Alvaxanthone, a Thymidylate Synthase Inhibitor with Nematocidal and Tumoricidal Activities

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.

Biotin Transport-Targeting Polysaccharide-Modified PAMAM G3 Dendrimer as System Delivering α-Mangostin into Cancer Cells and C. elegans Worms

“…U-118 MG cells retained relatively high adhesiveness even after treatment with conjugates at concentrations higher than the IC 50 values. Similar results were obtained for αM and other xanthones [ 5 , 49 ]. In these studies, the adhesion of squamous carcinoma cells was slightly more disturbed compared to fibroblasts, while the weakest effect was observed in glioblastoma cells.…”

“…Thus, lower concentrations of αM affected cancer than normal cells. Two other similar xanthones, namely alvaxanthone and rheediaxanthone B, induced higher activity of caspases-3/7 in cancer cell lines comparing to normal cells [ 49 ]. For αM conjugated with PAMAM G3 dendrimer, this effect was not seen—the most sensitive were fibroblasts.…”

Recent Trends in Enzyme Inhibition and Activation in Drug Design

“…In silico screening of a library of natural compounds aiming to search for novel inhibitors of parasitic nematode thymidylate synthase (TS) [10] was also reported. TS is a target of antitumor, antiviral, antifungal, and antiprotozoan chemotherapy.…”