New Acridine Thiourea Gold(I) Anticancer Agents: Targeting the Nucleus and Inhibiting Vasculogenic Mimicry

Two new 1-acridin-9-yl-3-methylthiourea
Au­(I) DNA intercalators
[Au­(ACRTU)2]Cl (2) and [Au­(ACRTU) (PPh3)]­PF6 (3) have been prepared. Both
complexes were highly active in the human ovarian carcinoma cisplatin-sensitive
A2780 cell line, exhibiting IC50 values in the submicromolar
range. Compounds 2 and 3 are also cytotoxic
toward different phenotypes of breast cancer cell lines MDA-MB-231
(triple negative), SK-BR-3 (HER2+, ERα–, and ERβ−),
and MCF-7 (ER+). Both complexes induce apoptosis through activation
of caspase-3 in vitro. While inhibition of some proteins
(thiol-containing enzymes) seems to be the main mechanism of action
for cytotoxic gold complexes, 2 and 3 present
a DNA-dependent mechanism of action. They locate in the cell nucleus
according to confocal microscopy and transmission electronic microscopy.
The binding to DNA resulted to be via intercalation
as shown by spectroscopic methods and viscometry, exhibiting a dose-dependent
response on topoisomerase I mediated DNA unwinding. In addition, 2 and 3 exhibit potent antiangiogenic effects
and are also able to inhibit vasculogenic mimicry of highly invasive
MDA-MB-231 cells.