ABSTRACT
Bioactive NHC-transition metal complexes have shown promise as anti-cancer agents, but their potential use as radiosensitizers has been neglected so far. We disclose here a new series of bimetallic platinum(II) complexes displaying NHC-type bridging ligands, (bis-NHC)[trans-Pt(RNH2)I2]2, that have been synthesized via a simple, two-step procedure. They display cytotoxicity in the micromolar range on cancerous cell lines, accumulate in cells, and bind to genomic DNA, by inducing DNA damages. Notably, these bimetallic complexes demonstrate significant radiosensitizing effects on both ovarian cells A2780 and nonsmall lung carcinoma cells H1299. Further investigations revealed that bimetallic species make irradiation-induced DNA damages more persistent by inhibiting repair mechanisms. Indeed, a higher and persistent accumulation of both γ-H2AX and 53BP1 foci post-irradiation was detected, in the presence of the NHC-Pt complexes. Overall, we provide the first in vitro evidence for the radiosensitizing properties of NHC-platinum complexes, which suggests their potential use in combined chemo-radio therapy protocols.
Subject(s)
Ovarian Neoplasms , Radiation-Sensitizing Agents , Humans , Female , Platinum/pharmacology , Amines , Cell Line, Tumor , Radiation-Sensitizing Agents/pharmacologyABSTRACT
N-Heterocyclic carbene (NHC) platinum complexes have been highlighted as a promising and original platform for building new cytotoxic drugs of the cisplatin series. Mixed NHC-amine Pt(II) complexes have been prepared via a facile and modular two step sequence leading to trans-configured square planar species. They have been characterized by spectroscopic methods and X-ray diffraction studies. Their efficiency against both cisplatin sensitive (CEM and H460) and resistant (A2780/DDP, CH1/DDP, and SK-OV-3) cell lines has been demonstrated by in vitro experiments.
Subject(s)
Antineoplastic Agents/chemistry , Imidazoles/chemistry , Organoplatinum Compounds/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Imidazoles/pharmacology , Magnetic Resonance Spectroscopy , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/pharmacology , Structure-Activity Relationship , X-Ray DiffractionABSTRACT
A new family of cyclometalated (N-heterocyclic carbene)-Pt(II) complexes bearing monodentate phosphines as ancillary ligands has been designed for use as precatalysts in 1,6-enyne cycloisomerization reactions. Highly enantioselective skeletal rearrangements of allylpropargyl-tosylamide derivatives have been developed by using (S)-Ph-Binepine as the chiral auxiliary. Enantiomeric excesses up to 97% have been obtained.
Subject(s)
Alkynes/chemistry , Heterocyclic Compounds, 1-Ring/chemical synthesis , Organometallic Compounds/chemical synthesis , Platinum/chemistry , Catalysis , Cyclization , Heterocyclic Compounds, 1-Ring/chemistry , Organometallic Compounds/chemistry , StereoisomerismABSTRACT
2-trifluoromethylquinolines 5 are synthesized in high yields using a perfluoroalkylated gem-iodoacetoxy derivative 3 and arylamines 4. The intermediate of this reaction, 2-trifluoromethyl-1,5-diazapentadiene compound 6, was isolated. The procedures are easy, and yields are in general high. This sequence represents a valuable new synthesis of substituted 2-trifluoromethylquinolines and of 2-trifluoromethyl-diazapentadienes (vinamidine compounds).
Subject(s)
Aniline Compounds/chemical synthesis , Quinolines/chemical synthesis , Vinblastine/analogs & derivatives , Vinblastine/chemical synthesis , Aniline Compounds/chemistry , Cyclization , Molecular Structure , Quinolines/chemistry , StereoisomerismABSTRACT
Incorporation of biotinylated-[rhodium(diphosphine)]+ complexes, with enantiopure amino acid spacers, in streptavidin affords solvent-tolerant and selective artificial metalloenzymes: up to 91% ee (S) in the hydrogenation of N-protected dehydroamino acids.
Subject(s)
Amino Acids/chemistry , Biotin/chemistry , Organometallic Compounds/chemistry , Phosphines/chemistry , Rhodium/chemistry , Streptavidin/chemistry , Catalysis , Hydrogenation , Ligands , Molecular Structure , Organometallic Compounds/chemical synthesis , Solvents/chemistry , StereoisomerismABSTRACT
We report on the generation of artificial metalloenzymes based on the noncovalent incorporation of biotinylated rhodium-diphosphine complexes in (strept)avidin as host proteins. A chemogenetic optimization procedure allows one to optimize the enantioselectivity for the reduction of acetamidoacrylic acid (up to 96% ee (R) in streptavidin S112G and up to 80% ee (S) in WT avidin). The association constant between a prototypical cationic biotinylated rhodium-diphosphine catalyst precursor and the host proteins was determined at neutral pH: log K(a) = 7.7 for avidin (pI = 10.4) and log K(a) = 7.1 for streptavidin (pI = 6.4). It is shown that the optimal operating conditions for the enantioselective reduction are 5 bar at 30 degrees C with a 1% catalyst loading.
Subject(s)
Avidin/analogs & derivatives , Enzymes/chemistry , Metalloproteins/chemistry , Phosphines/chemistry , Rhodium/chemistry , Streptavidin/analogs & derivatives , Acrylates/chemistry , Avidin/biosynthesis , Avidin/chemistry , Avidin/genetics , Bacillus subtilis/genetics , Bacillus subtilis/metabolism , Biotin/analogs & derivatives , Biotin/chemistry , Catalysis , Enzymes/chemical synthesis , Hydrogenation , Kinetics , Metalloproteins/chemical synthesis , Models, Molecular , Mutagenesis, Site-Directed , Stereoisomerism , Streptavidin/biosynthesis , Streptavidin/chemistry , Streptavidin/geneticsABSTRACT
Homogeneous and enzymatic catalysis offer complementary means to generate enantiomerically pure compounds. Incorporation of achiral biotinylated rhodium-diphosphine complexes into (strept)avidin yields artificial metalloenzymes for the hydrogenation of N-protected dehydroamino acids. A chemogenetic optimization procedure allows one to produce (R)-acetamidoalanine with 96% enantioselectivity. These hybrid catalysts display features reminiscent both of enzymatic and of homogeneous systems.
