Synthesis And Antitumor Activity Study Of Pyrrolidinyl Benzimidazole Carboxamide Derivatives

Breast cancer and ovarian cancer are diseases that seriously threaten women's health.Most breast cancers and ovarian cancers are related to Breast Cancer Susceptibility Gene?BRCA-1/2?.When BRCA gene is mutated,there will be high risk of breast or ovarian cancer.Poly?ADP-ribose?polymerase is an enzyme extensively involved in DNA replication,transcription and apoptosis processes in eukaryotes,also closely involved in DNA damage repair process,highly expressed in all kinds of cancer cells.When DNA in normal cells is damaged,it will be repaired by homologous recombination repair mechanism,in order to maintain the stability of DNA.Besides,DNA damage can be repaired by DNA damage response mechanism.Studies indicated that in BRCA-mutated cancer cells,homologous recombination repair mechanism is lacked,so DNA damage can only be repaired by PARP mediated DNA damage response process.When the activity of PARP is inhibited,DNA base excision repair process cannot take place.Therefore,inhibiting the activity of PARP can hinder DNA damage repairing process in cancer cells,leading to synthetic lethal effect,and thus acomplish the object to specifically kill BRCA-mutated cancer cells.Based on the X-ray cocrystal structure figure of Veliparib?ABT-888?,a PARP inhibitor drug in phase III clinical trial,we modified the structure of Veliparib,hoping to obtain PARP inhibitor compounds with high potency.We designed and synthesized16 compounds based on 3-pyrrolidinyl benzimidazole carboxamide as potent PARP inhibitors.PARP inhibition assay indicated that the synthesized compounds showed obvious PARP inhibition potency towards PARP-1 and PARP-2,in which compound11d with the best potency showed PARP-1 and PARP-2 inhibion IC₅₀ of 3.6 n M and3.2 n M;compound 11f showed PARP-1 and PARP-2 inhibion IC₅₀ of 3.9 n M and 4.2n M,which are all close to the IC₅₀ of positive control,Veliparib.Cell proliferation assay indicated that synthesized compounds showed evident inhibition potency towards BRCA-1-mutaed MDA-MB-436 cell line and BRCA-2-mutated CAPAN-1cell line.Among the compounds,11f showed the highest potency,with a IC₅₀ of 17.4?M in MDA-MB-436 cell line,better than Olaparib with IC₅₀of 30.4?M.More specifically,11f showed superior potency towards CAPAN-1 cell line,with IC₅₀ of11.4?M,while two known PARP inhibitors,namely Olaparib and Veliparib,showed low potency,with IC₅₀ higher than 100?M.Molecular docking studies indicated that11f can effectively bind with the active site of PARP-1,with the side chain inserted into the hydrophobic pocket of PARP-1,thus inhibit the activity of PARP.Conclusively,the compound 11f showed high PARP and cell proliferation inhibition potency,with potent antitumor application values.