Alvaxanthone, a Thymidylate Synthase Inhibitor with Nematocidal and Tumoricidal Activities
Piotr Maj,
Mattia Mori,
Justyna Sobich,
Joanna Markowicz,
Łukasz Uram,
Zbigniew Zieliński,
Deborah Quaglio,
Andrea Calcaterra,
Ylenia Cau,
Bruno Botta,
Wojciech Rode
Affiliations
Piotr Maj
Nencki Institute of Experimental Biology, 3 Pasteur Street, 02-093 Warsaw, Poland
Mattia Mori
Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, via Aldo Moro 2, 53100 Siena, Italy
Justyna Sobich
Nencki Institute of Experimental Biology, 3 Pasteur Street, 02-093 Warsaw, Poland
Joanna Markowicz
Faculty of Chemistry, Rzeszów University of Technology, 6 Powstańców Warszawy Ave, 35-959 Rzeszów, Poland
Łukasz Uram
Faculty of Chemistry, Rzeszów University of Technology, 6 Powstańców Warszawy Ave, 35-959 Rzeszów, Poland
Zbigniew Zieliński
Nencki Institute of Experimental Biology, 3 Pasteur Street, 02-093 Warsaw, Poland
Deborah Quaglio
Department of Chemistry and Technology of Drugs, Department of Excellence 2018–2022, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
Andrea Calcaterra
Department of Chemistry and Technology of Drugs, Department of Excellence 2018–2022, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
Ylenia Cau
Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, via Aldo Moro 2, 53100 Siena, Italy
Bruno Botta
Department of Chemistry and Technology of Drugs, Department of Excellence 2018–2022, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
Wojciech Rode
Nencki Institute of Experimental Biology, 3 Pasteur Street, 02-093 Warsaw, Poland
With the aim to identify novel inhibitors of parasitic nematode thymidylate synthase (TS), we screened in silico an in-house library of natural compounds, taking advantage of a model of nematode TS three-dimensional (3D) structure and choosing candidate compounds potentially capable of enzyme binding/inhibition. Selected compounds were tested as (i) inhibitors of the reaction catalyzed by TSs of different species, (ii) agents toxic to a nematode parasite model (C. elegans grown in vitro), (iii) inhibitors of normal human cell growth, and (iv) antitumor agents affecting human tumor cells grown in vitro. The results pointed to alvaxanthone as a relatively strong TS inhibitor that causes C. elegans population growth reduction with nematocidal potency similar to the anthelmintic drug mebendazole. Alvaxanthone also demonstrated an antiproliferative effect in tumor cells, associated with a selective toxicity against mitochondria observed in cancer cells compared to normal cells.
