Design, Synthesis And Anti-breast Cancer Activity Of Endoperoxygenase CDK 4/6 Inhibitor

Breast cancer has recently risen to the top of the incidence of malignant tumors in the world and become the most common cause of death for women.The health of Chinese women is also seriously threatened by the disease.The clinical features of breast cancer suggest that it is a highly heterogeneous disease with diverse molecular subtypes.The classified therapies based on different molecular subtypes have greatly reduced the mortality of breast cancer,but its morbidity remains high,and the problems of recurrence,metastasis or drug resistance after treatment remain.Cyclin-dependent kinase 4/6（CDK 4/6）plays a significant role in the regulation of the cell cycle and becomes a key target for breast cancer therapy.CDK 4/6 inhibitors have shown breakthrough efficacy in patients with breast cancer,so these inhibitors such as palbociclib,ribociclib,abemaciclib,and dalciclib have been approved for the treatment of patients with advanced or metastatic breast cancer.On the other hand,endoperoxides represented by artemisinin-type antimalarials exhibit significant antitumor activity.1,2-dioxane endoperoxides derived from the marine natural product plakortin exhibit significant antimalarial effects similar to artemisinins,but the antitumor activity of this class of compounds has not been reported.Therefore,based on the structure-activity relationship analysis of the marketed CDK4/6 inhibitors,the 1,2-dioxane with the endoperoxide structure was assembled with the active fragment（pyrido/pyrrolo[2,3-d]pyrimidine structure）in the structure of the CDK4/6 inhibitors palbociclib and ribociclib.Therefore,a series of1,2-dioxane-pyrido[2,3-d]pyrimidine derivatives and 1,2-dioxane-pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized in order to find more efficient anti-breast cancer compounds.A series of new 1,2-dioxane intermediates were synthesized from methyl acetoacetate,substituted alkenes and oxygen through cyclization,methylation and reduction.After coupling with pyrido/pyrrolo[2,3-d]pyrimidine fragments,novel 1,2-dioxane derivatives,1,2-dioxane-pyrido[2,3-d]pyrimidine derivatives and 1,2-dioxane-pyrrolo[2,3-d]pyrimidine derivatives were obtained.The structures of all compounds were confirmed by ¹H-NMR,¹³C-NMR,IR,MS and HRMS data.Breast cancer cells（T47D and MDA-MB-436）,normal breast cells（MCF-10A）and CDK6/Cyclin D3 kinase were used to evaluate the biological activity of the new compound.The results showed that compound SB2 had a significant anti-proliferation activity against breast cancer cells(T47D GI₅₀ = 8.42±0.93 μM,MDA-MB-436 GI₅₀= 18.74±1.78 μM),and its activity was close to that of positive control drug palbociclib.In addition,all the newly synthesized compounds had no significant toxicity to normal breast cells.The CDK6/Cyclin D3 kinase assay showed that the kinase inhibitory activities of compounds SB1(IC₅₀ = 0.126±0.018 μM)and SC7(IC₅₀ = 0.109±0.007 μM)were slightly weaker than that of positive control drug palbociclib.