Structure Optimizations And The Investigation Of Anti-Multi-Drug Resistance Of Indole-Chalcones

Chalcone,or 1,3-diphenyl-2-propen-1-one,is the main precursor for the biosynthesis of flavonoids and isoflavones.It has various pharmacological properties,however,it is limited to further clinical studies due to its multiple targets and unclear mechanism of action.In the early stage,a series of chalcone derivatives were designed and synthesized,and their anti-tumor target was firstly identified as microtubule protein by clicking chemical-photoaffinity in situ labeling technology.In the first part,seven indole-chalcone analogues were tentatively synthesized,and the indole-chalcone derivative FC77 with excellent anti-tumor multi-drug resistance activity was obtained.Further mechanism studies showed that FC77 could block cells in G2/M phase,directly bind to microtubules and inhibit microtubules dynamics.In the second part,31 derivatives of FC77 with three scaffold templates was obtained,showing significant multidrug resistance activity against colorectal cancer.Structure-activity relationship studies showed that: 1)indolyl and ?-methyl substitution are the key pharmacophore to anti-tumor and anti-tumor resistance;2)trimethoxy on the benzene ring can greatly enhance the anti-tumor activity;3)the 4-and 5-site substitutions on the indole ring are favorable against tumor activity.Biological activity showed that FC116 had a strong sensitivity to a variety of cancer cells,especially drug-resistant colorectal cancer cells,and had a synergistic effect with oxaliplatin.Mechanism studies showed that FC116 can effectively inhibit microtubule aggregation and block cells in the G2/M phase by down-regulating the expression of Cyclin B1.In vivo,FC116 significantly suppressed tumour growth,achieving 78% at the dose of 3 mg/kg.All results indicated that FC116 was deserved further investigations for cancer therapy.