Liquid-crystal micro droplets can serve as optical micro resonators for applications such as laser sources, active filters and all-optical switches. Especially interesting are resonators, in which the resonance frequency can be tuned by size, shape, temperature or electric field. Different optical modes can be excited in the droplets with a fluorescent dye using an external excitation source of light. Our contribution (research programme team member S. Pajk) was design and synthesis of a fluorescent dye, which, because of its physical and chemical properties, is spontaneously distributed in the droplet of liquid crystal with negligible partitioning to the surrounding media of the droplet. This was achieved by attaching lipophilic anchor to otherwise freely water-soluble dye rhodamine B.
COBISS.SI-ID: 22940455
We have designed, synthesized, and evaluated 5-benzylidenerhodanine- and 5-benzylidenethiazolidine- 2,4-dione-based compounds as inhibitors of bacterial enzyme MurD with E. coli IC50 in the range 45- 206 ìM. The high-resolution crystal structure of MurD in complex with (R,Z)-2-(3-[{4-([2,4-dioxothiazolidin- 5-ylidene]methyl)phenylamino}methyl)benzamido)pentanedioic acid [(R)-32] revealed details of the binding mode of the inhibitor within the active site and provides a good foundation for structurebased design of a novel generationof MurD inhibitors.
COBISS.SI-ID: 2876529
17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is an enzyme that catalyzes NADPH-dependent reduction of the weak estrogen, estrone, into the most potent estrogen, estradiol, which exerts proliferative effects via the estrogen receptors. Overexpression of 17beta-HSD1 in estrogen-responsive tissues is related to the development of hormone-dependent diseases, such as breast cancer and endometriosis; thus, 17beta-HSD1 represents an attractive target for the development of new therapies. We have discovered that simple coumarines 1 and 2 significantly inhibit 17beta-HSD1 in a recombinant enzyme assay, with high selectivity against 17beta-HSD2. We postulated that the introduction of various p-substituted phenyl moieties to position 6 or 7 of the coumarin core using the Suzuki-Miyaura cross-coupling reaction would provide mimetics of steroidal structures with improved inhibition of 17beta-HSD1. The best inhibitor in the series proved to be 6a, with an IC(50) of 270 nM, and with exceptional selectivity for 17beta-HSD1 over 17beta-HSD2 and against the alpha and beta estrogen receptors.
COBISS.SI-ID: 27732441
Serine proteases have proven to be promising pharmacological targets in contemporary drug discovery for cancer treatment. Since azaphenylalanine-basedcompounds manifest cytotoxic activity, we have selected serine protease inhibitors designed and synthesized in-house with large hydrophobic naphthalene moiety for screening. The cytotoxic potential of screened molecules was correlated to modifications of R1 residues. The most cytotoxic were compounds with greater basicity; amidinopiperidines, piperidines and benzamidines. Amidinopiperidine-based compounds exert cytotoxicity in low mM range, with IC50 18 mM and 22 mM for inhibitors 15 and 16 respectively. These compounds exhibited selective cytotoxicity towards the Burkitt's lymphoma cells Ramos and Daudi, and proved nontoxic to PMBC, Jurkat and U937. They induce caspase-dependent apoptotic cell death, as demonstrated by the use of a pan-caspase inihibitor, zVADfmk, which was able to rescue Ramos cells from compound(s)-induced apoptosis. We confirm a disruption of thepro-survival pathway in Burkittʼs lymphoma through NFkB inhibition. The accumulation of phosphorylated precursor (p105) and inhibitory (IkB) molecules with no subsequent release of active NFkB implicated the involvement of proteasome. Indeed, we show that the amidinopiperidine-based compounds inhibit all three proteolytical activities of the human 20S proteasome, with the most prominent effect being on the trypsin-like activity. Consistently, treatment of Ramos cells with these compounds led to an increase in ubiquitinated proteins. The amidinopiperidine-based serine protease inhibitors presented are, as selective inducers of apoptosis in Burkitt's lymphoma cells, promising leads for the development of novel chemotherapeutics.
COBISS.SI-ID: 3286129
Human cathepsin B has many house-keeping functions, such as protein turnover in lysosomes. However, dysregulation of its activity is associated with numerous diseases, including cancers. We present here the structure-based design and synthesis of new cathepsin B inhibitors using the cocrystal structure of 5-nitro-8-hydroxyquinoline in the cathepsin B active site. A focused library of over 50 compounds was prepared by modifying positions 5, 7,and 8 of the parent compound nitroxoline. The kinetic parameters and modes of inhibition were characterized, and the selectivities of the most promising inhibitors were determined. The best performing inhibitor 17 was effective in cell-based in vitro models of tumor invasion, where it significantly abrogated invasion of MCF-10A neoT cells. These data show that we have successfully explored the structure-activity relationships of nitroxoline derivatives to provide new inhibitors that could eventually lead to compounds with clinical usefulness against the deleterious effects of cathepsin B in cancer progression.
COBISS.SI-ID: 3370865