Tine De Ryck

Design, synthesis and structure-activity relationships of some novel, highly potent anti-invasive (E)- and (Z)-stilbenes.

In our ongoing exploration of the structure-activity landscape of anti-invasive chalcones, we have prepared and evaluated a number of structurally related (E)- and (Z)-stilbenes. These molecules exhibited an extraordinary high in vitro potency in the chick heart invasion assay, being active up to 10nmolL(-1), a concentration level a 100-fold lower than the lowest effective doses that have been reported for natural analogues. Furthermore, they possess an interesting pharmacological profile in silico.

Exploration of the SAR of anti-invasive chalcones: Synthesis and biological evaluation of conformationally restricted analogues

In order to get a clearer view on the active geometry of anti-invasive chalcones, we have prepared a number of isoxazoles and related substances as conformationally restrained mimics of 1,3-diarylpropenones, and also of (Z)-stilbenes. In vitro anti-invasive activity data for 3,5-isoxazoles and 4,5-isoxazoles, together with an in silico geometrical comparison, point towards an active conformation for chalcones more resembling their s-trans geometry than the s-cis counterpart.

Westernized diets lower arsenic gastrointestinal bioaccessibility but increase microbial arsenic speciation changes in the colon

Arsenic (As) is an important contaminant present in food and water. Several studies have indicated that the occurrence of As based skin lesions is significantly different when root and gourd rich diets are consumed compared to meat rich diets. Additionally, urinary As speciation from orally exposed individuals appears to depend on the composition of the diet. These observations imply that diet composition can affect both the bioavailable As fraction as the As speciation in the body. In this study, we used the in vitro gastrointestinal method (IVG) to evaluate how an Asian type diet (fiber rich) and a Western type diet (fat and protein rich), differ in their capability to release inorganic As (iAs(V)) and dimethyl arsinate (DMA(V)) from a rice matrix following gastrointestinal digestion. Moreover, we used a validated dynamic gut simulator to investigate whether diet background affects As metabolism by gut microbiota in a colon environment. An Asian diet background resulted in a larger As bioaccessibility (81.2%) than a Western diet background (63.4%). On the other hand, incubation of As contaminated rice with human colon microbiota in the presence of a Western type diet resulted in a larger amount of hazardous As species - monomethyl arsonite and monomethylmonothio arsonate - to be formed after 48 h. The permeability of these As species (60.5% and 50.5% resp.) across a Caco-2 cell line was significantly higher compared to iAs(V) and DMA(V) (46.5% and 28% resp.). We conclude that dietary background is a crucial parameter to incorporate when predicting bioavailability with bioaccessibility measurements and when assessing health risks from As following oral exposure.

Further studies on anti-invasive chemotypes: An excursion from chalcones to curcuminoids.

In our ongoing search for new anti-invasive chemotypes, we have made an excursion from previously reported potent 1,3-diarylpropenones (chalcones) to congeners bearing longer linkers between the aromatic moieties. Nine 1,ω-diarylalkenones, including curcumin and bisdemethoxycurcumin, were evaluated in the chick heart invasion assay. Unfortunately, these compounds proved less potent and more toxic than earlier evaluated chemotypes. In the 1,3-diarylpenta-2,4-dien-1-one series, fluoro and/or trimethoxy substitution caused an increase in potency. This agrees with observations made earlier for the chalcone class.

Low-dose irradiation affects the functional behavior of oral microbiota in the context of mucositis.

The role of host–microbe interactions in the pathobiology of oral mucositis is still unclear; therefore, this study aimed to unravel the effect of irradiation on behavioral characteristics of oral microbial species in the context of mucositis. Using various experimental in vitro setups, the effects of irradiation on growth and biofilm formation of two Candida spp., Streptococcus salivarius and Klebsiella oxytoca in different culture conditions were evaluated. Irradiation did not affect growth of planktonic cells, but reduced the number of K. oxytoca cells in newly formed biofilms cultured in static conditions. Biofilm formation of K. oxytoca and Candida glabrata was affected by irradiation and depended on the culturing conditions. In the presence of mucins, these effects were lost, indicating the protective nature of mucins. Furthermore, the Galleria melonella model was used to study effects on microbial virulence. Irradiated K. oxytoca microbes were more virulent in G. melonella larvae compared to the nonirradiated ones. Our data indicate that low-dose irradiation can have an impact on functional characteristics of microbial species. Screening for pathogens like K. oxytoca in the context of mucosits could be useful to allow early detection and immediate intervention.

4-Fluoro-3',4',5'-trimethoxychalcone as a new anti-invasive agent. From discovery to initial validation in an in vivo metastasis model.

Invasion and metastasis are responsible for 90% of cancer-related mortality. Herein, we report on our quest for novel, clinically relevant inhibitors of local invasion, based on a broad screen of natural products in a phenotypic assay. Starting from micromolar chalcone hits, a predictive QSAR model for diaryl propenones was developed, and synthetic analogues with a 100-fold increase in potency were obtained. Two nanomolar hits underwent efficacy validation and eADMET profiling; one compound was shown to increase the survival time in an artificial metastasis model in nude mice. Although the molecular mechanism(s) by which these substances mediate efficacy remain(s) unrevealed, we were able to eliminate the major targets commonly associated with antineoplastic chalcones.

Effects of Irradiation on Epithelial Wound Healing and Microbial Diversity in an in-vitro Oral Mucosa Model

The impact of irradiation on host-microbe crosstalk is still underexplored. By use of an in vitro oral mucosa model, we show an impact of irradiation on epithelial wound healing depending on the microbial composition and functionality. 454-pyrosequencing analyses pointed to a slight increase in abundance of Rothia, Granulicatella and Gemella in our model after irradiation. Further research is needed to unravel the effects of irradiation on the oral microbiota and the host-microbe interactions more in detail.