Cancer cells usually adapt metabolic phenotypes to chemotherapeutics.Adefensive strategy against this flexibility is to modulate signaling pathwaysr elevant to cancer bioenergetics.Atriphenylphosphonium-modified terpyridine platinum(II) complex (TTP) was designed to inhibit thioredoxin reductase (TrxR) and multiple metabolisms of cancer cells. TTP exhibited enhanced cytotoxicity against cisplatin-insensitive human ovarian cancer cells in ac aspase-3-independent manner and showed preferential inhibition to mitochondrial TrxR. The morphology and function of mitochondria were severely damaged, and the levels of mitochondrial and cellular reactive oxygen species were decreased. As ar esult, TTP exerted strong inhibition to both mitochondrial and glycolytic bioenergetics,t hus inducing cancer cells to enter ah ypometabolic state.
Platinum(IV) complexes are prodrugs of cisplatin with multiple potential advantages over platinum(II) drugs. Mitochondria play pivotal roles in producing energy and inducing death of cancer cells. Two platinum(IV) complexes, namely, c,c,t-[Pt(NH)Cl(OH)(OCOCHCHCHCHPPh)]Br and c,c,t-[Pt(NH)Cl(OCOCHCHCHCHPPh)]Br, were designed to explore the effect of mitochondrion-targeting group(s) on the bioactivity and cytotoxicity of platinum(IV) complexes. The complexes were characterized by electrospray ionization mass spectrometry, reverse-phase high-performance liquid chromatography, and multinuclear (H, C,P, and Pt) NMR spectroscopy. The introduction of triphenylphosphonium targeting group(s) markedly influences the reactivity and cytotoxicity of the Pt(IV) complexes. The targeted complex displays more potent disruptive effect on mitochondria but less inhibitory effect on cancer cells than cisplatin. The lipophilicity of the Pt(IV) complexes is enhanced by the targeting group(s), while their reactivity to DNA is decreased. As a result, the mitochondrial morphology and adenosine triphosphate producing ability are impaired, which constitutes an alternative pathway to inhibit cancer cells. This study shows that both the reactivity of platinum(IV) center and the property of axial targeting ligand exert influences on the cytotoxicity of targeted Pt(IV) complexes. For targeting groups with pharmacological activities, their intrinsic function could enrich the anticancer mechanism of Pt(IV) complexes.
The synthesis and reactivity of a series of sodium and rare-earth metal complexes stabilized by a dianionic N-aryloxo-functionalized beta-ketoiminate ligand were presented. The reaction of acetylacetone with 1 equiv of 2-amino-4-methylphenol in absolute ethanol gave the compound 4-(2-hydroxy-5-methylphenyl)imino-2-pentanone (LH2, 1) in high yield. Compound 1 reacted with excess NaH to afford the novel sodium cluster [LNa2(THF)2]4 (2) in good isolated yield. Structure determination revealed that complex 2 has the 22-vertex cage structure. Reactions of complex 2 with anhydrous LnCl3 in a 1:4 molar ratio, after workup, gave the desired lanthanide chlorides [LLnCl(DME)]2 [Ln = Y (3), Yb (4), Tb (5)] as dimers. A further study revealed that complexes 3-5 are inert for chlorine substitution reactions. (ArO)3Ln(THF) (ArO = 2,6-Bu(t)2-4-MeC6H2O) reacted with compound 1 in a 1:1 molar ratio in tetrahydrofuran (THF), after workup, to give the desired rare-earth metal aryloxides as dimers [LLn(OAr)(THF)]2 [Ln = Nd (6), Sm (7), Yb (8), Y (9)] in high isolated yields. All of these complexes are well characterized, and the definitive molecular structures of complexes 2 and 4-6 were determined. It was found that complexes 6-9 can be used as efficient initiators for L-lactide polymerization, and the ionic radii of the central metals have a significant effect on the catalytic activity.
The synthesis and catalytic activity of lanthanide monoamido complexes supported by a beta-diketiminate ligand are described. Donor solvents, such as DME, can cleave the chloro bridges of the dinuclear beta-diketiminate ytterbium dichloride {[(DIPPh)2nacnac]YbCl(mu-Cl)3Yb[(DIPPh)2nacnac](THF)} (1) [(DIPPh)2nacnac = N,N-diisopropylphenyl-2,4-pentanediimine anion] to produce the monomeric complex [(DIPPh)2nacnac]YbCl2(DME) (2) in high isolated yield. Complex 2 is a useful precursor for the synthesis of beta-diketiminate-ytterbium monoamido derivatives. Reaction of complex 2 with 1 equiv of LiNPri2 in THF at room temperature, after crystallization in THF/toluene mixed solvent, gave the anionic beta-diketiminate-ytterbium amido complex [(DIPPh)2nacnac]Yb(NPri2)(mu-Cl)2Li(THF)2 (3), while similar reaction of complex 2 with LiNPh2 produced the neutral complex [(DIPPh)2nacnac]Yb(NPh2)Cl(THF) (4). Recrystallization of complex 3 from toluene solution at elevated temperature led to the neutral beta-diketiminate-lanthanide amido complex [{(DIPPh)2nacnac}Yb(NPri2)(mu-Cl)]2 (5). The reaction medium has a significant effect on the outcome of the reaction. Complex 2 reacted with 1 equiv of LiNPri2 and LiNC5H10 in toluene to produce directly the neutral beta-diketiminate-lanthanide amido complexes 5 and [{(DIPPh)2nacnac}Yb(NC5H10)(THF)(mu-Cl)]2 (6), respectively. These complexes were well characterized, and their crystal structures were determined. Complexes 4-6 exhibited good catalytic activity for the polymerization of methyl methacrylate and epsilon-caprolactone.
Cancer
is characterized by abnormal cellular energy metabolism, which preferentially
switches to aerobic glycolysis rather than oxidative phosphorylation
as a means of glucose metabolism. Many key enzymes involved in the
abnormal glycolysis are potential targets of anticancer drugs. Platinum(IV)
complexes are potential anticancer prodrugs and kinetically more inert
than the platinum(II) counterparts, which offer an opportunity to
be modified by functional ligands for activation or targeted delivery.
A novel platinum(IV) complex, c,c,t-[Pt(NH3)2Cl2(C10H15N2O3S)(C2HO2Cl2)] (DPB), was designed to explore the
effects of axial ligands on the reactivity and bioactivity of the
complex as well as on tumor energy metabolism. The complex was characterized
by electrospray ionization mass spectrometry and multinuclear (1H, 13C, and 195Pt) NMR spectroscopy.
The introduction of dichloroacetate (DCA) markedly increases the lipophilicity,
reactivity, and cytotoxicity of the complex and blocks the growth
of cancer cells having active glycolysis, and the introduction of
biotin (C10H16N2O3S) enhances
the tumor-targeting potential of the complex. The cytotoxicity of
DPB is increased dramatically in a variety of cancer cell lines as
compared with the platinum(IV) complex PB without the DCA group. DPB
alters the mitochondrial membrane potential and disrupts the mitochondrial
morphology. The levels of mitochondrial and cellular reactive oxygen
species are also decreased. Furthermore, the mitochondrial function
of tumor cells was impaired by DPB, leading to the inhibition of both
glycolysis and glucose oxidation and finally to the death of cancer
cells via a mitochondria-mediated apoptotic pathway. These findings
demonstrate that DPB suppresses cancer cells mainly through altering
metabolic pathways and highlight the importance of dual-targeting
for the efficacy of anticancer drugs.
Three divalent ytterbium complexes supported by a β-diketiminate ligand were synthesized
for the first time. The mixed-ligand ytterbium chlorides (CH3C5H4)[(DIPPh)2nacnac]YbCl
(1), (C9H7)[(DIPPh)2nacnac]YbCl (2), and (ArO)[(DIPPh)2nacnac]YbCl(THF) (3) ((DIPPh)2nacnac
= N,N-diisopropylphenyl-2, 4-pentanediimine anion, ArO = 2,6-di-tert-butyl-4-methylphenoxo), which were obtained in high yield by using [(DIPPh)2nacnac]YbCl2(THF)2 as precursor,
were reduced by Na/K alloy in THF to afford the corresponding divalent species
(CH3C5H4)[(DIPPh)2nacnac]Yb(THF) (4), (C9H7)[(DIPPh)2nacnac]Yb(THF) (5), and {(ArO)[(DIPPh)2nacnac]Yb(THF)}(THF) (6), respectively. Complexes 2−6 were well characterized,
and crystal structures of complexes 4−6 were determined. These divalent complexes exhibit
good catalytic activity for the polymerization of methyl methacrylate.
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