12 research outputs found
Mechanistic Study on the Photochemical âLight Switchâ Behavior of [Ru(bpy)<sub>2</sub>dmdppz]<sup>2+</sup>
[RuÂ(bpy)<sub>2</sub>dmdppz]<sup>2+</sup> (bpy = 2,2â˛-bipyridine
and dmdppz = 3,6-dimethyl dipyridylphenazine), a strained RuÂ(II) polypyridyl
complex, is a derivative of the well-known luminescent âlight
switchâ, [RuÂ(bpy)<sub>2</sub>dppz]<sup>2+</sup> (dppz = dipyridylphenazine).
[RuÂ(bpy)<sub>2</sub>dmdppz]<sup>2+</sup> is of interest because it
acts as a photochemical sensor and metalating agent for DNA. Here
we report a detailed study to elucidate the mechanism of ligand substitution
by investigating the photochemical reaction in a variety of solvents
and by determining the effects of different incoming ligands, the
incoming ligand concentration, and the temperature dependence. Results
from these studies indicate that the mechanism of substitution is
associative or interchange associative, in contrast with the dissociative
mechanism of other photolabile RuÂ(II) polypyridyl complexes
Combining a Ru(II) âBuilding Blockâ and Rapid Screening Approach to Identify DNA Structure-Selective âLight Switchâ Compounds
A chemically
reactive RuÂ(II) âbuilding blockâ, able
to undergo condensation reactions with substituted diamines, was utilized
to create a small library of luminescent âlight switchâ
dipyrido-[3,2-<i>a</i>:2â˛,3â˛-<i>c</i>] phenazine (dppz) complexes. The impact of substituent identity,
position, and the number of substituents on the light switch effect
was investigated. An unbiased, parallel screening approach was used
to evaluate the selectivity of the compounds for a variety of different
biomolecules, including protein, nucleosides, single stranded DNA,
duplex DNA, triplex DNA, and G-quadruplex DNA. Combining these two
approaches allowed for the identification of hit molecules that showed
different selectivities for biologically relevant DNA structures,
particularly triplex and quadruplex DNA
Coordination of Hydroxyquinolines to a Ruthenium Bis-dimethyl-phenanthroline Scaffold Radically Improves Potency for Potential as Antineoplastic Agents
A series
of ruthenium coordination complexes containing hydroxyquinoline
ligands were synthesized that exhibited radically improved potencies
up to 86-fold greater than clioquinol, a known cytotoxic compound.
The complexes were also >100-fold more potent than clioquinol in
a
tumor spheroid model, with values similar to currently used chemotherapeutics
for the treatment of solid tumors. Cytotoxicity occurs through rapid
processes that induce apoptosis but appear to be mediated by cell-cycle
independent mechanisms. The ruthenium complexes do not inhibit the
proteasome at concentrations relevant for cell death, and contrary
to previous reports, clioquinol and other hydroxyquinoline compounds
do not act as direct proteasome inhibitors to induce cell death
Strained Ruthenium Complexes Are Potent Light-Activated Anticancer Agents
Strained ruthenium (Ru) complexes have been synthesized
and characterized
as novel agents for photodynamic therapy (PDT). The complexes are
inert until triggered by visible light, which induces ligand loss
and covalent modification of DNA. An increase in cytotoxicity of 2
orders of magnitude is observed with light activation in cancer cells,
and the compounds display potencies superior to cisplatin against
3D tumor spheroids. The use of intramolecular strain may be applied
as a general paradigm to develop light-activated ruthenium complexes
for PDT applications
Modifying Charge and Hydrophilicity of Simple Ru(II) Polypyridyl Complexes Radically Alters Biological Activities: Old Complexes, Surprising New Tricks
Compounds
capable of light-triggered cytotoxicity are appealing
potential therapeutics, because they can provide spatial and temporal
control over cell killing to reduce side effects in cancer therapy.
Two simple homoleptic RuÂ(II) polypyridyl complexes with almost-identical
photophysical properties but radically different physiochemical properties
were investigated as agents for photodynamic therapy (PDT). The two
complexes were identical, except for the incorporation of six sulfonic
acids into the ligands of one complex, resulting in a compound carrying
an overall â4 charge. The negatively charged compound exhibited
significant light-mediated cytotoxicity, and, importantly, the negative
charges resulted in radical alterations of the biological activity,
compared to the positively charged analogue, including complete abrogation
of toxicity in the dark. The charges also altered the subcellular
localization properties, mechanism of action, and even the mechanism
of cell death. The incorporation of negative charged ligands provides
a simple chemical approach to modify the biological properties of
light-activated RuÂ(II) cytotoxic agents
Design of Cytochrome P450 1B1 Inhibitors <i>via</i> a Scaffold-Hopping Approach
Cytochrome
P450 1B1 (CYP1B1) is a potential drug target in cancer
research that is overexpressed in several solid tumors but is present
only at low levels in healthy tissues. Its expression is associated
with resistance to common chemotherapeutics, while inhibitors restore
efficacy to these drugs in model systems. The majority of CYP1B1 inhibitors
are derived from a limited number of scaffolds, and few have achieved
outstanding selectivity against other human CYPs, which could impede
clinical development. This study explores a new chemical space for
CYP1B1 inhibitors using a scaffold-hopping approach and establishes
2,4-diarylthiazoles as a promising framework for further development.
From a small library, compound 15 emerged as the lead,
with picomolar CYP1B1 inhibition, and over 19,000-fold selectivity
against its relative, CYP1A1. To investigate the activity of 15, molecular dynamics, optical spectroscopy, point mutations,
and traditional structureâactivity relationships were employed
and revealed key interactions important for the development of CYP1B1
inhibitors
Photoactive Ru(II) Complexes With Dioxinophenanthroline Ligands Are Potent Cytotoxic Agents
Two
novel strained rutheniumÂ(II) polypyridyl complexes containing a 2,3-dihydro-1,4-dioxinoÂ[2,3-<i>f</i>]-1,10-phenanthroline (dop) ligand selectively ejected
a methylated ligand when irradiated with >400 nm light. The best
compound exhibited a 1880-fold increase in cytotoxicity in human cancer
cells upon light-activation and was 19-fold more potent than the well-known
chemotherapeutic, cisplatin
Bacterial Cytological Profiling Reveals the Mechanism of Action of Anticancer Metal Complexes
Target
identification and mechanistic studies of cytotoxic agents
are challenging processes that are both time-consuming and costly.
Here we describe an approach to mechanism of action studies for potential
anticancer compounds by utilizing the simple prokaryotic system, <i>E. coli,</i> and we demonstrate its utility with the characterization
of a ruthenium polypyridyl complex [RuÂ(bpy)<sub>2</sub>dmbpy<sup>2+</sup>]. Expression of the photoconvertible fluorescent protein Dendra2
facilitated both high throughput studies and single-cell imaging.
This allowed for simultaneous ratiometric analysis of inhibition of
protein production and phenotypic investigations. The profile of protein
production, filament size and population, and nucleoid morphology
revealed important differences between inorganic agents that damage
DNA vs more selective inhibitors of transcription and translation.
Trace metal analysis demonstrated that DNA is the preferred nucleic
acid target of the ruthenium complex, but further studies in human
cancer cells revealed altered cell signaling pathways compared to
the commonly administrated anticancer agent cisplatin. This study
demonstrates <i>E. coli</i> can be used to rapidly distinguish
between compounds with disparate mechanisms of action and also for
more subtle distinctions within in studies in mammalian cells
Photoactive Ru(II) Complexes With Dioxinophenanthroline Ligands Are Potent Cytotoxic Agents
Two
novel strained rutheniumÂ(II) polypyridyl complexes containing a 2,3-dihydro-1,4-dioxinoÂ[2,3-<i>f</i>]-1,10-phenanthroline (dop) ligand selectively ejected
a methylated ligand when irradiated with >400 nm light. The best
compound exhibited a 1880-fold increase in cytotoxicity in human cancer
cells upon light-activation and was 19-fold more potent than the well-known
chemotherapeutic, cisplatin
Photoactive Ru(II) Complexes With Dioxinophenanthroline Ligands Are Potent Cytotoxic Agents
Two
novel strained rutheniumÂ(II) polypyridyl complexes containing a 2,3-dihydro-1,4-dioxinoÂ[2,3-<i>f</i>]-1,10-phenanthroline (dop) ligand selectively ejected
a methylated ligand when irradiated with >400 nm light. The best
compound exhibited a 1880-fold increase in cytotoxicity in human cancer
cells upon light-activation and was 19-fold more potent than the well-known
chemotherapeutic, cisplatin