Institute of Organic Chemistry, TU Braunschweig, Hagenring 30, 38106 Braunschweig, Germany.
Org Biomol Chem. 2013 Sep 28;11(36):6119-30. doi: 10.1039/c3ob40896e.
The marine natural product flustramine A was synthesised via oxidative cyclisation of Nb-methylated 1-prenyl-2-tert-prenyl-6-bromotryptamine and subsequent reduction of the resulting amidinium salt. Only the tert-prenyl group migrated, whereas the 1-prenyl group remained in place. Interestingly, the 2-tert-prenylated precursor revealed to be the biologically most active of our entire series of 21 compounds. Required for cytotoxicity and antimicrobial activity was the presence of a non-cyclised tryptamine side chain carrying a free secondary amine, whereas the presence of a 6-bromo substituent did not enhance cytotoxicity. In a panel of 42 human tumor cell lines, most sensitive were the lung and mammary cancer cell lines LXFA629L (IC50 1.9 μM) and MAXF401NL (IC50 2.4 μM), respectively. In a serial dilution assay, satisfying IC50 values of 5.9 μM against Micrococcus luteus and 7.7 μM each against Mycobacterium phlei were determined for Nb-methyl-1-prenyl-2-tert-prenyl-6-bromotryptamine.
海洋天然产物弗斯他汀 A 是通过 Nb-甲基化的 1-异戊烯基-2-叔戊烯基-6-溴色胺的氧化环化以及随后还原所得的脒盐合成的。只有叔戊烯基发生迁移，而 1-异戊烯基保持原位。有趣的是，2-叔戊烯基前体被证明是我们整个 21 种化合物系列中生物活性最强的一种。细胞毒性和抗菌活性所需的是携带游离仲胺的未环化色胺侧链的存在，而 6-溴取代基并不能增强细胞毒性。在 42 个人类肿瘤细胞系的小组中，最敏感的是肺和乳腺癌细胞系 LXFA629L（IC50 为 1.9 μM）和 MAXF401NL（IC50 为 2.4 μM）。在一系列稀释测定中，对 Micrococcus luteus 的 Nb-甲基-1-异戊烯基-2-叔戊烯基-6-溴色胺的 IC50 值分别为 5.9 μM 和对 Mycobacterium phlei 的 7.7 μM。
