title: Development of derivatives of 3, 3'-diindolylmethane as potent Leishmania donovani bi-subunit topoisomerase IB poisons.
abstract: BACKGROUND
  The development of 3, 3'-diindolyl methane (DIM) resistant parasite Leishmania donovani (LdDR50) by adaptation with increasing concentrations of the drug generates random mutations in the large and small subunits of heterodimeric DNA topoisomerase I of Leishmania (LdTOP1LS). Mutation of large subunit of LdTOP1LS at F270L is responsible for resistance to DIM up to 50 µM concentration.
  
  
  RESULTS
  In search of compounds that inhibit the growth of the DIM resistant parasite and inhibit the catalytic activity of mutated topoisomerase I (F270L), we have prepared three derivatives of DIM namely DPDIM (2,2'-diphenyl 3,3'-diindolyl methane), DMDIM (2,2'-dimethyl 3,3'-diindolyl methane) and DMODIM (5,5'-dimethoxy 3,3'-diindolyl methane) from parent compound DIM. All the compounds inhibit the growth of DIM resistant parasites, induce DNA fragmentation and stabilize topo1-DNA cleavable complex with the wild type and mutant enzyme.
  
  
  CONCLUSIONS
  The results suggest that the three derivatives of DIM can act as promising lead molecules for the generation of new anti-leishmanial agents.
authors.affiliation: Molecular Parasitology Laboratory, Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Roy
authors.forename: Sayan
authors.initials: S
authors.lastname: Chowdhury
authors.forename: Souvik
authors.initials: S
authors.lastname: Sengupta
authors.forename: Madhumita
authors.initials: M
authors.lastname: Mandal
authors.forename: Parasuraman
authors.initials: P
authors.lastname: Jaisankar
authors.forename: Ilda
authors.initials: I
authors.lastname: D'Annessa
authors.forename: Alessandro
authors.initials: A
authors.lastname: Desideri
authors.forename: Hemanta K
authors.initials: HK
authors.lastname: Majumder
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D053837:DNA Cleavage / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D004351:Drug Resistance / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D005453:Fluorescence; D016678:Genome / Q000235:genetics; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D007893:Leishmania donovani / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development; D008018:Life Cycle Stages / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D010271:Parasites / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D021122:Protein Subunits / Q000037:antagonists & inhibitors* / Q000378:metabolism; D059004:Topoisomerase I Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004268:DNA-Binding Proteins; D007211:Indoles; D021122:Protein Subunits; D059004:Topoisomerase I Inhibitors; D004247:DNA; D004264:DNA Topoisomerases, Type I; C016392:3,3'-diindolylmethane