School of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Western Road, Cork, Ireland.
Sorbonne Universités, UPMC Univ Paris 06, CNRS USR3151, Kinase Inhibitor Specialized Screening facility, KISSf, Station Biologique, Place Georges Teissier, Roscoff, France.
Bioorg Med Chem. 2018 Aug 7;26(14):4209-4224. doi: 10.1016/j.bmc.2018.07.012. Epub 2018 Jul 9.
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.
本文描述了一系列新型吲哚衍生物作为抗癌剂的合成和生物评价。双吲哚马来酰亚胺模板已被用作一种多功能药效团，用于进行化学多样化研究。从马来酰亚胺开始，首先研究了在端基引入氧（羟马来酰亚胺），并通过筛选激酶抑制活性来评估生物活性，确定取代基衍生的选择性。接下来，将羟马来酰亚胺模板扩展到吲哚氮的取代，再次通过激酶抑制来评估，确定了相对于 GSK-3 和 CDK 激酶的独特选择性模式。随后，使用 NCI-60 细胞筛选评估了双吲哚马来酰亚胺的抗癌活性，揭示了对多种细胞系（如 SNB-75 CNS 癌症、A498 和 UO-31 肾、MDA MB435 黑色素瘤和一组白血病细胞系）的生长抑制谱的发现。通过调节此模板进行选择性激酶抑制的潜力是显而易见的，这将为未来的选择性临床候选药物提供信息。
