needed to fully characterize epipyridone as a potential encouraging drug against ovarian cancer, a tumor extremely resistant to chemotherapy. Another class of compounds described here are verticillins, which are epipolitiodiopopiperazine (ETP) alkaloids with potent cytotoxic activity isolated from terrestrial filamentous fungi. Initial studies found that verticillin A exhibited nanomolar cytotoxic activity in high grade serous ovarian cancer (HGSOC) cell lines. Verticillin D was then studied to determine if the higher yielding compound could be used for further semi-synthesis. Verticillin D exhibited nanomolar cytotoxic activity OVCAR4 and OVCAR8 HGSOC cell lines and significantly reduced 2D foci, 3D spheroid. Despite in vitro cytotoxic activity, verticillin D in vivo studies do not show reduced tumor burden compared to the positive control taxol. Unfortunately, mice treated with verticillin D displayed liver damage, while formulation and dosing to optimize verticillin A did not show any problems with toxicity but it was unable to reduce tumor burden. Thus, future studies will determine if efficacy can be improved through either optimization of drug delivery or further synthetic derivatization (AU)

• FAPESP's process: 19/11563-2 - Prospecting for anticancer secondary metabolites produced by phytopathogenic fungi
• Grantee: Jaqueline Moraes Bazioli
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)