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: Pascaline N Fonteh, Frankline K Keter, Debra Meyer
• Journal: Journal of inorganic biochemistry (J Inorg Biochem) Vol. 105 Issue 9 Pg. 1173-80 (Sep 2011) ISSN: 1873-3344 [Electronic] United States
• PMID: 21708102 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• 5-(6)-carboxyfluorescein diacetate succinimidyl ester
• Anti-HIV Agents
• CD4 Antigens
• Coordination Complexes
• Cytostatic Agents
• Fluoresceins
• Succinimides
• Thiosemicarbazones
• Gold
• Luciferases

Topics

• Anti-HIV Agents (chemical synthesis, pharmacology)
• CD4 Antigens (analysis, biosynthesis)
• CD4-Positive T-Lymphocytes (cytology, drug effects, metabolism, virology)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Coordination Complexes (chemical synthesis, pharmacology)
• Cytostatic Agents (chemical synthesis, pharmacology)
• Female
• Flow Cytometry
• Fluoresceins (analysis)
• Genes, Reporter
• Gold (chemistry, metabolism, pharmacology)
• HIV Infections (drug therapy, metabolism, pathology, virology)
• HIV-1 (drug effects, growth & development)
• HeLa Cells
• Humans
• Hydrophobic and Hydrophilic Interactions
• Luciferases (analysis)
• Magnetic Resonance Spectroscopy
• Models, Molecular
• Spectrophotometry, Infrared
• Succinimides (analysis)
• Thiosemicarbazones (chemical synthesis, pharmacology)
• Virus Replication (drug effects)