Semisynthetic pyrrolizidine alkaloid N-oxide antitumor agents. Esters of heliotridine.
Semisynthetic pyrrolizidine alkaloid N-oxide antitumor agents. Esters of heliotridine.
复制标题
半合成吡咯里西啶生物碱 N-氧化物抗肿瘤剂。
DOI：
10.1021/jm00403a008
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发表时间：
1988
影响因子：
7.3
通讯作者：
Powis,G
中科院分区：
文献类型：
--
作者：
Zalkow,LH;Glinski,JA;Gelbaum,LT;Moore,D;Melder,D;Powis,G
制备了天芥菜碱与(S)-(+)-和(R)-(-)-2-羟基-2-苯基丁酸的C-9和C-7单酯以及C-7,C-9二酯，转化成它们的A-氧化物，并在体内P388淋巴细胞白血病筛查中与相应的retronecine C-9单酯进行比较。还通过使用软琼脂集落形成测定法测量了一些游离碱及其相应的A-氧化物针对A204横纹肌肉瘤细胞系的相对体外细胞毒性。醋栗 C-7 处和醋栗酸 C-2' 处的立体化学似乎对该系统中的抗肿瘤活性具有显着影响。在天芥菜碱系列中，荆芥酸的构型对碳二咪唑酯化反应中的位点选择性（C-7 与 C-9）具有显着影响。提供了对该位点选择性的解释。 据报道，以摩尔计，retronecine (1) 和天芥菜碱 (2) 的二酯的毒性约为各自 C-9 单酯的 4 倍，天芥菜碱 C-9 单酯的毒性是瑞星连碱 C-9 单酯的 2-4 倍。 1 因此，得出的结论是，C-7 处的 an-OH 比 a/3-OH 具有更高的肝毒性。代谢吡咯（例如 3）是在肝脏中由 Cl 处含有双键的吡咯里西啶生物碱产生的，已被确定为细胞毒性剂。 2 3™ 4
The C-9 and C-7 monoesters and C-7, C-9 diesters of heliotridine with (S)-(+)-and (R)-(-)-2-hydroxy-2-phenylbutyric acid were prepared, converted into their A-oxides, and compared with the corresponding C-9 monoesters of retronecine in the in vivo P388 lymphocytic leukemia screen. Relative invitro cytotoxicities of some of the free bases and their corresponding A-oxides were also measured againstthe A204 rhabdomyosarcoma cell line by using the soft agar colony forming assay. Stereochemistry at C-7 of the necine and at C-2'of the necic acid appears to have a significant effect on the antitumor activity in this system. In the heliotridine series, the configuration of the necic acid has a pronounced effect on the site selectivity (C-7 vs C-9) in esterification with carbodiimidazole. An explanation for this site selectivity is offered.It has been reported that, on a molar basis, diesters of retronecine (1) and heliotridine (2) and about 4 times as toxic as the respective C-9 monoesters and heliotridine C-9 monoesters are 2-4 times as toxic as retronecine C-9 mo-noesters. 1 Thus, it was concluded that an-OH at C-7 leads to higherhepatotoxicity than a/3-OH. Metabolic pyrroles such as 3, produced in the liver from pyrrolizidine alkaloids containing a double bond at Cl, have been identified as the cytotoxic agents. 2 3™ 4