Antonow Dyeison, Jenkins Terence C, Howard Philip W, Thurston David E
Cancer Research UK Gene Targeted Drug Design Research Group, The School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1N 1AX, UK.
Bioorg Med Chem. 2007 Apr 15;15(8):3041-53. doi: 10.1016/j.bmc.2007.01.054. Epub 2007 Feb 2.
A 23-member C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione (PBD dilactam) library has been synthesized using Suzuki coupling, and the effect of base upon racemisation 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).
通过铃木耦合反应合成了一个由23个成员组成的C2-芳基吡咯并[2,1-c][1,4]苯并二氮杂卓-5,11-二酮（PBD双内酰胺）文库，并研究了碱对交叉偶联反应过程中C11a位外消旋化的影响。在NCI的初步筛选中，文库中的三个成员（21、30和33）具有足够的细胞毒性，值得进一步评估，并且发现其中一个（30，R = 对溴）在A498肾癌细胞系中在亚微摩尔水平具有细胞毒性。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双内酰胺（6）相比，在PBD双内酰胺骨架中引入C2-C3不饱和键和添加C2-芳基官能团可显著增强螺旋稳定性。
