Department of Chemistry, University of York, Heslington, York Y01 5DD, UK.
Carcinogenesis. 1980 Jan;1(1):79-90. doi: 10.1093/carcin/1.1.79.
A number of aflatoxin B1 (AFB1) derivatives have been synthesized including 8-acyloxy- and 8-benzoyloxy-9-hydroxy-8,9-dihydro-AFB1 compounds, AFB1-8,9-diol and [3H] AFB1 labelled at the 9 position. AFB1-hydroxyesters appear to be models of AFB1-8,9-oxide in that they are bacterial mutagens, stimulate unscheduled DNA synthesis in HeLa cells and react with DNA to give trans-8,9-dihydro-8(7-guanyl)-9-hydroxy-AFB1 as the major adduct after hydrolysis. The potency of the hydroxyesters increases with ease of release of the ester grouping at position 8. Absence of the hydroxyl at position 9 gives compounds which are readily hydrolysed in water but are not biologically active. The hydroxyesters hydrolyse in water to give AFB1-diol, providing a convenient means of synthesis of this compound. Studies with AFB1-diol show that it reacts with one molecule of Tris base, probably through the ring-opened furan form, with the amino group of the Tris. Acidification results in ring closure in an analogous manner to AFB1-diol. AFB1-diol binds to DNA in vitro as well as to liver slice DNA. The compound is mutagenic towards S. typhimurium TA100 without metabolic activation. The implications of these findings are discussed in relation to the mechanisms of AFB1 carcinogenicity.
已经合成了许多黄曲霉毒素 B1（AFB1）衍生物，包括 8-酰氧基-和 8-苯甲酰氧基-9-羟基-8,9-二氢-AFB1 化合物、AFB1-8,9-二醇和在 9 位标记的[3H]AFB1。AFB1-羟基酯似乎是 AFB1-8,9-氧化物的模型，因为它们是细菌诱变剂，刺激 HeLa 细胞的非计划 DNA 合成，并与 DNA 反应生成反式 8,9-二氢-8（7-鸟苷）-9-羟基-AFB1 作为主要加合物在水解后。羟基酯的效力随着在 8 位释放酯基的容易程度而增加。在 9 位不存在羟基会产生在水中容易水解但没有生物活性的化合物。羟基酯在水中水解生成 AFB1-二醇，为合成该化合物提供了一种方便的方法。AFB1-二醇的研究表明，它与三羟甲基氨基甲烷（Tris）的一个分子反应，可能通过开环呋喃形式与 Tris 的氨基反应，酸化以类似于 AFB1-二醇的方式导致环闭合。AFB1-二醇在体外与 DNA 结合，与肝切片 DNA 结合。该化合物在未经代谢激活的情况下对 S. typhimurium TA100 具有致突变性。这些发现的意义在讨论 AFB1 致癌性的机制时进行了讨论。
