title: New bis(thiosemicarbazonate) gold(III) complexes inhibit HIV replication at cytostatic concentrations: potential for incorporation into virostatic cocktails.
abstract: Four bis(thiosemicarbazonate)gold(III) complexes (1-4) with a general formula [Au(L)]Cl {L=L1, glyoxal-bis(N(4)-methylthiosemicarbazone); L2, glyoxal-bis(N(4)-ethylthiosemicarbazone); L3, diacetyl-bis(N(4)-methylthiosemicarbazone); L4, diacetyl-bis(N(4)-ethylthiosemicarbazone)} were synthesised and screened for activity against the human immunodeficiency virus (HIV). Complexes 1-4 were characterised using (1)H-NMR and IR spectroscopy; and their purity established by micronanalysis. Complex 3 inhibited viral infection of TZM-bl cells by 98% (IC(50)=6.8±0.6μM) at a non toxic concentration of 12.5μM while complex 4 inhibited infection of these cells by 72 and 98% (IC(50)=5.3±0.4μM) at concentrations of 6.25 and 12.5μM respectively. The mechanism of inhibition of infection in TZM-bl cells is presumably as a result of the cytostatic or anti-proliferative activity that was observed for complex 4 in real time cell electronic sensing (RT-CES) and carboxyflourescein succinimidyl ester (CFSE) analysis. Treatment of T lymphocytes from HIV infected individuals with 4 decreased CD4+ T cell expression (p=0.0049) as demonstrated by multi-parametric flow cytometry without suppressing cytokine production. None of the ligands (L1-L4) demonstrated anti-viral activity, supporting the importance of metal (gold) complexation in these potential drugs. Complexes 3 and 4 were shown to have ideal lipophilicity values that were similar when shake flask (0.97±0.5 and 2.42±0.6) and in silico prediction (0.8 and 1.5) methods were compared. The activity and drug-like properties of complexes 3 and 4 suggests that these novel metal-based compounds could be combined with virus inhibitory drugs to work as cytostatic agents in the emerging class of anti-HIV drugs known as virostatics.
authors.affiliation: Department of Biochemistry, University of Pretoria, Hatfield Campus, Pretoria 0002, South Africa.
authors.forename: Pascaline N
authors.initials: PN
authors.lastname: Fonteh
authors.forename: Frankline K
authors.initials: FK
authors.lastname: Keter
authors.forename: Debra
authors.initials: D
authors.lastname: Meyer
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D015704:CD4 Antigens / Q000032:analysis / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000494:pharmacology*; D054697:Cytostatic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D005452:Fluoresceins / Q000032:analysis; D017930:Genes, Reporter; D006046:Gold / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D006367:HeLa Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008156:Luciferases / Q000032:analysis; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D013055:Spectrophotometry, Infrared; D013388:Succinimides / Q000032:analysis; D013882:Thiosemicarbazones / Q000138:chemical synthesis / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D019380:Anti-HIV Agents; D015704:CD4 Antigens; D056831:Coordination Complexes; D054697:Cytostatic Agents; D005452:Fluoresceins; D013388:Succinimides; D013882:Thiosemicarbazones; D006046:Gold; D008156:Luciferases