Thurston D E, Bose D S, Howard P W, Jenkins T C, Leoni A, Baraldi P G, Guiotto A, Cacciari B, Kelland L R, Foloppe M P, Rault S
CRC Gene Targeted Drug Design Research Group, School of Pharmacy and Biomedical Sciences, University of Portsmouth, St. Michael's Building, White Swan Road, Portsmouth, Hants P01 2DT, U.K.
J Med Chem. 1999 Jun 3;42(11):1951-64. doi: 10.1021/jm981117p.
Several A-ring-modified analogues of the DNA-binding antitumor agent DC-81 (5) have been synthesized in order to study structure-reactivity/cytotoxicity relationships. For two molecules (23 and 30) the modifications required the addition of a fourth ring to give the novel dioxolo[4,5-h]- and dioxano[5,6-h]pyrrolo[2,1-c][1, 4]benzodiazepin-11-one (PBD) ring systems, respectively. Another three analogues (34, 38, and 48) have the native benzenoid A-ring replaced with pyridine, diazine, or pyrimidine rings to give the novel pyrrolo[2,1-c][1,4]pyridodiazepine, pyrrolo[2,1-c][1, 4]diazinodiazepine, and pyrrolo[2,1-c][1,4]pyrimidinodiazepine systems, respectively. The other new analogues (16a,b) have extended chains at the C8-position of the DC-81 structure. During the synthesis of these compounds, a novel tin-mediated regiospecific cleavage reaction of the dioxole intermediate 18 was discovered, leading to the previously unknown iso-DC-81 (20). In addition, an unusual simultaneous nitration-oxidation reaction of 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (8) was found to produce 3-(4-carboxy-2-methoxy-5-nitrophenoxy)propanoic acid (9), a key intermediate, in high yield. In general, the results of cytotoxicity and DNA-binding studies indicated that none of the changes made to the A-ring of the PBD system significantly improved either binding affinity or cytotoxicity in comparison to DC-81. This result suggests that the superior potency of natural products such as anthramycin (1), tomaymycin (2), and sibiromycin (3) is due entirely to differences in C-ring structure, and in particular exo or endo unsaturation at the C2-position and C2-substituents containing unsaturation. This study also provided information regarding the influence of A-ring substitution pattern on the relative stability of the interconvertible N10-C11 carbinolamine, carbinolamine methyl ether, and imine forms of PBDs.
为了研究结构-反应活性/细胞毒性关系，已合成了几种DNA结合抗肿瘤剂DC-81（5）的A环修饰类似物。对于两个分子（23和30），修饰需要添加第四个环，分别得到新型的二氧杂环戊烯并[4,5-h]-和二氧杂环己烷并[5,6-h]吡咯并[2,1-c][1,4]苯并二氮杂卓-11-酮（PBD）环系。另外三个类似物（34、38和48）具有将天然苯环A环分别替换为吡啶、二嗪或嘧啶环，从而分别得到新型的吡咯并[2,1-c][1,4]吡啶并二氮杂卓、吡咯并[2,1-c][1,4]二嗪并二氮杂卓和吡咯并[2,1-c][1,4]嘧啶并二氮杂卓体系。其他新类似物（16a,b）在DC-81结构的C8位具有延长链。在这些化合物的合成过程中，发现了二氧杂环戊烯中间体18的一种新型锡介导的区域特异性裂解反应，得到了以前未知的异-DC-81（20）。此外，发现4-(3-羟基丙氧基)-3-甲氧基苯甲酸（8）发生了异常的同时硝化-氧化反应，以高产率生成了关键中间体3-(4-羧基-2-甲氧基-5-硝基苯氧基)丙酸（9）。总体而言，细胞毒性和DNA结合研究结果表明，与DC-81相比，对PBD体系A环所做的任何改变均未显著提高结合亲和力或细胞毒性。该结果表明，诸如安曲霉素（1）、托马霉素（2）和西伯利亚霉素（3）等天然产物的卓越效力完全归因于C环结构的差异，特别是C2位的外或内不饱和以及含有不饱和键的C2取代基。本研究还提供了有关A环取代模式对PBD可相互转化的N10-C11氨基醇、氨基醇甲醚和亚胺形式相对稳定性影响的信息。
