title: Inhibition of human immunodeficiency virus proliferation by macrocyclic polyamines and their metal complexes.
abstract: The macrocyclic polyamines, cyclen and cyclam, and their derivatives have been tested for inhibitory activity against the cytopathogenic effect (CPE) of human immunodeficiency virus type 1 strain HTLV-IIIB (HIV-1IIIB) on CD4+ human lymphoblastoma MT-4 cells. Cyclam and its derivatives were complexed with a variety of transition metal ions NiII, ZnII, CuII, FeIII and CoIII. The divalent metal complexes effected lower toxicity and greater anti-HIV-1 activity, while the trivalent metal complexes had no effect on HIV-1-dependent CPE. When dimerized, the anti-HIV activity of monomers was significantly enhanced. A potent inhibition of CPE by biscyclam was transiently observed 4 d after the virus infection, but was not seen at 6 d due to severe toxicity. The toxicity of biscyclam, referred to as delayed toxicity, could be overcome by a metal complexation. The strain specificities of biscyclams were further studied by testing their effects on syncytium formation between HIV-infected and uninfected human acute lymphoblastic leukemia MOLT-4 cells. The 50% inhibitory concentrations of biscyclams against HIV-2GH-1-dependent syncytium formation were less than one hundredth those for the other HIV strains (HIV-1IIIB, HIV-1RF and HIV-1SF-2).
authors.affiliation: Institute of Pharmaceutical Science, Hiroshima University School of Medicine, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Inouye
authors.forename: T
authors.initials: T
authors.lastname: Kanamori
authors.forename: T
authors.initials: T
authors.lastname: Yoshida
authors.forename: X
authors.initials: X
authors.lastname: Bu
authors.forename: M
authors.initials: M
authors.lastname: Shionoya
authors.forename: T
authors.initials: T
authors.lastname: Koike
authors.forename: E
authors.initials: E
authors.lastname: Kimura
mesh_terms: D002413:Cations, Divalent / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D003035:Cobalt / Q000737:chemistry; D000080027:Cyclams; D003588:Cytopathogenic Effect, Viral; D004347:Drug Interactions; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007501:Iron / Q000737:chemistry; D008670:Metals / Q000737:chemistry*; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects
chemical_list: D002413:Cations, Divalent; D000080027:Cyclams; D006571:Heterocyclic Compounds; D008670:Metals; D018894:Reverse Transcriptase Inhibitors; C024560:cyclam; D003035:Cobalt; C038072:cyclen; D007501:Iron; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase