Exploring quercetin and luteolin derivatives as antiangiogenic agents

The formation of new blood vessels from the pre-existing vasculature (angiogenesis) is a crucial stage in cancer progression and, indeed, angiogenesis inhibitors are now used as anticancer agents, clinically. Here we have explored the potential of flavonoid derivatives as antiangiogenic agents. Specifically, we have synthesised methoxy and 4-thio derivatives of the natural flavones quercetin and luteolin, two of which (4-thio quercetin and 4-thio luteolin) had never been previously reported. Seven of these compounds showed significant (P<0.05) antiangiogenic activity in an in vitro scratch assay. Their activity ranged from an 86% inhibition of the vascular endothelium growth factor (VEGF)-stimulated migration (observed for methoxyquercetin at 10 µM and for luteolin at 1 µM) to a 36% inhibition (for thiomethoxy quercetin at 10 µM). Western blotting studies showed that most (4 out of 7) compounds inhibited phosphorylation of the VEGF receptor-2 (VEGFR2), suggesting that the antiangiogenic activity was due to an interference with the VEGF/VEGFR2 pathway. Molecular modelling studies looking at the affinity of our compounds towards VEGFR and/or VEGF confirmed this hypothesis, and indeed the compound with the highest antiangiogenic activity (methoxyquercetin) showed the highest affinity towards VEGFR and VEGF. As reports from others have suggested that structurally similar compounds can elicit biological responses via a non-specific, promiscuous membrane perturbation, potential interactions of the active compounds with a model lipid bilayer were assessed via DSC. Luteolin and its derivatives did not perturb the model membrane even at concentrations 10 times higher than the biologically active concentration and only subtle interactions were observed for quercetin and its derivatives. Finally, cytotoxicity assessment of these flavonoid derivatives against MCF-7 breast cancer cells demonstrated also a direct anticancer activity albeit at generally higher concentrations than those required for an antiangiogenic effect (10 fold higher for the methoxy analogues). Taken together these results show promise for flavonoid derivatives as antiangiogenic agents.

A three-fold framework for understanding HRM practices in South-Eastern European SMEs

Purpose We study particular structural and organisational factors affecting the formality of human resource management (HRM) practices in small and medium-sized enterprises (SMEs) in South-Eastern European (SEE) post-communist countries, in particular Serbia, Romania, Bulgaria and the Former Yugoslav Republic of Macedonia (FYROM) in order to understand the antecedents of formalization in such settings. Design/methodology/approach Adopting a quantitative approach, this study analyses data gathered through a survey of 168 managers of SMEs from throughout the region. Findings The results show that HRM in SMEs in the SEE region can be understood through a three-fold framework which includes: degree of internationalisation of SMEs, sector of SMEs and organisational size of SMEs. These three factors positively affect the level of HRM formalisation in SEE SMEs. These findings are further attributed to the particular political and economic context of the post-communist SEE region. Research limitations/implications Although specific criteria were set for SME selection, we do not suggest that the study reflects a representative picture of the SEE region because we used a purposive sampling methodology. Practical implications This article provides useful insights into the factors which influence HRM in SMEs in a particular context. The findings can help business owners and managers understand how HRM can be applied in smaller organisations, particularly in post-communist SEE business contexts. Originality/value HRM in SMEs in this region has hardly been studied at all despite their importance. Therefore, this exploratory research seeks to expand knowledge relating to the application of HRM in SMEs in SEE countries which have their business environments dominated by different dynamics in comparison to western European ones.