Inhibition of Human Immunodeficiency Virus Proliferation by Macrocyclic Polymines and Their Metal Complexes.
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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-III<SUB>B</SUB> (HIV-1<SUB>IIIB</SUB>) on CD4<SUP>+</SUP> human lymphoblastoma MT-4 cells. Cyclam and its derivatives were complexed with a variety of transition metal ions Ni<SUP>II</SUP>, Zn<SUP>II</SUP>, Cu<SUP>II</SUP>, Fe<SUP>III</SUP> and Co<SUP>III</SUP>. 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-2<SUB>GH-1</SUB>-dependent syncytium formation were less than one hundredth those for the other HIV strains (HIV-1<SUB>IIIB</SUB>, HIV-1<SUB>RF</SUB> and HIV-1<SUB>SF-2</SUB>).
- Biological and Pharmaceutical Bulletin
Biological and Pharmaceutical Bulletin 17(2), 243-250, 1994
The Pharmaceutical Society of Japan