Institute of Organic Chemistry, TU Braunschweig, Braunschweig, Germany.
Org Biomol Chem. 2012 Sep 21;10(35):7120-33. doi: 10.1039/c2ob25909e. Epub 2012 Aug 7.
The symmetrical disulfide psammaplin A from the marine sponge Pseudoceratina sp. was synthesized and structurally altered by replacement of one of the α-(hydroxyimino)acyl units by a fluorescent 4-coumarinacetyl moiety. Thus, the first fluorescent analogs of psammaplin A were obtained. Structural variation also covered the substitution pattern of the phenyl ring. Cytotoxicity of psammaplin A against the mouse fibroblast cell line L-929 (IC(50) 0.42 μg mL(-1)) was about two-fold higher than that of the fluorescent hybrid compounds, whereas the disulfide containing two 4-coumarinacetyl moieties was inactive. Fluorescence microscopy revealed uptake of the 4-coumarinacetyl-α-(hydroxyimino)acyl hybrids into the cytoplasm leading to fluorescence in close proximity of the nuclear envelope, most likely in the Golgi apparatus. We did not observe strong fluorescence inside the nucleus, where most of the target histone deacetylases are located. We conclude that reduction of the disulfide probably takes place outside the nucleus. The psammaplin-derived thiol exhibited potent activity against histone deacetylase in the low nanomolar range, but diminished cytotoxicity. Antimicrobial activity of the new derivatives was also determined.
从海洋海绵 Pseudoceratina sp. 中提取的对称二硫代 psammaplin A 并通过用荧光 4-香豆酰基部分替代其中一个 α-（羟亚氨基）酰基单元进行了结构改变。因此，获得了 psammaplin A 的第一个荧光类似物。结构变化还涵盖了苯基环的取代模式。psammaplin A 对小鼠成纤维细胞系 L-929 的细胞毒性（IC（50）为 0.42 μg mL（-1））比荧光杂合化合物高约两倍，而含有两个 4-香豆酰基的二硫代化合物则没有活性。荧光显微镜显示，4-香豆酰基-α-（羟亚氨基）酰基杂合物被摄取到细胞质中，导致靠近核膜的荧光，最有可能在高尔基氏体中。我们没有观察到细胞核内有强烈的荧光，大多数靶组蛋白去乙酰化酶都位于细胞核内。我们得出结论，二硫键的还原很可能发生在核外。来源于 psammaplin 的巯基在纳摩尔范围内对组蛋白去乙酰化酶表现出很强的活性，但细胞毒性降低。还确定了新衍生物的抗菌活性。
