We
report herein the design, synthesis, and biological investigation
of a series of novel Pt(IV) prodrugs with non-steroidal anti-inflammatory
drugs naproxen, diclofenac, and flurbiprofen, as well as these with
stearic acid in the axial position. Six Pt(IV) prodrugs 5–10 were designed, which showed superior antiproliferative activity
compared to cisplatin as well as an ability to overcome tumor cell
line resistance to cisplatin. By tuning the drug lipophilicity via
variation of the axial ligands, the most potent Pt(IV) prodrug 7 was obtained, with an enhanced cellular accumulation of
up to 153-fold that of cisplatin and nanomolar cytotoxicity both in
2D and 3D cell cultures. Pt2+ species were detected at
different depths of MCF-7 spheroids after incubation with Pt(IV) prodrugs
using a Pt-coated carbon nanoelectrode. Cisplatin accumulation in
vivo in the murine mammary EMT6 tumor tissue of BALB/c mice after
Pt(IV) prodrug injection was proved electrochemically as well. The
drug tolerance study on BALB/c mice showed good tolerance of 7 in doses up to 8 mg/kg.
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.
The
modification of Chan–Lam–Evans cross-coupling
reaction for the selective Se-arylation of 2-selenohydantoins under
base-free mild conditions via aryl boronic acids is described herein.
This approach was used to synthesize novel 5-arylidene-3-substituted-2-(arylselanyl)-imidazoline-4-ones
with high yields. The anticancer activity of the final compounds was
evaluated in vitro against different cancer cells, and thus, the possibility
of 5-arylidene-3-substituted-2-(arylselanyl)-imidazoline-4-ones successful
application as cytotoxic agents was demonstrated.
A novel approach to the synthesis of pH-sensitive prodrugs has been proposed: thiourea drug modification. Resulting prodrugs can release the cytotoxic agent and the biologically active 2-thiohydantoin in the acidic environment of tumor cells. The concept of acid-catalyzed cyclization of thioureas to 2-thiohydantoins has been proven using a FRET model. Dual prodrugs of model azidothymidine, cytotoxic doxorubicin, and 2-thiohydantoin albutoin were obtained, which release the corresponding drugs in the acidic environment. The resulting doxorubicin prodrug was tested on prostate cancer cells and showed that the thiourea-modified prodrug is less cytotoxic (average IC50 ranging from 0.5584 to 0.9885 μM) than doxorubicin (IC50 ranging from 0.01258 to 0.02559 μM) in neutral pH 7.6 and has similar toxicity (average IC50 ranging from 0.4970 to 0.7994 μM) to doxorubicin (IC50 ranging from 0.2303 to 0.8110 μM) under mildly acidic conditions of cancer cells. Cellular and nuclear accumulation in PC3 tumor cells of Dox prodrug is much higher than accumulation of free doxorubicin.
In recent research paper Dr. Suxing Jin et al. reported two multispecific platinum(IV) complexes DNP and NP with non‐steroidal anti-inflammatory drug naproxen (NPX) as axial ligand(s). Herein, we сlarify a...
Nitrosonium ethyl sulfate reacts with O-alkylphenols and N,N-dialkylanilines to give the corresponding 4-nitrosoarenes. The reaction is not accompanied by side processes characteristic of common nitrosating agents. Diazotization of primary aromatic amines with nitrosonium ethyl sulfate yields stable diazonium salts, which are promising reagents for organic synthesis.
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