Preparation of Physalins Possessing High Antitumor Activity

Physalin N and Physalin O were isolated from the extracts of epigeal part of Physalis alkekengi var。francheti （日语名称： Hozuki）。Based on ^1 H and ^<13>C NMR spectral analysis physalin N was assumed to be 7 alpha-hydroxy 1 derivative of physalin B.类似地，物理素O被假定为25、27--物理素A的二氢衍生物。通过催化氢化生理素O获得预期的7-脱氢-2， 3， 5， 6， 25，27-六氢生理素A，和酸-2，7-二氢生理素M的催化脱氢，已知的生理素L的脱氢产物。因此，物理素的结构已经稳定，如（25 S）-25，27-二氢物理素是不平等的。另一种固定的、有意地命名的蛋白质P也是孤立的，并且它的^<13>C核磁共振特别指示，蛋白质P不可能有普通的蛋白质骨架，而是一种反向结构称为新蛋白蛋白骨架。核磁共振、紫外线和CD光谱分析及其衍生物对已知4，7-二氢神经素B的化学转化已稳定为5 α-羟基-6，7-二氢神经素-5，6-二氢神经素B的拮抗剂活性及其衍生物已被测试过，并已提出了后续结构-活性关系：（i）环A中的结合环己酮对活动非常重要。（ii）α-羟基和α-环氧基团在活动中标记为“A”或“B”。iii）β-羟基和β-环氧基团在环中增加或不影响活动。甲基氧化物桥C（14）-O-C（27）和双键C（25）=C（27）和物理素骨架的重要性并不确定。基于以上结构-活性关系的高分子设计和合成方法的准备。

Physalin N and physalin O were isolated from the extracts of epigeal part of Physalis alkekengi var. francheti (Japanese name : Hozuki). Based on ^1H and ^<13>C NMR spectral analysis physalin N was assumed to be 7alphaーhydroxy1 derivative of physalin B. Similarly, physalin O was assumed to be 25, 27-dihydro derivative of physalin A. Upon catalytic hydrogenation physalin O gave the expected 7-dehydroxyー2, 3, 5, 6, 25, 27-hexahydrophysalin A, and acidーcatalyzed dehydration of physalin O afforded 2, 7-didehydrophysalin M, the already known dehydration product of physalin L. Thus, the structure of physalin O has been established as (25S)-25, 27-dihydrophysalin A unequivocally. Another constituent, tentatively named physalin P, was also isolated and its ^<13>C NMR spectra indicated that physalin P did not possess usual physalin skeleton but the rearranged structure called neophysalin skeleton. NMR, UV, and CD spectral analyses and the chemical transformation to the known 4, 7-didehydroneophysalin B have established the structure of physalin P to be 5alpha-hydroxy-6, 7-didehydro-5, 6-dihydroneophysalin B.Antitumor activities of physalins and their derivatives were tested against HeLa cells, and the following structure-activity relationships have been proposed : i) Conjugated cyclohexenone at ring A is very important to the activity. ii) alpha-Hydroxy and alpha-epoxy groups at ring A or B markedly decrease the activity. iii) beta-hydroxy and beta-epoxy groups at ring A increase or do not affect the activity. Importance of methylene oxide bridge C(14)-O-C(27) and double bond C(25)=C(27) and of physalin skeleton are not certain.Molecular design and synthetic approach towards the preparation of highly active physalins based on the above structure-activity relationship are being undertaken.