Synthesis and bioactivity evaluation of novel CDK8 inhibitors with steroid structure
OBJECTIVE Steroid derivatives with novel structures and cyclin-dependent kinase 8(CDK8)inhibitory activity were synthesized to provide lead compounds for the development of novel anti-tumor drugs.METHODS Pregnenolone was used as the starting material,and the steroid C-17 and C-3 positions were modified by the key Sonogashira alkyne coupling reaction and amine group introduction,respectively.The prepared compounds were tested for IC50 of the CDK8 kinase.RESULTS Ten targeted molecules were synthesized,among which compound Ⅰe exhibited the strongest kinase inhibitory activity(IC50=18 nmol·L-1).CONCLUSION By optimizing the structure of steroid,new compounds with potent CDK8 kinase inhibitory activity were obtained,which can provide reference for the development of anti-tumor drugs.
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