Shi Q, Verdier-Pinard P, Brossi A, Hamel E, McPhail A T, Lee K H
Natural Products Laboratory, School of Pharmacy, University of North Carolina at Chapel Hill 27599, USA.
J Med Chem. 1997 Mar 14;40(6):961-6. doi: 10.1021/jm960663k.
A series of novel 7-O-substituted deacetamidothiocolchicine derivatives has been synthesized and evaluated for their inhibitory activity against tubulin polymerization, the binding of [3H]-colchicine to tubulin, and the growth of human Burkitt lymphoma cells. Of these new derivatives, thiocolchicone (8), wherein an acetamido group in thiocolchicine is replaced by a carbonyl oxygen at C(7), was obtained from deacetythiocolchicine (6) by Schiffs base equilibration and acid hydrolysis. Reduction of thiocolchiocone with sodium borohydride yielded the racemic alcohol 9, the structure of which was verified by X-ray crystallographic analysis. Optically pure alcohols 9a,b were obtained by treatment of 9 with the optically pure reagent (1S)-(-)-camphanic chloride followed by chromatographic separation of the camphanate esters and hydrolysis of the diastereomers. X-ray crystallographic analysis established the aS,7S-configuration of 9a. Racemic and optically active esters 11-15, 11a,b, 12a, 14a, and 15a were obtained by esterification of the corresponding alcohols. The compounds showing activity equivalent to or greater than (-)-thiocolchicione (2a) in all the biological assays were three (-)-aS,7S optically pure enantiomers: the alcohol 9a, the acetate 11a (an oxygen isostere of thiocolchicine), and the isonicotinoate 15a. In addition, the ketone 8 and two (-)-aS,7S enantiomers (12a, 14a) had high activity in the biochemical assays with tubulin but reduced antiproliferative activity. In all cases, optically pure isomers with the (-)-aS,7S configuration exhibited greater biological activity than racemic mixtures or isomers or isomers with the (+)-aR,7R configuration.
合成了一系列新型的7 - O - 取代脱乙酰氨基硫代秋水仙碱衍生物，并对其抑制微管蛋白聚合的活性、[3H] - 秋水仙碱与微管蛋白的结合以及人伯基特淋巴瘤细胞的生长进行了评估。在这些新衍生物中，硫代秋水仙酮（8）是通过席夫碱平衡和酸水解从脱乙酰硫代秋水仙碱（6）制得的，其中硫代秋水仙碱中的乙酰氨基在C(7)处被羰基氧取代。用硼氢化钠还原硫代秋水仙酮得到外消旋醇9，其结构通过X射线晶体学分析得以确证。用光学纯试剂(1S)-(-)-樟脑酰氯处理9，然后对樟脑酸酯进行色谱分离并水解非对映异构体，得到光学纯醇9a,b。X射线晶体学分析确定了9a的aS,7S构型。通过相应醇的酯化反应得到了外消旋和光学活性酯11 - 15、11a,b、12a、14a和15a。在所有生物学试验中表现出与(-)-硫代秋水仙酮（2a）相当或更高活性的化合物是三种(-)-aS,7S光学纯对映体：醇9a、乙酸酯11a（硫代秋水仙碱的氧类似物）和异烟碱酸酯15a。此外，酮8和两种(-)-aS,7S对映体（12a、14a）在微管蛋白的生化试验中具有高活性，但抗增殖活性降低。在所有情况下，具有(-)-aS,7S构型的光学纯异构体比外消旋混合物或具有(+)-aR,7R构型的异构体表现出更高的生物学活性。
