Ruthenium(II)-arene complexes with biotin-containing ligands were prepared so that a novel drug delivery system based on tumor-specific vitamin-receptor mediated endocytosis could be developed. The complexes were characterized by spectroscopic methods and their in vitro anticancer activity in cancer cell lines with various levels of major biotin receptor (COLO205, HCT116 and SW620 cells) was tested in comparison with the ligands. In all cases, coordination of ruthenium resulted in significantly enhanced cytotoxicity. The affinity of Ru(II) -biotin complexes to avidin was investigated and was lower than that of unmodified biotin. Hill coefficients in the range 2.012-2.851 suggest strong positive cooperation between the complexes and avidin. To estimate the likelihood of binding to the biotin receptor/transporter, docking studies with avidin and streptavidin were conducted. These explain, to some extent, the in vitro anticancer activity results and support the conclusion that these novel half-sandwich ruthenium(II)-biotin conjugates may act as biological vectors to cancer cells, although no clear relationship between the cellular Ru content, the cytotoxicity, and the presence of the biotin moiety was observed.
We demonstrated the clinical and immunologic effect of probiotic and vitamin D supplementation on SLIT. Probiotic supplementation showed better clinical and immunologic response in children with allergic rhinitis.
The tubulin-microtubule system is a common target of many anticancer drugs. However, the use of chemotherapeutics frequently leads to the development of a clinically relevant phenomenon of multidrug resistance (MDR). One of the basic mechanisms involved in MDR involves elevated expression and/or activity of several ATP-binding cassette superfamily members (ABC transporters) which are normally responsible for the efflux of xenobiotics or secondary metabolites outside the cell. Here we present the synthesis and biological characteristics of ferrocenyl analogues of plinabulin, i.e. one of the so-called "spindle poisons". We found that replacement of the phenyl group of plinabulin by the ferrocenyl moiety turns this compound into a potent inhibitor of ABCB1 and ABCG2, thus making it possible to overcome the multidrug resistance phenomenon. We also demonstrated that the alkyl group attached to the imidazole moiety of ferrocenyl analogues of plinabulin strongly affects their potency to inhibit tubulin polymerization.
Friedel−Crafts acylation of ferrocene with a biotin-derived carboxylic acid having 6-aminohexanoyl linkers attached to the biotin carboxylic group and with desthiobiotin afforded the corresponding ferrocene−biotin bioconjugates. These compounds as well as biotinyl ferrocenyl ketone exhibit high affinity for avidin. Their cytotoxicity against cancer cell lines having various levels of biotin receptors (SMVT) was measured and revealed that lines displaying high levels of SMVT (SW620) were the most susceptible. This suggests that biotin serves as a biological vector delivering cytotoxic ferrocenyl moieties to cancer cells. The crystal structure of the complex of avidin with a conjugate having two linker units between biotin and ferrocene was determined and revealed stabilization of several different conformations of the ligand within the protein binding pocket.
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