INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUS PROLIFERATION BY MACROCYCLIC POLYAMINES AND THEIR METAL-COMPLEXES

The macrocyclic polyamines, cyclen and cyclam, and their derivatives h ave been tested for inhibitory activity against the cytopathogenic eff ect (CPE) of human immunodeficiency virus type 1 strain HTLV-IIIB (HIV -1(IIIB)) on CD4(+) human lymphoblastoma MT-4 cells. Cyclam and its de rivatives were complexed with a variety of transition metal ions Ni-II , Zn-II, Cu-II, Fe-III and Co-III The divalent metal complexes effecte d 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 4d after the virus infection, but was not seen at 6d due to severe toxicity. The to xicity of biscyclam, referred to as delayed toxicity, could be overcom e by a metal complexation. The strain specificities of biscyclams were further studied by testing their effects on syncytium formation betwe en HIV-infected and uninfected human acute lymphoblastic leukemia MOLT -4 cells. The 50% inhibitory concentrations of biscyclams against HIV- 2(GH-1)-dependent syncytium formation were less than one hundredth tho se for the other HIV strains (HIV-1(IIIB), HIV-1(RF) and HIV-1(SF-2).