title: Antiparasitic compounds that target DNA.
abstract: Designed, synthetic heterocyclic diamidines have excellent activity against eukaryotic parasites that cause diseases such as sleeping sickness and leishmania and adversely affect millions of people each year. The most active compounds bind specifically and strongly in the DNA minor groove at AT sequences. The compounds enter parasite cells rapidly and appear first in the kinetoplast that contains the mitochondrial DNA of the parasite. With time the compounds are also generally seen in the cell nucleus but are not significantly observed in the cytoplasm. The kinetoplast decays over time and disappears from the mitochondria of treated cells. At this point the compounds begin to be observed in other regions of the cell, such as the acidocalcisomes. The cells typically die in 24-48h after treatment. Active compounds appear to selectively target extended AT sequences and induce changes in kinetoplast DNA minicircles that cause a synergistic destruction of the catenated kinetoplast DNA network and cell death.
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA. wdw@gsu.edu
authors.forename: W David
authors.initials: WD
authors.lastname: Wilson
authors.forename: Farial A
authors.initials: FA
authors.lastname: Tanious
authors.forename: Amanda
authors.initials: A
authors.lastname: Mathis
authors.forename: Denise
authors.initials: D
authors.lastname: Tevis
authors.forename: James Edwin
authors.initials: JE
authors.lastname: Hall
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry* / Q000494:pharmacology; D016054:DNA, Protozoan / Q000737:chemistry* / Q000187:drug effects; D016503:Drug Delivery Systems; D056890:Eukaryota / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D009690:Nucleic Acid Conformation / Q000187:drug effects; D010419:Pentamidine / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000977:Antiparasitic Agents; D016054:DNA, Protozoan; D006571:Heterocyclic Compounds; D010419:Pentamidine