6 research outputs found
Radical Chemistry and Cytotoxicity of Bioreductive 3āSubstituted Quinoxaline Diā<i>N</i>āOxides
The
radical chemistry and cytotoxicity of a series of quinoxaline di-<i>N</i>-oxide (QDO) compounds has been investigated to explore
the mechanism of action of this class of bioreductive drugs. A series
of water-soluble 3-trifluoromethyl (<b>4</b>ā<b>10</b>), 3-phenyl (<b>11</b>ā<b>19</b>), and 3-methyl
(<b>20</b>-<b>21</b>) substituted QDO compounds were designed
to span a range of electron affinities consistent with bioreduction.
The stoichiometry of loss of QDOs by steady-state radiolysis of anaerobic
aqueous formate buffer indicated that one-electron reduction of QDOs
generates radicals able to initiate chain reactions by oxidation of
formate. The 3-trifluoromethyl analogues exhibited long chain reactions
consistent with the release of the HO<sup>ā¢</sup>, as identified
in EPR spin trapping experiments. Several carbon-centered radical
intermediates, produced by anaerobic incubation of the QDO compounds
with N-terminal truncated cytochrome P450 reductase (POR), were characterized
using <i>N</i>-<i>tert</i>-butyl-Ī±-phenylnitrone
(PBN) and 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline-<i>N</i>-oxide (DEPMPO) spin
traps and were observed by EPR. Experimental data were well simulated
for the production of strongly oxidizing radicals, capable of H atom
abstraction from methyl groups. The kinetics of formation and decay
of the radicals produced following one-electron reduction of the parent
compounds, both in oxic and anoxic solutions, were determined using
pulse radiolysis. Back oxidation of the initially formed radical anions
by molecular oxygen did not compete effectively with the breakdown
of the radical anions to form oxidizing radicals. The QDO compounds
displayed low hypoxic selectivity when tested against oxic and hypoxic
cancer cell lines <i>in vitro</i>. The results from this
study form a kinetic description and explanation of the low hypoxia-selective
cytotoxicity of QDOs against cancer cells compared to the related
benzotriazine 1,4-dioxide (BTO) class of compounds
Anticancer Ruthenium(Ī·<sup>6</sup>ā<i>p</i>ācymene) Complexes of Nonsteroidal Anti-inflammatory Drug Derivatives
Oxicams
are a versatile family of heterocyclic compounds, and the
two representatives meloxicam and piroxicam are widely used drugs
for the treatment of a variety of inflammatory and rheumatic diseases
in humans. As cancer-associated inflammation is known to occur in
carcinogenesis, we aimed to combine compounds carrying bioactive oxicam
moieties with rutheniumĀ(arene) fragments, known for anticancer activity.
Ru<sup>II</sup>(arene) complexes with methyl ester derivatives of
the oxicam scaffold were prepared and characterized by standard methods
and crystallographically. The organoruthenium compounds formed from
Ru<sup>II</sup>(Ī·<sup>6</sup>-<i>p</i>-cymene) chlorido
moieties and oxicam-based ligands were subjected to bioanalytical
investigations to establish their physicochemical properties with
regard to stability in DMSO and water as well as reactivity toward
the amino acids l-histidine (His), l-methionine
(Met), and l-cysteine (Cys) and the DNA model compound guanosine
5ā²-monophosphate (5ā²-GMP). The compounds hydrolyzed
rapidly in water to give the respective aqua complexes, formed amino
acid complexes with Met and His, but decompose with Cys, while interaction
with 5ā²-GMP was through its phosphate residue. The anticancer
activity of the complexes against the colon carcinoma HCT116 and breast
cancer MDA MB 231 cancer cell lines was established using an <i>in vitro</i> assay. The cytotoxicity was found strongly dependent
on the lipophilicity of the compound, as was shown through correlation
with log<i> k</i><sub>w</sub> and clog<i> P</i> values of the ligands. The most lipophilic compound [chloridoĀ(methyl
4-oxido-2-benzyl-2<i>H</i>-1,2-benzothiazine-3-carboxylate-1,1-dioxide)Ā(Ī·<sup>6</sup>-<i>p</i>-cymene)ĀrutheniumĀ(II)] was the most active
in the cell assays, with an IC<sub>50</sub> of 80 Ī¼M in HCT116
cells
New IminodiacetateāThiosemicarbazone Hybrids and Their Copper(II) Complexes Are Potential Ribonucleotide Reductase R2 Inhibitors with High Antiproliferative Activity
As ribonucleotide
reductase (RNR) plays a crucial role in nucleic acid metabolism, it
is an important target for anticancer therapy. The thiosemicarbazone
Triapine is an efficient R2 inhibitor, which has entered ā¼20
clinical trials. Thiosemicarbazones are supposed to exert their biological
effects through effectively binding transition-metal ions. In this
study, six iminodiacetateāthiosemicarbazones able to form transition-metal
complexes, as well as six dicopperĀ(II) complexes, were synthesized
and fully characterized by analytical, spectroscopic techniques (IR,
UVāvis; <sup>1</sup>H and <sup>13</sup>C NMR), electrospray
ionization mass spectrometry, and X-ray diffraction. The antiproliferative
effects were examined in several human cancer and one noncancerous
cell lines. Several of the compounds showed high cytotoxicity and
marked selectivity for cancer cells. On the basis of this, and on
molecular docking calculations one lead dicopperĀ(II) complex and one
thiosemicarbazone were chosen for in vitro analysis as potential R2
inhibitors. Their interaction with R2 and effect on the FeĀ(III)<sub>2</sub>-YĀ· cofactor were characterized by microscale thermophoresis,
and two spectroscopic techniques, namely, electron paramagnetic resonance
and UVāvis spectroscopy. Our findings suggest that several
of the synthesized proligands and copperĀ(II) complexes are effective
antiproliferative agents in several cancer cell lines, targeting RNR,
which deserve further investigation as potential anticancer drugs
New IminodiacetateāThiosemicarbazone Hybrids and Their Copper(II) Complexes Are Potential Ribonucleotide Reductase R2 Inhibitors with High Antiproliferative Activity
As ribonucleotide
reductase (RNR) plays a crucial role in nucleic acid metabolism, it
is an important target for anticancer therapy. The thiosemicarbazone
Triapine is an efficient R2 inhibitor, which has entered ā¼20
clinical trials. Thiosemicarbazones are supposed to exert their biological
effects through effectively binding transition-metal ions. In this
study, six iminodiacetateāthiosemicarbazones able to form transition-metal
complexes, as well as six dicopperĀ(II) complexes, were synthesized
and fully characterized by analytical, spectroscopic techniques (IR,
UVāvis; <sup>1</sup>H and <sup>13</sup>C NMR), electrospray
ionization mass spectrometry, and X-ray diffraction. The antiproliferative
effects were examined in several human cancer and one noncancerous
cell lines. Several of the compounds showed high cytotoxicity and
marked selectivity for cancer cells. On the basis of this, and on
molecular docking calculations one lead dicopperĀ(II) complex and one
thiosemicarbazone were chosen for in vitro analysis as potential R2
inhibitors. Their interaction with R2 and effect on the FeĀ(III)<sub>2</sub>-YĀ· cofactor were characterized by microscale thermophoresis,
and two spectroscopic techniques, namely, electron paramagnetic resonance
and UVāvis spectroscopy. Our findings suggest that several
of the synthesized proligands and copperĀ(II) complexes are effective
antiproliferative agents in several cancer cell lines, targeting RNR,
which deserve further investigation as potential anticancer drugs
New IminodiacetateāThiosemicarbazone Hybrids and Their Copper(II) Complexes Are Potential Ribonucleotide Reductase R2 Inhibitors with High Antiproliferative Activity
As ribonucleotide
reductase (RNR) plays a crucial role in nucleic acid metabolism, it
is an important target for anticancer therapy. The thiosemicarbazone
Triapine is an efficient R2 inhibitor, which has entered ā¼20
clinical trials. Thiosemicarbazones are supposed to exert their biological
effects through effectively binding transition-metal ions. In this
study, six iminodiacetateāthiosemicarbazones able to form transition-metal
complexes, as well as six dicopperĀ(II) complexes, were synthesized
and fully characterized by analytical, spectroscopic techniques (IR,
UVāvis; <sup>1</sup>H and <sup>13</sup>C NMR), electrospray
ionization mass spectrometry, and X-ray diffraction. The antiproliferative
effects were examined in several human cancer and one noncancerous
cell lines. Several of the compounds showed high cytotoxicity and
marked selectivity for cancer cells. On the basis of this, and on
molecular docking calculations one lead dicopperĀ(II) complex and one
thiosemicarbazone were chosen for in vitro analysis as potential R2
inhibitors. Their interaction with R2 and effect on the FeĀ(III)<sub>2</sub>-YĀ· cofactor were characterized by microscale thermophoresis,
and two spectroscopic techniques, namely, electron paramagnetic resonance
and UVāvis spectroscopy. Our findings suggest that several
of the synthesized proligands and copperĀ(II) complexes are effective
antiproliferative agents in several cancer cell lines, targeting RNR,
which deserve further investigation as potential anticancer drugs
From Catalysis to Cancer: Toward StructureāActivity Relationships for Benzimidazol-2-ylidene-Derived <i>N</i>āHeterocyclic-Carbene Complexes as Anticancer Agents
The promise of the metalĀ(arene) structure
as an anticancer pharmacophore has prompted intensive exploration
of this chemical space. While <i>N</i>-heterocyclic carbene
(NHC) ligands are widely used in catalysis, they have only recently
been considered in metal complexes for medicinal applications. Surprisingly,
a comparatively small number of studies have been reported in which
the NHC ligand was coordinated to the Ru<sup>II</sup>(arene) pharmacophore
and even less with an Os<sup>II</sup>(arene) pharmacophore. Here,
we present a systematic study in which we compared symmetrically substituted
methyl and benzyl derivatives with the nonsymmetric methyl/benzyl
analogues. Through variation of the metal center and the halido ligands,
an in-depth study was conducted on ligand exchange properties of these
complexes and their biomolecule binding, noting in particular the
stability of the MāC<sub>NHC</sub> bond. In addition, we demonstrated
the ability of the complexes to inhibit the selenoenzyme thioredoxin
reductase (TrxR), suggested as an important target for anticancer
metalāNHC complexes, and their cytotoxicity in human tumor
cells. It was found that the most potent TrxR inhibitor diiodidoĀ(1,3-dibenzylbenzimidazol-2-ylidene)Ā(Ī·<sup>6</sup>-p-cymene)ĀrutheniumĀ(II) <b>1b</b><sup><b>I</b></sup> was also the most cytotoxic compound of the series, with the
antiproliferative effects in general in the low to middle micromolar
range. However, since there was no clear correlation between TrxR
inhibition and antiproliferative potency across the compounds, TrxR
inhibition is unlikely to be the main mode of action for the compound
type and other target interactions must be considered in future