Alvaxanthone, a Thymidylate Synthase Inhibitor with Nematocidal and Tumoricidal Activities.

Piotr Maj,Ylenia Cau,Bruno Botta,Mattia Mori,Łukasz Uram,Andrea Calcaterra,Wojciech Rode,Zbigniew Zieliński,Justyna Sobich,Joanna Markowicz,Deborah Quaglio

doi:10.3390/molecules25122894

Abstract

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.

Highlights

Thymidylate synthase (TS; EC 2.1.1.45) catalyzes the reductive methylation of deoxyuridine monophosphate by N5,10 -methylenetetrahydrofolate to generate thymidylateand dihydrofolate
The in-house library of natural product contains around 1000 small molecules isolated, purified, and characterized mostly from plants used in the traditional medicine of South America countries, as well as a number of chemical derivatives
To pursue the aim of identifying potential thymidylate synthase (TS) inhibitors, here, 865 compounds from the library were screened against the crystallographic structure of C. elegans TS in complex with

Summary

Introduction

Thymidylate synthase (TS; EC 2.1.1.45) catalyzes the reductive methylation of deoxyuridine monophosphate (dUMP) by N5,10 -methylenetetrahydrofolate (meTHF) to generate thymidylate (dTMP)and dihydrofolate. Molecules 2020, 25, 2894 at all), including T. spiralis infective muscle larvae [16,17,18,19] and C. elegans dauer larvae [17], the latter corresponding to developmentally arrested infective larvae of parasitic nematodes [14]. It pointed to the high TS level as a result of an unusual cell cycle regulation, leading to a long-term cell cycle arrest, in the developmentally arrested larvae (discussed in Reference [17,18]). In view of the latter, a possibility to selectively interfere with nematode TS catalytic/non-catalytic activities could be applied in an attempt to kill a parasite and to study the physiological significance of the high expression of TS in nematodes’

Methods

Results

Conclusion