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Abstract: A series of 2,9-substituted 6-guanidinopurines, structurally related to the cyclin-dependent kinase (CDK) inhibitors olomoucine and roscovitine, has been synthesized and characterized. A new copper-catalyzed method for the synthesis of 2-substituted 6-guanidino-9-isopropylpurines under mild reaction conditions has been developed. All prepared compounds were screened for their CDK1 and CDK2 inhibitory activities, cytotoxicity and antiproliferative effects in the breast cancer-derived cell line MCF7. The most active derivative 16g possessed an identical side chain in the C2 position to roscovitine; this compound displayed approximately five fold higher inhibitory activity towards CDK2/cyclin E and more than ten fold increase in cytotoxicity in MCF7 cells. Interestingly and in contrast to previously described findings, (S)-6-guanidinopurine derivatives were generally more active than their (R)-counterparts. Kinase selectivity profiling of (R)- and (S)-enantiomers 16e and 16g, respectively, revealed that introduction of a guanidino group at the C6 position of the purine moiety decreased selectivity towards protein kinases compared to roscovitine. Nevertheless, increased inhibitory activity and decreased selectivity offer a good starting point for further development of new protein kinase inhibitors. [Copyright &y& Elsevier]

Abstract: Flavone eupatorin is one of the constituents of Orthosiphon stamineus, a medicinal herb used in folk medicine in South East Asia for treatment of various disorders. In our study, we investigated the antiproliferative properties of a chloroform extract of the leaves of O. stamineus and of pure eupatorin. The compound was able to reduce the number of viable cancer cells to the same extent as the extract, with IC50 values in micromolar range. Moreover, both the eupatorin standard and the extract caused cells to arrest in the G2/M phase of the cell cycle. This clearly demonstrates that eupatorin contributes significantly to the overall extract activity. Induction of mitotic catastrophe, accompanied by key molecular events defining apoptosis, is the mechanism of eupatorin-induced cell death. Importantly, eupatorin (at the doses cytotoxic to cancer cells) did not kill normal cells; it only limited migration of HUVEC endothelial cells and their ability to create tubes. The ability of eupatorin to nonspecifically inhibit many protein kinases was proven and is the probable cause of its cellular effects. In summary, eupatorin emerges as a promising agent in anticancer research. [Copyright &y& Elsevier]

Chondroitin sulfate (CS) was regio-specifically modified to an unsaturated derivative (ΔCS) with a double bond in positions 4 and 5 of N -acetyl- d -galactosamine. The structure of ΔCS was elucidated in detail by two dimensional nuclear magnetic resonance, ultraviolet spectroscopy and mass spectrometry. The introduction of a nucleophilic C C double bond into a polymer backbone had no influence on biocompatibility of CS, which was demonstrated by MTT live-dead assay and enzymatic degradation in vitro . On the other hand the chemical modification significantly enhanced the reactivity of ΔCS towards numerous oxidizing agents, which might be promising for a variety of biomedical and cosmetic applications. [ABSTRACT FROM AUTHOR]

Hyaluronic acid (HA) containing C C double bond in positions 4 and 5 of N -acetyl-glucosamine ring (ΔHA) is an unique material, which could be used for biomedical applications and cosmetics. The main advantage of the C C double bond is its ability to react with a wide range of oxidation agents. Location of the C C double bond directly on the glucopyranose ring allows to change the chemical capabilities and simultaneously to mimic the intrinsic physical properties of HA without introduction of linkers or other substances. The synthesis, structural analysis and basic chemical and biological characteristics of this novel biopolymer are described in details. In vitro cytotoxicity assays showed selective activity of ΔHA against cancer cell lines in comparison with standard human fibroblasts so this material has great potential in the field of anticancer drugs. [ABSTRACT FROM AUTHOR]