Remarkable enhancement in the DNA-binding ability of C2-fluoro substituted pyrrolo[2,1-c][1,4] benzodiazepines and their anticancer potential
Remarkable enhancement in the DNA-binding ability of C2-fluoro substituted pyrrolo[2,1-c][1,4] benzodiazepines and their anticancer potential
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DOI：
10.1016/j.bmc.2008.12.068
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发表时间：
2009-02-15
影响因子：
3.5
通讯作者：
Sastry, G. Narahari
中科院分区：
文献类型：
--
作者：
Kamal, Ahmed;Rajender;Sastry, G. Narahari
设计并合成了c2 -氟取代DC-81及其二聚体，该二聚体由两个c2 -氟取代DC-81亚基通过简单的烷烃间隔剂和对称的烷基氧基间隔剂侧臂的哌嗪部分连接到c8位置。这些氟取代吡咯[2,1-c][1,4]苯二氮卓类药物具有显著的dna结合能力，大多数具有良好的抗癌活性，其GI（50）值在微摩尔至纳摩尔浓度范围内。DNA热变性研究表明，这些化合物中的一些（14a-c和15）在28.9-38℃范围内增加了δ T-m值，这一点被限制性内切酶研究进一步证实。本研究表明，与DSB-120和SJG-136 （δ T-m = 10.2和25.7℃）相比，除了在烷基氧基连接体之间加入哌嗪环外，在c2位置引入氟取代对于增强dna结合能力的重要性。此外，在这类二聚体中，dna结合能力与氟取代的变化已经通过分子模型研究进行了研究。一些代表性的c2 -氟取代二聚体（8a和14a）在美国国家癌症研究所（NCI）的60种癌细胞系试验中也显示出显著的抗癌活性。(c) 2009 Elsevier Ltd.版权所有。
C2-Fluoro substituted DC-81, and its dimers that comprise of two C2-fluoro substituted DC-81 subunits tethered to their C8-position through simple alkane spacers as well as piperazine moiety side-armed with symmetrical alkyloxy spacers have been designed and synthesized. These fluoro substituted pyrrolo[2,1-c][1,4] benzodiazepines have shown remarkable DNA-binding ability and most of them possess promising anticancer activity, having GI(50) values in micromolar to nanomolar concentration range. DNA thermal denaturation studies show that some of these compounds (14a-c and 15) increase the Delta T-m values in the range of 28.9-38 degrees C, and this is further confirmed by the restriction endonuclease studies. This study illustrates the importance of introducing fluoro substitution at the C2-position apart from the incorporation of a piperazine ring in between the alkyloxy linker for enhancement of the DNA-binding ability in comparison to DSB-120 and SJG-136 (Delta T-m = 10.2 and 25.7 degrees C). Moreover, the variations in the DNA-binding ability with respect to fluoro substitution in this class of dimers has been investigated by molecular modeling studies. Some representative C2-fluoro substituted dimers (8a and 14a) have also exhibited significant anticancer activity in the 60 cancer cell line assay of the National Cancer Institute (NCI). (c) 2009 Elsevier Ltd. All rights reserved.