A versatile design strategy is presented towards new monoanionic pincer luminophores, showing that cyclometallating C^N^N ligands can yield phosphorescent Pt(ii) complexes even if a neutral 1,2,3-triazole ring is inserted by click chemistry. The overall charge, intermolecular interactions and excited state properties can be manipulated and controlled by varying the nature of the ancillary ligand, and its effect on the structural and the triplet state characteristics can be thoroughly investigated and correlated by means of theory and spectroscopy.
The first dinuclear metal-mediated base pair containing divalent metal ions has been prepared. A combination of the neutral bis(monodentate) purine derivative 1,N -ethenoadenine (ϵA), which preferentially binds two metal ions with a parallel alignment of the N-M bonds, and the canonical nucleobase thymine (T), which readily deprotonates in the presence of Hg and thereby partially compensates the charge accumulation due to the two closely spaced divalent metal ions, yields the dinuclear T-Hg -ϵA base pair. This metal-mediated base pair stabilizes the DNA oligonucleotide duplex as shown by an increase of 8 °C in its melting temperature. Formation of the base pair was demonstrated by temperature-dependent UV spectroscopy as well as by titration experiments monitored by UV and CD spectroscopy.
Oxidative damage in DNA is one of the primary sources of mutations in the cell. The activities of repair enzymes 8-oxoguanine DNA glycosylase (OGG1) and human MutT Homologue 1 (NUDT1 or MTH1), which work together to ameliorate this damage, are closely linked to mutagenesis, genotoxicity, cancer, and inflammation. Here we have undertaken the development of smallmolecule dual inhibitors of the two enzymes as tools to test the relationships between these pathways and disease. The compounds preserve key structural elements of known inhibitors of the two enzymes, and they were synthesized and assayed with recently developed luminescence assays of the enzymes. Further structural refinement of initial lead molecules yielded compound 5 (SU0383) with IC 50 (NUDT1) = 0.034 μM and IC 50 (OGG1) = 0.49 μM. The compound SU0383 displayed low toxicity in two human cell lines at 10 μM. Experiments confirm the ability of SU0383 to increase sensitivity of tumor cells to oxidative stress. Dual inhibitors of these two enzymes are expected to be useful in testing multiple hypotheses regarding the roles of 8-oxo-dG in multiple disease states.
A family of Pt(II) complexes bearing
monoanionic C^N^N ligands
as luminophoric units as well as a set of monodentate ligands derived
from allenylidene and carbene species were synthesized and characterized
in terms of structure and photophysical properties. In addition, we
present the extraordinary molecular structure of a phosphorescent
complex carrying an allenylidene ligand. Depending on the co-ligand,
an effect can be observed in the photoluminescence lifetimes and quantum
yields as well as in the radiative and radiation less deactivation
rate constants. Their correlation with the substitution pattern was
analyzed by comparing the photoluminescence in fluid solution at room
temperature and in frozen glassy matrices at 77 K. Moreover, in order
to gain a deeper understanding of the electronic states responsible
for the optical properties, density functional theory calculations
were performed. Finally, the cytotoxicity of the complexes was evaluated in vitro, showing that the cationic complexes exhibit strong
effects at low micromolar concentrations. The calculated half-maximum
effective concentrations (EC50 values) were 4 times lower
in comparison to the established antitumor agent oxaliplatin. In contrast,
the neutral species are less toxic, rendering them as potential bioimaging
agents.
1,N6‐Ethenoadenine (ϵA) and cytosine (C) are able to form two different metal‐mediated base pairs. When the glycosidic bonds are arranged in a cisoid manner (i.e., in antiparallel‐stranded DNA), the ϵA:C mispair binds one AgI ion, leading to a mononuclear ϵA‐AgI‐C base pair that contains a synergistic hydrogen bond. In contrast, a transoid orientation of the glycosidic bonds (as found in parallel‐stranded DNA) results in the formation of a dinuclear metal‐mediated base pair ϵA‐AgI2‐C.
Impaired DNA repair activity has been shown to greatly increase rates of cancer clinically. It has been hypothesized that upregulating repair activity in susceptible individuals may be a useful strategy for inhibiting tumorigenesis. Here, we report that selected tyrosine kinase (TK) inhibitors including nilotinib, employed clinically in the treatment of chronic myeloid leukemia, are activators of the repair enzyme Human MutT Homolog 1 (MTH1). MTH1 cleanses the oxidatively damaged cellular nucleotide pool by hydrolyzing the oxidized nucleotide 8-oxo-2'-deoxyguanosine (8-oxo-dG)TP, which is a highly mutagenic lesion when incorporated into DNA. Structural optimization of analogues of TK inhibitors resulted in compounds such as SU0448, which induces 1000 ± 100% activation of MTH1 at 10 μM and 410 ± 60% at 5 μM. The compounds are found to increase the activity of the endogenous enzyme, and at least one (SU0448) decreases levels of 8-oxo-dG in cellular DNA. The results suggest the possibility of using MTH1 activators to decrease the frequency of mutagenic nucleotides entering DNA, which may be a promising strategy to suppress tumorigenesis in individuals with elevated cancer risks.
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