A series
of 73 ligands and 73 of their Cu+2 and Cu+1 copper
complexes with different geometries, oxidation states
of the metal, and redox activities were synthesized and characterized.
The aim of the study was to establish the structure–activity
relationship within a series of analogues with different substituents
at the N(3) position, which govern the redox potentials of the Cu+2/Cu+1 redox couples, ROS generation ability, and
intracellular accumulation. Possible cytotoxicity mechanisms, such
as DNA damage, DNA intercalation, telomerase inhibition, and apoptosis
induction, have been investigated. ROS formation in MCF-7 cells and
three-dimensional (3D) spheroids was proven using the Pt-nanoelectrode.
Drug accumulation and ROS formation at 40–60 μm spheroid
depths were found to be the key factors for the drug efficacy in the
3D tumor model, governed by the Cu+2/Cu+1 redox
potential. A nontoxic in vivo single-dose evaluation
for two binuclear mixed-valence Cu+1/Cu+2 redox-active
coordination compounds, 72k and 61k, was
conducted.
Prostate-specific membrane antigen
(PSMA), also known as glutamate
carboxypeptidase II (GCPII), is a suitable target for specific delivery
of antitumor drugs and diagnostic agents due to its overexpression
in prostate cancer cells. In the current work, we describe the design,
synthesis, and biological evaluation of novel low-molecular PSMA ligands
and conjugates with fluorescent dyes FAM-5, SulfoCy5, and SulfoCy7. In vitro evaluation of synthesized PSMA ligands on the activity
of PSMA shows that the addition of aromatic amino acids into a linker
structure leads to a significant increase in inhibition. The conjugates
of the most potent ligand with FAM-5 as well as SulfoCy5 demonstrated
high affinities to PSMA-expressing tumor cells in vitro. In vivo biodistribution in 22Rv1 xenografts in
Balb/c nude mice of PSMA-SulfoCy5 and PSMA-SulfoCy7 conjugates with a novel PSMA ligand demonstrated good visualization
of PSMA-expressing tumors. Also, the conjugate PSMA-SulfoCy7 demonstrated the absence of any explicit toxicity up to 87.9 mg/kg.
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