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.
Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, Viikinkaari 5 E (P.O. Box 56), University of Helsinki, FI-00014 Helsinki, Finland.
Mar Drugs. 2018 Dec 3;16(12):481. doi: 10.3390/md16120481.
The first total synthesis of the marine bromotyrosine purpurealidin I () using trifluoroacetoxy protection group and its dimethylated analog () 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 () showed no selectivity but its simplified pyridin-2-yl derivative () 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.
本文报道了海洋溴酪氨酸紫螺肽 I（）的首次全合成，使用三氟乙酰氧基保护基和其二甲基化类似物（），以及 16 个缺乏酪胺部分的简化溴酪氨酸衍生物。对其进行了细胞毒性评估，针对人恶性黑色素瘤细胞系（A-375）和正常皮肤成纤维细胞（Hs27），并与 33 个紫螺肽简化酰胺进行了结构-活性关系研究。合成的无酪胺部分简化类似物保留了细胞毒性活性。紫螺肽 I（）没有选择性，但它的简化吡啶-2-基衍生物（）在选择性方面有了最好的改善（选择性指数 4.1）。这表明海洋溴酪氨酸是开发细胞毒性剂的有前途的支架，而要充分了解其 SAR 的要素并提高选择性，则需要进一步优化简化溴酪氨酸衍生物。
