Inhibition of human immunodeficiency virus proliferation by macrocyclic polyamines and their metal complexes.
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).
Inouye
Y
Y
Institute of Pharmaceutical Science, Hiroshima University School of Medicine, Japan.
Kanamori
T
T
Yoshida
T
T
Bu
X
X
Shionoya
M
M
Koike
T
T
Kimura
E
E
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
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