title: Gold(I) complex of 1,1'-bis(diphenylphosphino) ferrocene-quinoline conjugate: a virostatic agent against HIV-1.
abstract: HIV infection is known for replicating in proliferating CD(+) T-cells. Treatment of these cells with cytostatic (anti-proliferation) compounds such as hydroxyurea interferes with the cells's ability support HIV replication. Combinations of such cytostatic compounds with proven anti-retroviral drugs (like ddI) are known as virostatic, and have been shown to aid in the control of the infection. The use of two different drugs in virostatic combinations however, carries the risk of adverse effects including drug-drug interactions, which could lead to augmented toxicities and reduced efficacy. Here, a novel digold(I) complex of ferrocene-quinoline (3) was investigated for cytostatic behaviour as well as anti-viral activity which if demonstrated would eliminate concerns of drug-drug interactions. The complex was synthesized and characterized by NMR, FT-IR and mass spectroscopy and the molecular structure was confirmed by X-ray crystallography. Bio-screening involved viability dyes, real time electronic sensing and whole virus assays. The complex showed significant (p = 0.0092) inhibition of virus infectivity (83 %) at 10 ug/mL. This same concentration caused cytostatic behaviour in TZM-bl cells with significant (p < 0.01) S and G2/M phase cell cycle arrest. These data supports 3 as a virostatic agent, possessing both anti-viral and cytostatic characteristics. In the absence of 3, TZM-bl cells were infected by a pseudovirus and this was demonstrated through luminescence in a luciferase assay. Pre-incubation of the virus with 3 decreased luminescence, indicating the anti-viral activity of 3. Complex 3 also showed cytostatic behavior with increased S-phase and G2/M phase cell cycle arrest.
authors.affiliation: Department of Biochemistry, University of Pretoria, Hatfield Campus, Pretoria, 0002, South Africa.
authors.forename: Ntombenhle
authors.initials: N
authors.lastname: Gama
authors.affiliation: Inorganic Chemistry Research Group, Chemical Physics, Center for Chemistry and Chemical Engineering, Lund University, Box 124, 22100, Lund, Sweden.|Department of Chemistry, University of Johannesburg, Kingsway Campus, Johannesburg, Auckland Park, 2006, South Africa.
authors.forename: Kamlesh
authors.initials: K
authors.lastname: Kumar
authors.affiliation: Inorganic Chemistry Research Group, Chemical Physics, Center for Chemistry and Chemical Engineering, Lund University, Box 124, 22100, Lund, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Ekengard
authors.affiliation: Department of Chemistry, University of Jyväskylä, 40014, Jyväskylä, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Haukka
authors.affiliation: Department of Chemistry, University of Johannesburg, Kingsway Campus, Johannesburg, Auckland Park, 2006, South Africa. jdarkwa@uj.ac.za.
authors.forename: James
authors.initials: J
authors.lastname: Darkwa
authors.affiliation: Inorganic Chemistry Research Group, Chemical Physics, Center for Chemistry and Chemical Engineering, Lund University, Box 124, 22100, Lund, Sweden. ebbe.nordlander@chemphys.lu.se.
authors.forename: Ebbe
authors.initials: E
authors.lastname: Nordlander
authors.affiliation: Department of Biochemistry, University of Pretoria, Hatfield Campus, Pretoria, 0002, South Africa. dmeyer@uj.ac.za.|Dean's Office, Faculty of Science, University of Johannesburg, Kingsway Campus, Johannesburg, Auckland Park, 2006, South Africa. dmeyer@uj.ac.za.
authors.forename: Debra
authors.initials: D
authors.lastname: Meyer
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D005296:Ferrous Compounds / Q000737:chemistry / Q000494:pharmacology*; D006046:Gold / Q000737:chemistry / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D000075163:Metallocenes; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D050607:Organogold Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010720:Phosphines / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D005296:Ferrous Compounds; D000075163:Metallocenes; D050607:Organogold Compounds; D010720:Phosphines; D011804:Quinolines; D006046:Gold; C037219:quinoline; C519379:1,1'-bis(diphenylphosphino)ferrocene
keywords: Chloroquine; Cytostatic; Gold complexes; HIV-1; Virostatic