title: Synthetic modified pyrrolo[1,4] benzodiazepine molecules demonstrate selective anticancer activity by targeting the human ligase 1 enzyme: An in silico and in vitro mechanistic study.
abstract: Human DNA ligase1 (hLig1) is the major replicative enzyme in proliferating mammalian cells that join Okazaki fragments of the lagging strand during DNA replication. Interruptions in the process of ligation cause DNA damage to accumulate, resulting in cytotoxicity and cell death. In the present study we demonstrate that pyrrolo[1,4] benzodiazepine (PBD) derivatives exhibit anticancer properties by targeting the nick sealing activity of hLig1 as opposed to the DNA interaction activity known for such compounds. Our in silico and in vitro assays demonstrate the binding of these molecules with amino acid residues present in the DNA binding domain (DBD) of the hLig1 enzyme. Two of these hLig1 inhibitors S010-015 and S010-018 demonstrated selective cytotoxicity against DLD-1 (colon cancer) and HepG2 (hepatic cancer) cells in a dose dependant manner. The molecules also reduced cell viability and colony formation at concentrations of ⩽20μM in DLD-1 and HepG2 cells and induced apoptotic cell death. In yet another significant finding, the molecules reduced the migration of cancer cells in wound healing experiments, indicating their anti-metastatic property. In summary, we report the anticancer activity of PBD derivatives against DLD-1 and HepG2 cells and propose a new molecular target for their activity.
authors.affiliation: Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, B.S. 10/1, Janakipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shameem
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, B.S. 10/1, Janakipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Ravi
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, B.S. 10/1, Janakipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Shagun
authors.initials: S
authors.lastname: Krishna
authors.affiliation: Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, B.S. 10/1, Janakipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Chandan
authors.initials: C
authors.lastname: Kumar
authors.affiliation: Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, B.S. 10/1, Janakipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Mohammad Imran
authors.initials: MI
authors.lastname: Siddiqi
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, B.S. 10/1, Janakipuram Extension, Sitapur Road, Lucknow 226031, India. Electronic address: b_kundu@cdri.res.in.
authors.forename: Bijoy
authors.initials: B
authors.lastname: Kundu
authors.affiliation: Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, B.S. 10/1, Janakipuram Extension, Sitapur Road, Lucknow 226031, India. Electronic address: d.banerjee@cdri.res.in.
authors.forename: Dibyendu
authors.initials: D
authors.lastname: Banerjee
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D001570:Benzodiazepinones / Q000494:pharmacology*; D002460:Cell Line; D004247:DNA / Q000187:drug effects; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000378:metabolism*; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D013050:Spectrometry, Fluorescence; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D017931:DNA Primers; C000601832:S010-015; C000601833:S010-018; D004247:DNA; D011088:DNA Ligases; D000072481:DNA Ligase ATP
keywords: Apoptosis; Colon cancer; DNA ligase 1; Hepatic cancer; Ligase inhibitor; PBD derivatives; Replication