Browsing by Author "Galkin, Anna"

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  • Galkin, Anna (Helsingin yliopisto, 2008)
    Nature provides a great diversity of different kinds of health-promoting compounds and is an important source of new biologically active molecules for drug discovery. In addition various polyphenolic compounds, affecting wellbeing, are gained from daily nutrition and from concentrated health promoting products. The discovery of new molecules and determination of the effects of natural compounds require the development of new, high-capacity assays. The apoptosis assay for screening of new potential drug compounds was optimized with natural compounds and then used to study the apoptosis-inducing effects of derivatives of 5-(hydroxymethyl)isophthalic acid. Two of the compounds seemed to be potent and selective apoptosis inducers and should be studied further for possible use in cancer therapy. An automated PKC assay was developed and used to screen the protein kinase C inhibiting effects of 81 extracts from plants growing in Finland. Twenty-one extracts from 7 plants significantly inhibited protein kinase C. The inhibition was usually induced by all parts of the plants. Fractionation of an active extract showed that the method is suitable for identifying compounds from natural product extracts and provides a quick and low-volume non-radioactive alternative to PKC experiments. To make permeation studies more effective and more suitable for screening purposes, an automated 7-day, 96-well plate Caco-2 permeability model was developed to provide preliminary information on the permeability of pharmacologically active compounds. The absorption studies of flavonoids and alkyl gallates showed that the degree of hydroxylation, molecular configuration and the length of the side chain governed the ability of the molecules to cross the Caco-2 cell monolayer and to be retained on the phospholipid membrane. As the number of OH-groups in the structure or the number of the carbons in alkyl chain increased the permeability decreased and the membrane affinity increased. The permeation study on coumarins indicated that all the coumarins studied are highly permeable in the gut lumen and that P-glycoprotein efflux does not limit absorption. The type and position of substituents affected permeability more than the number of substituents. In order to evaluate the effects of concentrated natural products on concomitant medication, the influence of raspberry extract and its fractions on the permeability of commonly used drugs was studied with the Caco-2 cell line. Raspberry samples affected the permeability of some model drugs, probably by interactions with the cell membranes. The findings of this thesis show that nature is an excellent source for the discovery of new drugs when effective methods are used. Such methods make the screening of natural products fast and easy, even from complex matrices.