Synthesis and Antiproliferative Activity of Marine Bromotyrosine Purpurealidin I and Its Derivatives
Chinmay Bhat,
Polina Ilina,
Irene Tilli,
Manuela Voráčová,
Tanja Bruun,
Victoria Barba,
Nives Hribernik,
Katja-Emilia Lillsunde,
Eero Mäki-Lohiluoma,
Tobias Rüffer,
Heinrich Lang,
Jari Yli-Kauhaluoma,
Paula Kiuru,
Päivi Tammela
Affiliations
Chinmay Bhat
Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, Viikinkaari 5 E (P.O. Box 56), University of Helsinki, FI-00014 Helsinki, Finland
Polina Ilina
Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, Viikinkaari 5 E (P.O. Box 56), University of Helsinki, FI-00014 Helsinki, Finland
Irene Tilli
Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, Viikinkaari 5 E (P.O. Box 56), University of Helsinki, FI-00014 Helsinki, Finland
Manuela Voráčová
Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, Viikinkaari 5 E (P.O. Box 56), University of Helsinki, FI-00014 Helsinki, Finland
Tanja Bruun
Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, Viikinkaari 5 E (P.O. Box 56), University of Helsinki, FI-00014 Helsinki, Finland
Victoria Barba
Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, Viikinkaari 5 E (P.O. Box 56), University of Helsinki, FI-00014 Helsinki, Finland
Nives Hribernik
Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, Viikinkaari 5 E (P.O. Box 56), University of Helsinki, FI-00014 Helsinki, Finland
Katja-Emilia Lillsunde
Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, Viikinkaari 5 E (P.O. Box 56), University of Helsinki, FI-00014 Helsinki, Finland
Eero Mäki-Lohiluoma
Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, Viikinkaari 5 E (P.O. Box 56), University of Helsinki, FI-00014 Helsinki, Finland
Tobias Rüffer
Institute of Chemistry, Technische Universität Chemnitz, 09107 Chemnitz, Germany
Heinrich Lang
Institute of Chemistry, Technische Universität Chemnitz, 09107 Chemnitz, Germany
Jari Yli-Kauhaluoma
Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, Viikinkaari 5 E (P.O. Box 56), University of Helsinki, FI-00014 Helsinki, Finland
Paula Kiuru
Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, Viikinkaari 5 E (P.O. Box 56), University of Helsinki, FI-00014 Helsinki, Finland
Päivi Tammela
Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, Viikinkaari 5 E (P.O. Box 56), University of Helsinki, FI-00014 Helsinki, Finland
The first total synthesis of the marine bromotyrosine purpurealidin I (1) using trifluoroacetoxy protection group and its dimethylated analog (29) is reported along with 16 simplified bromotyrosine derivatives lacking the tyramine moiety. Their cytotoxicity was evaluated against the human malignant melanoma cell line (A-375) and normal skin fibroblast cells (Hs27) together with 33 purpurealidin-inspired simplified amides, and the structure⁻activity relationships were investigated. The synthesized simplified analogs without the tyramine part retained the cytotoxic activity. Purpurealidin I (1) showed no selectivity but its simplified pyridin-2-yl derivative (36) had the best improvement in selectivity (Selectivity index 4.1). This shows that the marine bromotyrosines are promising scaffolds for developing cytotoxic agents and the full understanding of the elements of their SAR and improving the selectivity requires further optimization of simplified bromotyrosine derivatives.
