Fundamental relationships between structure, reactivity, and biological activity for the duocarmycins and CC-1065.
Fundamental relationships between structure, reactivity, and biological activity for the duocarmycins and CC-1065.
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DOI：
10.1021/jm9006214
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发表时间：
2009-10-08
影响因子：
7.3
通讯作者：
Boger DL
中科院分区：
文献类型：
--
作者：
MacMillan KS;Boger DL
duocarmycin(1和2)1属于一个小的天然产物家族（图1），还包括yatakemycin(3) 2和CC-1065(4) 3。它们特别有效的细胞毒活性来源于它们在小凹槽中富含at的区域结合和烷基化DNA的能力。4-8这一天然产物家族将一系列显著的分子特征整合到紧凑的结构中，能够同时表达多种功能。就像它们的前辈去霉素和netropsin一样，分子的整体曲率和形状导致它们优先结合在更窄、更深、富含at的小凹槽中，在那里稳定的范德华接触是最大的（形状选择识别）。8-11烷基化亚基乙烯酰胺对交叉共轭的环丙烷具有显著的稳定性。我们已经提出，通过DNA微小凹槽结合诱导的构象变化破坏这种乙烯酰胺偶联，使环丙烷与环己二烯酮偶联，激活其亲核攻击，并为DNA烷基化反应提供催化作用（形状依赖性催化，图2）。值得注意的是，这些化合物在达到其生物靶标之前相对不具有反应性。在那里它们被选择性地激活以进行DNA烷基化（基于靶标的激活）。这类化合物的独特之处在于，这种活化过程没有发生化学变化或分子反应。相反，它只是通过结合引起的化合物的构象变化而发生。定义结构和反应性之间的关键关系以及量化这些影响程度的研究在此详细介绍。与它们独特的激活方法同样重要的是内在反应性和生物效力之间的抛物线关系，这是通过研究天然产物和众多合成类似物而得出的（图3）。这大概反映了化合物需要足够的稳定性才能达到其生物目标，而一旦达到目标，就需要足够的反应性才能有效地烷基化DNA。这种抛物线关系的建立定义了这类天然产物的反应性和稳定性的最佳平衡，以及旨在定义这种抛物线关系并加以利用的关键研究
The duocarmycins (1 and 2) 1 belong to a small family of natural products (Figure 1) that also include yatakemycin (3) 2 and CC-1065 (4). 3 Their exceptionally potent cytotoxic activity is derived from their ability to bind and alkylate DNA in AT-rich regions of the minor groove. 4-8 This family of natural products incorporates a remarkable set of molecular features integrated into compact structures capable of simultaneously expressing multiple functions. 9 Much like their predecessors distamycin and netropsin, the overall curvature and shape of the molecules lead to their preferential binding in the narrower, deeper, AT-rich minor groove where stabilizing van der Waals contacts are maximized (shape-selective recognition). 8-11 The alkylation subunit vinylogous amide conveys a remarkable stability to a cross-conjugated and otherwise reactive cyclopropane. We have suggested that the disruption of this vinylogous amide conjugation by way of a DNA minor groove binding-induced conformational change brings the cyclopropane into conjugation with the cyclohexadienone, activating it for nucleophilic attack, and provides the catalysis for the DNA alkylation reaction (shape-dependent catalysis, Figure 2). 8, 12, 13 Significantly, these compounds are relatively unreactive until they reach their biological target, where they are selectively activated for DNA alkylation (target-based activation). 14 Unique to this class, this activation occurs without a chemical change or reaction of the molecule. Rather, it occurs simply through a binding-induced conformational change in the compound. Studies that define the key relationships between structure and reactivity and quantitate the magnitude of these effects are detailed herein.Just as important as their unique method of activation is a parabolic relationship between intrinsic reactivity and biological potency that has emerged from studying the natural products and numerous synthetic analogues (Figure 3). 15 Presumably this reflects the requirement for sufficient stability for the compounds to reach their biological target balanced against the need for sufficient reactivity to efficiently alkylate DNA once they do. Establishment of this parabolic relationship defined what this optimal balance of reactivity and stability is for this class of natural products, and key studies designed to define this parabolic relationship and exploit
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影响因子：
2.7
作者：
Boger, DL;Goldberg, J;McKie, JA
通讯作者：
McKie, JA
影响因子：
3.6
作者：
Boger, DL;Turnbull, P
通讯作者：
Turnbull, P
影响因子：
3.6
作者：
Boger, DL;Garbaccio, RM
通讯作者：
Garbaccio, RM
影响因子：
3.6
作者：
Boger, DL;Han, NH;Kitos, PA
通讯作者：
Kitos, PA
影响因子：
3.6
作者：
Boger, DL;Turnbull, P
通讯作者：
Turnbull, P