The Duocarmycins: Synthetic and Mechanistic Studies
The Duocarmycins: Synthetic and Mechanistic Studies
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双卡霉素：合成和机理研究
DOI：
10.1002/chin.199525306
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发表时间：
1995
期刊：
影响因子：
--
通讯作者：
D. Boger
中科院分区：
文献类型：
--
作者：
D. Boger
最近的两项工作描述了一类新的特别有效的抗肿瘤抗生素的初始成员的分离和结构测定，所述抗生素包括倍癌霉素SA（1）、1，2A（2）、3-5 B1-B2，6和C1-C2。4 '5，7' 8鉴于它们与（+）-CC-1065（3）9-16及其相关类似物的显著效力和结构相似性，已经进行了13-22次实质性的努力来定义它们的性质。22-48在这些研究中，这些药物已被证明通过DNA的序列选择性烷基化发挥其生物学作用。26-31已发现腺嘌呤N3与最少取代的环丙烷碳的可逆30立体电子控制34加成发生在DNA小沟中所选的富含AT的位点内，27，31，并且已经进行了大量的努力来确定DNA烷基化选择性的起源，以建立DNA烷基化与随后的生物学性质之间的联系，32，40和定义结构，化学反应性和生物活性之间关系的基本原则。在这里，我们提供了一个总结的研究进行的意图，解决这些重要的问题的功能反应性和分子识别。多卡霉素SA（1）和多卡霉素A（2）的全合成。尽管人们对倍癌霉素及其显著的性质感兴趣，但对其合成的成功努力42 -48以及将该技术扩展到相关试剂的努力受到限制。21，26，27，31，33-35对于倍癌霉素SA（1），这是特别令人惊讶的，因为与2不同，它的分离量不足以进行详细的评价
Two recent efforts have described the isolation and structure determination of the initial members of a new class of exceptionally potent antitumor antibiotics including duocarmycinsSA (l), 1, 2 A (2), 3-5 B1-B2, 6and C1-C2. 4’5, 7’8 Given their remarkable potency and structural similarity to (+)-CC-1065 (3) 9-16 and its related analogs, 13-22 substantial efforts have been devoted to defining their properties. 22-48 In these studies, the agents have been shown to exert their biological effects through a sequence selective alky-lation of DNA. 26-31 The reversible, 30 stereoelectronically-controlled34 adenine N3 addition to the least substituted cyclopropane carbon has been found to occur within selected AT-rich sites in the minor groove of DNA, 27, 31 and extensive efforts have been devoted to determining the origin of the DNA alkylation selectivity, to establishing the link between DNA alkylation and the ensuing biological properties, 32, 40 and to defining the fundamental principles under-lying the relationships between structure, chemical reactivity, and biologicalactivity. Herein, we provide a summary of studies conducted with the intention of addressing these important questions of functional reactivity and molecular recognition. Total Synthesis of Duocarmycin SA (1) and Duocarmycin A (2). Despite the interest in the duocarmycins and their remarkable properties, suc-cessful efforts on their synthesis42-48 and the extension of the technology to related agents havebeen limited. 21, 26, 27, 31, 33-35 This is especially surprising with duocarmycin SA (1) since it, unlike 2, was isolated in insufficient quantity to permit a detailed evaluation