Hydrogen-bond-assisted organocatalytic acetalization of secondary alcohols: experimental and theoretical studies.

An efficient method was developed for the acetalization of secondary alcohols in the presence of simple protic pyridinium salts. Direct correlations between the structure and activity of the synthesized catalysts were described. Stabilization via hydrogen bonding of the hemiacetal intermediate by the pyridine derivatives, along with an appropriate increase in the reaction rate, was revealed. The nature of the observed experimental acceleration of the examined reactions catalyzed by pyridinium salts comprising electron-withdrawing groups at certain positions of the pyridinium ring was studied. In this vein, the interpretation of the hydrogen-bonded pretransition-state complexes and transition-state complexes with strong catalysts was also discussed in terms of partial proton transfer. It was concluded that optimized pretransition-state complexes of the catalyst and reactant are useful for the prediction of catalyst efficiency prior to the experiment.

Design, synthesis, and functional evaluation of CO-releasing molecules triggered by Penicillin†G amidase as a model protease.

Protease-triggered CO-releasing molecules (CORMs) were developed. The viability of the approach was demonstrated through the synthesis of compounds consisting of an η(4) -oxydiene-Fe(CO)3 moiety connected to a penicillin G amidase (PGA)-cleavable unit through a self-immolative linker. The rate of PGA-induced hydrolysis was investigated by HPLC analysis and the subsequent CO release was quantitatively assessed through headspace gas chromatography. In an in vitro assay with human endothelial cells, typical biological effects of CO, that is, inhibition of the inflammatory response and the induction of heme oxygenase-1 expression, were observed only upon co-administration of the CORM and PGA. This work forms a promising basis for the future development of protease-specific CORMs for potential medicinal applications.

Synthesis and cytostatic properties of polyfunctionalized furanoallocolchicinoids.

A series of furan-based allocolchicinoids was prepared from commercially available colchicine via a nine-step reaction sequence. Cytostatic activity, cell cycle arrest, apoptosis, tubulin and F-actin expression were studied in vitro in 2D and 3D cultures of normal and tumor epithelial keratinocytes, endothelial and mesenchymal cells. Among the prepared furanoallocolchicine analogues, 14a and 7a displayed the most pronounced anti-cancer activity. These compounds induced two types of effects: (a) cell cycle arrest in the G2/M phase as a direct consequence of effective tubulin binding (metaphase effect), and (b) pronounced cell stress (as evidenced by the overexpression of tubulin and F-actin), which was caused by the hyperpolarization of mitochondrial and lysosomal membranes (interphase effect).

Synthesis and biological evaluation of furanoallocolchicinoids.

A series of conformationally flexible furan-derived allocolchicinoids was prepared from commercially available colchicine in good to excellent yields using a three-step reaction sequence. Cytotoxicity studies indicated the potent activity of two compounds against human epithelial and lymphoid cell lines (AsPC-1, HEK293, and Jurkat) as well as against Wnt-1 related murine epithelial cell line W1308. The results of in vitro experiments demonstrated that the major effect of these compounds was the induction of cell cycle arrest in the G2/M phase as a direct consequence of effective tubulin binding. In vivo testing of the most potent furanoallocolchicinoid 10c using C57BL/6 mice inoculated with Wnt-1 tumor cells indicated significant inhibition of the tumor growth.