Synthesis and biological evaluation of a series of novel indole derivatives as anticancer agents is described. A bisindolylmaleimide template has been derived as a versatile pharmacophore with which to pursue chemical diversification. Starting from maleimide, the introduction of an oxygen to the headgroup (hydroxymaleimide) was initially investigated and the bioactivity assessed by screening of kinase inhibitory activity, identifying substituent derived selectivity. Extension of the hydroxymaleimide template to incorporate substitution of the indole nitrogens was next completed and assessed again by kinase inhibition identifying unique selectivity patterns with respect to GSK-3 and CDK kinases. Subsequently, the anticancer activity of bisindolylmaleimides were assessed using the NCI-60 cell screen, disclosing the discovery of growth inhibitory profiles towards a number of cell lines, such as SNB-75 CNS cancer, A498 and UO-31 renal, MDA MB435 melanoma and a panel of leukemia cell lines. The potential for selective kinase inhibition by modulation of this template is evident and will inform future selective clinical candidates.

描述了一系列新型的吲哚衍生物作为抗癌剂的合成和生物学评价。bisindolylmaleimide模板已作为一种通用的药效团，可以用来进行化学多样化。从马来酰亚胺开始，最初研究了向头基（羟基马来酰亚胺）中引入氧，并通过筛选激酶抑制活性，鉴定取代基衍生的选择性来评估生物活性。接下来完成羟基马来酰亚胺模板的延伸以结合吲哚氮的取代，并通过激酶抑制再次评估，从而鉴定针对GSK-3和CDK激酶的独特选择性模式。随后，使用NCI-60细胞筛选评估了比辛多利马来酰亚胺的抗癌活性，公开了针对许多细胞系，例如SNB-75 CNS癌，A498和UO-31肾，MDA MB435黑素瘤和一组白血病细胞系的生长抑制谱的发现。通过调节该模板选择性抑制激酶的潜力是显而易见的，并将为将来的选择性临床候选药物提供参考。