Isolation and structural modification of 7-deoxynarciclasine and 7-deoxy-trans-dihydronarciclasine
Isolation and structural modification of 7-deoxynarciclasine and 7-deoxy-trans-dihydronarciclasine
复制标题
DOI：
10.1021/np058068l
复制
发表时间：
2006-01-01
影响因子：
5.1
通讯作者：
Bell, JA
中科院分区：
文献类型：
--
作者：
Pettit, GR;Eastham, SA;Bell, JA
作为 pancratistatin (1) 结构-活性关系研究的延伸，首先评估了用于分离从 Hymenocallis littoralis 中分离的 7-脱氧水仙素 (2b) 和 7-脱氧-反式-二氢水仙素 (3a) 混合物的各种技术。对于原本困难的分离，一种有效的解决方案是内酰胺羰基化。待使用氢化铝锂还原的受保护的(4c和5c)醇2b和3a的基团。甲硅烷基酯/丙酮化物保护的 6a 裂解（TBAF，然后用 H2SO4）得到胺 8。采用 X 射线晶体结构测定来确认 3,4-丙酮化物-5-氮杂-6-脱氧水仙环素 (6b)、5-氮杂-6-脱氧水仙环素 (8a) 和 5-氮杂-6-脱氧-反式-二氢水仙环素 (9a, 9b)。针对鼠 P388 淋巴细胞白血病和一组人类癌细胞系，发现母体天然产物 7-脱氧水仙环素 (2b) 和 7-脱氧-反式-二氢水仙环素 (3a) 通常比具有结构修饰的化合物具有更强的癌细胞生长抑制作用（GI(50) 0.1 至 < 0.01 μg/mL） 作为胺 8 的 10 倍或更多。异卡巴斯蒂利 3a 的反式环连接被证明是水仙环素 (2a) 的重要修饰，可改善该系列中的癌细胞生长抑制。
As an extension of structure-activity relationship studies of pancratistatin (1), various techniques were first evaluated for separating the mixtures of 7-deoxynarciclasine (2b) and 7-deoxy-trans-dihydronarciclasine (3a) isolated from Hymenocallis littoralis. An efficient solution for that otherwise difficult separation then allowed the lactam carbonyl. Group of protected (4c and 5c) alcohols 2b and 3a to be reduced employing lithium aluminum hydride. Cleavage (TBAF followed by H2SO4) of the silyl ester/acetonide protected 6a gave amine 8. X-ray crystal structure determinations were employed to confirm the structures of 3,4-acetonide-5-aza-6-deoxynarciclasine (6b), 5-aza-6-deoxynarciclasine (8a), and 5-aza-6-deoxy-trans-dihydronarciclasine (9a, 9b). Against the murine P388 lymphocytic leukemia and a panel of human cancer cell lines, the parent natural products, 7-deoxynarciclasine (2b) and 7-deoxy-trans-dihydronarciclasine (3a), were found to generally be more cancer cell growth inhibitory (GI(50) 0.1 to < 0.01 mu g/mL) than the compounds with structural modifications such as amine 8 by a factor of 10 or more. The trans ring juncture of isocarbostyril 3a proved to be an important modification of narciclasine (2a) for improving cancer cell growth inhibition in this series.