Synthesis and Cytotoxicity Evaluation of Spirocyclic Bromotyrosine Clavatadine C Analogs |
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| Authors: | Piyush A. Patel,Tanja Bruun,Polina Ilina,Heidi Mä kkylä ,Antti Lempinen,Jari Yli-Kauhaluoma,Pä ivi Tammela,Paula S. Kiuru |
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| Affiliation: | 1.Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland; (P.A.P.); (T.B.); (A.L.); (J.Y.-K.);2.Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland; (P.I.); (H.M.); (P.T.) |
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| Abstract: | Marine-originated spirocyclic bromotyrosines are considered as promising scaffolds for new anticancer drugs. In a continuation of our research to develop potent and more selective anticancer compounds, we synthesized a library of 32 spirocyclic clavatadine analogs by replacing the agmatine, i.e., 4-(aminobutyl)guanidine, side chain with different substituents. These compounds were tested for cytotoxicity against skin cancer using the human melanoma cell line (A-375) and normal human skin fibroblast cell line (Hs27). The highest cytotoxicity against the A-375 cell line was observed for dichloro compound 18 (CC50 0.4 ± 0.3 µM, selectivity index (SI) 2). The variation of selectivity ranged from SI 0.4 to reach 2.4 for the pyridin-2-yl derivative 29 and hydrazide analog of 2-picoline 37. The structure–activity relationships of the compounds in respect to cytotoxicity and selectivity toward cancer cell lines are discussed. |
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| Keywords: | Clavatadine C spirocyclic bromotyrosines cytotoxicity cancer selectivity marine compounds melanoma A-375 cell line |
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