Synthesis of a novel C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione library:: Effect of C2-aryl substitution on cytotoxicity and non-covalent DNA binding
Synthesis of a novel C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione library:: Effect of C2-aryl substitution on cytotoxicity and non-covalent DNA binding
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DOI：
10.1016/j.bmc.2007.01.054
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发表时间：
2007-04-15
影响因子：
3.5
通讯作者：
Thurston, David E.
中科院分区：
文献类型：
--
作者：
Antonow, Dyeison;Jenkins, Terence C.;Thurston, David E.
采用Suzuki偶联法合成了一个23元的c2 -芳基吡咯[2,1 -c][1,4]苯二氮卓-5,1 -二酮（PBD dilactam）文库，并研究了交叉偶联反应中碱对c11a位消旋化的影响。三个文库成员（21,30和33）在NCI的初步筛选中具有足够的细胞毒性，值得进一步评估，其中一个（30,R = p-Br）在A498肾癌细胞系中被发现具有亚微摩尔水平的细胞毒性。DNA热变性研究表明，这种活性可能与非共价DNA相互作用有关，并且还表明，与未取代的PBD dilactam相比，在PBD dilactam骨架上引入C2-C3不饱和和添加c2 -芳基功能显著增强了螺旋稳定性(6)。(c) 2007 Elsevier Ltd。版权所有。
A 23-member C2-aryl pyrrolo[2, 1-c][ 1,4]benzodiazepine-5,1 1-dione (PBD dilactam) library has been synthesized using Suzuki coupling, and the effect of base upon racernisation at the C11a-position during the cross-coupling reaction studied. Three library members (21, 30 and 33) were sufficiently cytotoxic in the NCI's preliminary screen to warrant further evaluation, and one (30, R = p-Br) was found to be cytotoxic at the sub-micromolar level in the A498 renal cancer cell line. DNA thermal denaturation studies suggested that this activity may be associated with non-covalent DNA interaction, and also demonstrated that introduction of C2-C3 unsaturation and addition of C2-aryl functionalities to the PBD dilactam skeleton significantly enhanced helix stabilisation compared to the unsubstituted PBD dilactam (6). (c) 2007 Elsevier Ltd. All rights reserved.