The Synthesis And Bioactivity Study Of Imatinib Analoges And An Oridonin Derivative

Partâ… The synthesis and bioactivity study of Imatinib analogesImatinib mesylate targets tyrosine kinase BCR-ABL and has been demonstrated good efficacy in treating chronic myloid leukemia clinically; however, most patients treated with Imatinib still harbor molecular residue disease and some develop resistance due to ABL kinase domain mutations.To develop novel BCR-ABL kinase inhibitor, we have designed 12 novel Imatinib analoges through modifications of the side chains.We have synthesized compounds and screened them in K562 Cell line, and one of the compounds showed good activity. We summarized the Structure-Activity Relationship of Imatinib analogues based on the result, and it gives us insight for the further modification of Imatinib.Partâ…¡The syntheses and biological activity of 7, 14-OH Oridonin derivativesWe obtained 7, 14-OH Oridonin derivative (Ori-01) through semi-synthesis. This synthesis route leads to the desired compounds in generally high yield.Ori-01 has improved activity comparing to Oridonin in the study of inhibiting the proliferation of Kasumi-1 cells. Ori-01 is showed to induce Kasumi-1 cell differentiation at low concentrations and promote the degradation of the fusion protein AML1-ETO, which is resulted from t(8; 21).In conclusion, Ori-01 could be developed as a promising novel anti-leukemia drug.