Synthesis, chemical properties, and biological evaluation of CC-1065 and duocarmycin analogues incorporating the 5-methoxycarbonyl-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one alkylation subunit
Synthesis, chemical properties, and biological evaluation of CC-1065 and duocarmycin analogues incorporating the 5-methoxycarbonyl-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one alkylation subunit
复制标题
DOI：
10.1021/jo001772g
复制
发表时间：
2001-04-06
影响因子：
3.6
通讯作者：
Hedrick, MP
中科院分区：
文献类型：
--
作者：
Boger, DL;Hughes, TV;Hedrick, MP
描述了 5-甲氧基羰基-1,2,9,9a-四氢环丙[c]苯并[e]吲哚-4-酮 (C5-CO2Me-CBI) 的合成，这是一种带有 C5 甲氧基羰基的取代 CBI 衍生物，及其相应的 5-羟甲基衍生物，旨在建立取代基电子对试剂功能反应性的影响以及由此对其 DNA 烷基化速率的影响。还详细介绍了直接 C5-CO2Me-CBI 前体的拆分及其并入 16 和 17（多卡霉素类似物）的对映体。对 N-BOC-C5-CO2Me-CBI (12) 的溶剂分解反应性和区域选择性的研究表明，C5 甲酯的引入适度减慢了溶剂分解速率 (1.8x，pH 3)，而不改变固有的反应区域选择性 (>20:1)。 C5-CO2Me-CBI和CBI的N-CO2Me衍生物的X射线结构的比较揭示了与反应区域选择性和化合物的相对反应性的相关性。后者与反应性较低的 C5-CO2Me-CBI 具有良好的相关性，表现出缩短的 N2-C2a 键长（1.386 与 1.390 埃）和较小的 chi (1) 二面角（8.1 度与 21.2 度），表明插烯酰胺共轭性更大，并伴随着环丙烷共轭性的减少（交叉共轭）（更短的键长）。 DNA 烷基化特性的建立表明，基于 C5-CO2Me-CBI 的试剂保留了与天然产物相同的烷基化选择性。更重要的是，相对于 CBI，C5 甲酯被发现可降低 DNA 烷基化速率 (0.77x)，这与其固有的较低反应性一致。这些结果表明，之前观察到的 C7 取代 CBI 类似物（包括 CCBI (7-cyano-CBI)）DNA 烷基化速率的增加与基于其固有反应性的预期相反。与 17 不同，其中 C5 甲酯不结合在小沟中，C7 取代基位于小沟中，延长了试剂的刚性长度，进一步增强了 DNA 结合诱导的构象变化，该构象变化负责激活亲核攻击和催化 DNA 烷基化反应。
The synthesis of 5-methoxycarbonyl-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (C5-CO2Me-CBI), a substituted CBI derivative bearing a C5 methoxycarbonyl group, and its corresponding 5-hydroxymethyl derivative are described in efforts to establish substituent electronic effects on the agents' functional reactivity and the resulting effect this has on their rate of DNA alkylation. Resolution of an immediate C5-CO2Me-CBI precursor and its incorporation into both enantiomers of 16 and 17, analogues of the duocarmycins, are also detailed. A study of the solvolysis reactivity and regioselectivity of N-BOC-C5-CO2Me-CBI (12) revealed that the introduction of a C5 methyl ester modestly slowed the rate of solvolysis (1.8x, pH 3) without altering the inherent reaction regioselectivity ( >20:1). The comparison of the X-ray structures of the N-CO2Me derivatives of C5-CO2Me-CBI and CBI revealed correlations with the reaction regioselectivity and the relative reactivity of the compounds. The latter correlated well with the less reactive C5-CO2Me-CBI exhibiting a shortened N2-C2a bond length (1.386 vs 1.390 Angstrom) and smaller chi (1) dihedral angle (8.1 degrees vs 21.2 degrees) indicative of greater vinylogous amide conjugation and was accompanied by a diminished (cross-conjugated) cyclopropane conjugation (shorter bond lengths). Establishment of the DNA alkyation properties revealed that C5-CO2Me-CBI-based agents retained the identical alkylation selectivity of the natural products. More importantly, the C5 methyl ester was found to decrease the rate (0.77x) of DNA alkylation relative to CBI, consistent with its inherent lower reactivity. These results indicate that the previously observed increase in the rate of DNA alkylation for C7-substituted CBI analogues including CCBI (7-cyano-CBI) is contrary to expectations based on their inherent reactivities. Unlike 17, in which the C5 methyl ester does not bind in the minor groove, the C7 substituent lies in the minor groove extending the rigid length of the agents, further enhancing the DNA binding-induced conformational change responsible for activation toward nucleophilic attack and catalysis of the DNA alkylation reaction.