A gold(I) phosphine complex containing a naphthalimide ligand functions as a TrxR inhibiting antiproliferative agent and angiogenesis inhibitor.
The novel luminescent gold(I) complex [N-(N',N'-dimethylaminoethyl)-1,8-naphthalimide-4-sulfide](triethylphosphine)gold(I) was prepared and investigated for its primary biological properties. Cell culture experiments revealed strong antiproliferative effects and induction of apoptosis via mitochondrial pathways. Biodistribution studies by fluorescence microscopy and atomic absorption spectroscopy showed the uptake into cell organelles, an accumulation in the nuclei of tumor cells, and a homogeneous distribution in zebrafish embryos. In vivo monitoring of vascularisation in developing zebrafish embryos revealed a significant anti-angiogenic potency of the complex. Mechanistic experiments indicated that the inhibition of thioredoxin reductase (based on the covalent binding of a gold triethylphosphine fragment) might be involved in the pharmacodynamic behavior of this novel gold species.
Ott
Ingo
I
Institute of Pharmacy, Freie Universitat Berlin, Konigin-Luise-Strasse 2+4, 14195 Berlin, Germany. ottingo@zedat.fu-berlin.de
Qian
Xuhong
X
Xu
Yufang
Y
Vlecken
Danielle H W
DH
Marques
Ines J
IJ
Kubutat
Dominic
D
Will
Joanna
J
Sheldrick
William S
WS
Jesse
Patrick
P
Prokop
Aram
A
Bagowski
Christoph P
CP
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004625:Embryo, Nonmammalian / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D020714:Maximum Tolerated Dose; D018613:Microscopy, Confocal; D050607:Organogold Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*; D015027:Zebrafish
C538800:(N-(N',N'-dimethylaminoethyl)-1,8-naphthalimide-4-sulfide)(triethylphosphine)gold(I); D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D050607:Organogold Compounds; D013880:Thioredoxin-Disulfide Reductase