Gold(I)-phosphine-N-heterocycles: biological activity and specific (ligand) interactions on the C-terminal HIVNCp7 zinc finger.
The syntheses and the characterization by chemical analysis, (1)H and (31)P NMR spectroscopy, and mass spectrometry of a series of linear triphenylphosphine gold(I) complexes with substituted N-heterocycle ligands (L), [(PPh3)Au(I)(L)](+), is reported. The reaction of [(PPh3)Au(L)](+) (L = Cl(-) or substituted N- heterocyclic pyridine) with the C-terminal (Cys3His) finger of HIVNCp7 shows evidence by mass spectrometry (ESI-MS) and (31)P NMR spectroscopy of a long-lived {(PPh3)Au}-S-peptide species resulting from displacement of the chloride or pyridine ligand by zinc-bound cysteine with concomitant displacement of Zn(2+). In contrast, reactions with the Cys2His2 finger-3 of the Sp1 transcription factor shows significantly reduced intensities of {(PPh3)Au} adducts. The results suggest the possibility of systematic (electronic, steric) variations of "carrier" group PR3 and "leaving" group L as well as the nature of the zinc finger in modulation of biological activity. The cytotoxicity, cell cycle signaling effects, and cellular accumulation of the series are also reported. All compounds display cytotoxicity in the micromolar range upon 96 h continuous exposure to human tumor cells. The results may have relevance for the reported inhibition of viral load in simian virus by the gold(I) drug auranofin.
Institute of Chemistry, University of Campinas-UNICAMP , P.O. Box 6154, CEP 13083-970, Campinas, São Paulo, Brazil.
Camilla
C
Abbehausen
Erica J
EJ
Peterson
Raphael E F
RE
de Paiva
Pedro P
PP
Corbi
André L B
AL
Formiga
Yun
Y
Qu
Nicholas P
NP
Farrell
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002942:Circular Dichroism; D006046:Gold / Q000737:chemistry* / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D010720:Phosphines / Q000737:chemistry* / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D016335:Zinc Fingers; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000737:chemistry* / Q000378:metabolism
D006571:Heterocyclic Compounds; D008024:Ligands; C071884:NCP7 protein, Human immunodeficiency virus 1; D010720:Phosphines; D054301:gag Gene Products, Human Immunodeficiency Virus; D006046:Gold; C044646:phosphine