ABSTRACT
A series of new podophyllotoxin linked ß-carboline congeners have been synthesized by coupling various substituted ß-carboline acids with 4ß-aminopodophyllotoxin. Evaluation of their anticancer activity against a panel of human cancer cell lines such as lung cancer (A549), prostate cancer (DU-145), MDA MB-231 (breast cancer), HT-29 (colon cancer) and HeLa (cervical cancer) suggested that 7i and 7j are the most cytotoxic compounds with IC50 values of 1.07⯱â¯0.07⯵M and 1.14⯱â¯0.16 respectively against DU-145â¯cell line. Further, detailed biological studies such as cell cycle analysis, topoisomerase II inhibition, Comet assay, DNA binding studies and docking studies have revealed that these congeners are DNA interacting topoisomerase II inhibitors.
Subject(s)
Antineoplastic Agents/pharmacology , Carbolines/pharmacology , DNA Topoisomerases, Type II/metabolism , Podophyllotoxin/pharmacology , Topoisomerase II Inhibitors/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Carbolines/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Docking Simulation , Molecular Structure , Podophyllotoxin/chemistry , Structure-Activity Relationship , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/chemistryABSTRACT
A series of new ß-carboline-bisindole compounds were designed, synthesized and evaluated for their antiproliferative activity against human cancer cell lines, such as A549 (lung cancer), DU-145 (prostate cancer), HeLa (cervical cancer) and MCF-7 (breast cancer). All the compounds exhibited considerable antiproliferative activity. Among them, compounds 7g and 7r exhibited significant antiproliferative activity against DU-145 cells with IC50 values 1.86 and 1.80 µM respectively. Further, these compounds effectively inhibit DNA topoisomerase I activity and can also cleave the pBR322 plasmid upon irradiation with UV light. In addition, Annexin V-FITC assay suggested that these compounds induced apoptosis in DU- 145 cell line (prostate cancer). To know the binding mode of these compounds with DNA, spectroscopic studies were also carried out. These new compounds were showing a unique mode of binding with DNA, both biophysical studies such as UV-Visible, fluorescence, circular dichroism and molecular docking studies revealed that the ß-carboline-bisindole compounds exhibit combilexin type of interaction with DNA.
