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Browsing by Author "Bruun, Tanja"

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  • Bruun, Tanja (2018)
    Marine organisms can be regarded as a diverse source of bioactive compounds with the possibility to discover novel drug lead molecules. Sea sponges produce bromine containing alkaloids, bromotyrosines, from which several are active against cancer. Some bromotyrosines have spirocyclic structure and the innate three-dimensionality and structural novelty of spirocycles make them an interesting option in drug design. Clavatadine C, extracted from sponge Suberea clavata, is a bromine containing spirocyclohexa-dienylisoxazoline alkaloid. It’s symmetric spirocyclic core can be viewed as a restricted derivative of open chain oximes, such as purpurealidin I, a bromotyrosine extracted from Pseudoceratina purpurea. Earlier work with purpurealidin I derivatives against melanoma cell line has had some promising results. Inspired by these earlier results, eight spirocyclic clavatadine C derivatives were synthesized according the published synthesis route. The activities of seven synthesized clavatadine C derivatives were tested on A375 melanoma cell line. All spiro derivatives were active with CC50 values ranging between 1.0 μM and 3.4 μM. Also, the activities of 10 earlier synthesized bromotyrosine derivatives were tested, from which four open chain oximes had CC50 values between 13.5 μM and 27.8 μM. Interestingly, the most active compounds were chlorinated and unhalogenated spirocyclic derivatives. In general, the spirocyclic compounds were 2- to 8-fold more active than the corresponding open chain oximes. The selectivity of active compounds was determined as cytotoxicity against Hs27 fibroblasts and by comparing the CC50 values of these two cell lines. The most selective compound was brominated derivative which had three times better selectivity against melanoma cells. The weak selectivity was consistent with the trend with open chain oxime analogs. Despite the selectivity issue, the improved activity of spirocyclic derivatives are promising and support for further investigation of marine-based spirocyclic bromotyrosine derivatives against melanoma.