48 results on '"Wang, Fuyi"'
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2. Adenine–adenine, adenine–cytosine and cytosine–cytosine intrastrand crosslinks induced by a photoactivatable Pt(IV) anticancer prodrug.
- Author
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Lin, Jiafan, Huang, Jingjing, Zhang, Jishuai, Qin, Xinrui, Ma, Ziqi, Wu, Xiaoqin, Wang, Fuyi, Zhao, Yao, and Wu, Kui
- Subjects
ADENINE ,ELECTROSPRAY ionization mass spectrometry ,TANDEM mass spectrometry ,MASS spectrometry - Abstract
Four trinucleotides 5′-ATA-3′ (I), 5′-ATC-3′ (II), 5′-CTA-3′ (III) and 5′-CTC-3′ (IV) were introduced to interact with a diazido-based photoactivatable anticancer prodrug trans,trans,trans-[Pt
IV (N3 )2 (OH)2 (py)2 ] (py = pyridine; 1) upon light irradiation. Using electrospray ionization mass spectrometry (ESI-MS), we aimed to investigate the possibility of 1,3-intrastrand crosslinks at adenine and/or cytosine in the trinucleotides via the bi-functional trans-[PtII (py)2 ]2+ species generated by photodecomposition of complex 1. The primary mass spectrometry results showed that although mono- and di-platinated trinucleotides bound by mono-functional trans-[PtII (N3 )(py)2 ]+ species were the major platinated adducts, comparable amounts of bifunctional trans-[PtII (py)2 ]2+ -bound trinucleotides were also observed. Further tandem mass spectrometry of the trans-[PtII (py)2 ]2+ -bound trinucleotides showed the formation of 1,3-crosslinks between adenine–adenine, adenine–cytosine and cytosine–cytosine bases in the trinucleotides. The formation of such unique structures is not only distinct from the action modes of cisplatin with DNA but also an important complement to the acknowledged 1,3-GNG intrastrand crosslink by trans-Pt species, which may support the promising and distinct anticancer activities of such photoactivatable diazido Pt(IV) anticancer prodrugs and deserve further studies. [ABSTRACT FROM AUTHOR]- Published
- 2024
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3. Ruthenium(II) polypyridyl complexes with visible light-enhanced anticancer activity and multimodal cell imaging.
- Author
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Kang, Yan, Zhao, Yao, Wei, Yuanyuan, Zhang, Yang, Wang, Zhaoying, Luo, Qun, Du, Jun, and Wang, Fuyi
- Subjects
LIGANDS (Chemistry) ,ANTINEOPLASTIC agents ,CELL imaging ,SECONDARY ion mass spectrometry ,EPIDERMAL growth factor receptors ,RUTHENIUM ,ELECTROCHEMILUMINESCENCE - Abstract
Ruthenium(II) polypyridyl complexes have drawn growing attention due to their photophysical properties and anticancer activity. Herein we report four ruthenium(II) polypyridyl complexes [(N^N)
2 RuII (L)]2+ (1–4, L = 4-anilinoquinazoline derivatives, N^N = bidentate ligands with bis-nitrogen donors) as multi-functional anticancer agents. The epidermal growth factor receptor (EGFR) is overexpressed in a broad range of cancer cells and related to many kinds of malignance. EGFR inhibitors, such as gefitinib and erlotinib, have been approved as clinical anticancer drugs. The EGFR-inhibiting 4-anilinoquinazoline ligands greatly enhanced the in vitro anticancer activity of these ruthenium(II) polypyridyl complexes against a series of human cancer cell lines compared to [Ru(bpy)2 (phen)], but interestingly, these complexes were actually not potent EGFR inhibitors. Further mechanism studies revealed that upon irradiation with visible light, complexes 3 and 4 generated a high level of singlet oxygen (1 O2 ), and their in vitro anticancer activities against human non-small-cell lung (A549), cervical (HeLa) and squamous (A431) cancer cells were significantly improved. Specifically, complex 3 displayed potent phototoxicity upon irradiation with blue light, of which the photo-toxicity indexes (PIs) against HeLa and A431 cells were 11 and 8.3, respectively. These complexes exhibited strong fluorescence emission at ca. 600 nm upon excitation at about 450 nm. A subcellular distribution study by fluorescence microscopy imaging and secondary ion mass spectrometry imaging (ToF-SIMS) demonstrated that complex 3 mainly localized at the cytoplasm and complex 4 mainly localized in the nuclei of cells. Competitive binding with ctDNA showed that complex 4 was more favorable to bind to the DNA minor groove than complex 3. These differences support that complex 3 possibly exerts its anticancer activities majorly by photo-induced1 O2 generation and complex 4 by binding to DNA. [ABSTRACT FROM AUTHOR]- Published
- 2023
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4. Reaction of human telomeric unit TTAGGG and a photoactivatable Pt(IV) anticancer prodrug.
- Author
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Lin, Jiafan, Zhang, Jishuai, Ma, Ziqi, Wu, Xiaoqin, Wang, Fuyi, Zhao, Yao, Wu, Kui, and Liu, Yi
- Subjects
HUMAN DNA ,DNA adducts ,MASS spectrometry ,DAMAGES (Law) ,MOIETIES (Chemistry) - Abstract
The interaction of a photoactivatable diazidodihydroxido Pt(IV) prodrug, trans,trans,trans-[Pt(N
3 )2 (OH)2 (py)2 ] (py = pyridine; 1), with a hexamer straight human telomeric DNA unit sequence (5′-T1 T2 A3 G4 G5 G6 -3′, I) upon light irradiation was investigated by electrospray ionization mass spectroscopy (ESI-MS). In the primary mass spectrum, two major mono-platinated I adducts with the bound Pt moieties, trans-[PtII (N3 )(py)2 ]+ (1′) and trans-[PtII (py)2 ]2+ (1′′), respectively, were detected. It is rare to observe such high abundance and nearly equal intensity platinated DNA adducts formed by these two PtII species because 1′ is usually the only major reduced Pt(II) species produced by the photodecomposition of complex 1 in the presence of DNA while 1′′ was rarely detected as the major reduced PtII species reported previously. Subsequent tandem mass spectrometric analysis by collision-induced dissociation (CID) showed that in the former adduct {I + 1′}2+ , G6 and A3 were the platination sites. While in the latter adduct {I + 1′′}2+ , a potential intrastrand crosslink was speculated after G4 and G6 sites were identified. Additionally, other minor platinated adducts like di-platinated I adduct by 1′ with platination sites at G4 and G6 and mono-platinated I adducts containing base oxidation were also detected by mass spectrometry. Due to the rich guanines and their sensitivity to oxidation, the oxidation induced by 1 most probably occurred at guanine. The oxidation adducts were proposed as 8-hydroxyl guanine, spiroiminodihydantoin (Sp), 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG), 5-guanidinohydantoin (Gh), and/or dehydroguanidinohydantoin (DGh) referring to previous reports. The obtained results provide useful chemical information about the photoreaction between photoactivatable Pt(IV) anticancer prodrugs and human telomeric DNA. Such special damages of Pt(IV) prodrugs on human telomeric DNA implicate its active role in the mechanism of Pt(IV) prodrugs and further support the unique sequence-dependent photointeraction profile of complex 1 reacting with DNA. [ABSTRACT FROM AUTHOR]- Published
- 2023
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5. Molecular unravelling of the mechanism of overpotential change at the carbon nanotubes-modified gold electrode surface.
- Author
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Zhang, Yanyan, Jin, Jing, Xue, Yifei, Zhao, Yao, Luo, Qun, Mao, Lanqun, and Wang, Fuyi
- Subjects
CARBON nanotubes ,GOLD electrodes ,SECONDARY ion mass spectrometry ,OVERPOTENTIAL - Abstract
Using liquid secondary ion mass spectrometry, we in situ unraveled that the single walled carbon nanotubes-modified gold electrode surface is free of a dense adsorption phase and abundant in water molecules, which facilitated the electro-oxidation reaction of ascorbate. Such an understanding will expedite the knowledge-based development of electrochemical interfaces. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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6. Surface n-type band bending for stable inverted CsPbI3 perovskite solar cells with over 20% efficiency.
- Author
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Wang, Shuo, Li, Ming-Hua, Zhang, Yanyan, Jiang, Yan, Xu, Li, Wang, Fuyi, and Hu, Jin-Song
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- 2023
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7. Differentiated oxidation modes of guanine between CpG and 5mCpG by a photoactivatable Pt(IV) anticancer prodrug.
- Author
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Ma, Ziqi, Zhang, Jishuai, Lin, Jiafan, Li, Wenbing, Wu, Xiaoqin, Wang, Fuyi, Zhao, Yao, and Wu, Kui
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BLUE light ,DNA damage ,DINUCLEOTIDES ,DNA sequencing ,GUANINE ,MOIETIES (Chemistry) ,DNA adducts - Abstract
CpG and its cytosine-methylated counterpart (
5m CpG) are a unique reversible pair of sequences in regulating the expression of genes epigenetically. As DNA is the potential target of Pt-based anticancer metallodrugs, herein, we comparatively investigate the interactions of 5′-CpG and 5′-5m CpG with a photoactivatable anticancer Pt(IV) prodrug, trans,trans,trans-[PtIV (N3 )2 (OH)2 (py)2 ] (1; py = pyridine), to explore the effects of methylation on the platination and ROS-induced oxidation of the CpG motif. Mono-platinated dinucleotides were demonstrated by ESI-MS to be the main products for both 5′-CpG and 5′-5m CpG with the bound Pt moiety as [PtII (N3 )(py)2 ] generated by the photodecomposition of complex 1 under irradiation with blue light, accompanied by the formation of less abundant di-platinated adducts. G-N7 and C-N3/5m C-N3 were shown to be the major and minor platination sites, respectively, with G-N1 as the third and weakest platination site, in particular, in di-platinated products. Moreover, platinated dinucleotides associated with guanine and/or cytosine oxidation were also observed. Apart from 8-oxo-guanine (ox G) and N-formylamidoiminohydantoin (RedSp) reported previously, novel oxidation adducts 5-guanidinohydantoin (Gh) derived from guanine and 1-carbamoyl-4,5-dihydroxy-2-oxoimidazolidine (ImidCyt) derived from cytosine in CpG, and diimino imidazole (DIz) and 2,5-diaminoimidazol-4-one (imidazolone, Iz) derived from guanine and Imid5m Cyt derived from5m C in5m CpG were proposed according to MS information. These results showed that methylation exerted little effects on the platination modes of CpG, but triggered distinct oxidation pathways of CpG, perhaps causing discriminated DNA damage to CpG-rich genes. This work provides novel insights into the role of the anticancer photoactivatable Pt(IV) prodrug through damaging the epigenetically modified DNA sequences. [ABSTRACT FROM AUTHOR]- Published
- 2023
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8. Advances in applications of piezoelectronic electrons in cell regulation and tissue regeneration.
- Author
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Zhou, Lijun, Yuan, Tao, Jin, Fei, Li, Tong, Qian, Lili, Wei, Zhidong, Zheng, Weiying, Ma, Xiying, Wang, Fuyi, and Feng, Zhang-Qi
- Abstract
Bioelectricity plays a significant role in major biological processes and electrical stimulation is an effective and non-invasive way to promote cellular growth, differentiation and tissue regeneration. In tissue engineering, piezoelectric materials not only act as modulators to regulate behaviors and functions of cells and tissues, but are also used as scaffolds to regulate and guide cell growth and matrix synthesis, thus promoting the formation of new tissue. Piezoelectronic electrons are produced from piezoelectric materials upon mechanical stimuli and have similar effects on cells as an external electrical field. Devices based on piezoelectronics have been widely applied in bioelectronics and biomedical fields. In this review, the effects of piezoelectronic electrons on cells and their possible mechanisms are briefly introduced. Then, we overview the applications of piezoelectronic electrons in cell regulation and tissue regeneration according to the type of cells and tissues. Finally, future perspectives and challenges are also provided. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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9. Dual-platination and induced oxidation of uridine by a photoactivatable diazido Pt(IV) anticancer prodrug.
- Author
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Gao, Fang, Zhang, Jishuai, Wu, Xiaoqin, Zhao, Yao, Wang, Fuyi, and Wu, Kui
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URIDINE ,ELECTROSPRAY ionization mass spectrometry ,NUCLEIC acids ,BASE pairs ,NUCLEAR magnetic resonance spectroscopy - Abstract
Photoactivatable Pt(IV) anticancer prodrug trans,trans,trans-[Pt(N
3 )2 (OH)2 (pyridine)2 ] (1) has been shown to bind to and induce oxidation of all four DNA nucleobases. Herein, to further render the binding spectrum of complex 1 to nucleic acids, the interaction between complex 1 and uridine, an exclusive RNA component, was investigated by electrospray ionization mass spectrometry (ESI-MS) and NMR spectroscopy. The results showed that complex 1 can bind to uridine through the N3 (major) and O4 (minor) sites upon light irradiation to form the major mono-platinated uridine adduct and the minor di-platinated uridine adduct. Moreover, mono-platinated uridine associated with the oxidation of uridine to 5-hydroxyuridine and 6-hydroxyuridine was also observed. This is the first report that the photoactivatable Pt(IV) prodrug binds to and induces the oxidation of uridine, and also the last piece of the puzzle for the interactions of complex 1 with nucleobases. Combined with our previous results about the interactions between complex 1 and DNA bases, these data showed a wide interaction spectrum of this kind of photoactivatable diazido Pt(IV) prodrugs with nucleobases through such dual-action modes, strongly suggesting that RNA may be a potential target of Pt(IV) prodrugs. [ABSTRACT FROM AUTHOR]- Published
- 2022
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10. Surface fluoride management for enhanced stability and efficiency of halide perovskite solar cells via a thermal evaporation method.
- Author
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Gu, Wei-Min, Zhang, Yue, Jiang, Ke-Jian, Yu, Guanghui, Xu, Yanting, Huang, Jin-Hua, Zhang, Yanyan, Wang, Fuyi, Li, Yawen, Lin, Yuze, Jiao, Xinning, Gao, Cai-Yan, Fan, Haochen, Wu, Ningning, Zhou, Xueqin, and Song, Yanlin
- Abstract
Halide perovskites are highly promising semiconductors for photovoltaics due to their high efficiency and simple solution processing. However, their halide-terminated surface is unstable due to the low binding energy of the Pb–I bond in the perovskites, which allows for surface defect formation and ion migration under external stresses, deteriorating the performance of perovskite solar cells (PSCs). Here, phenethylammonium fluoride (PEAF) is deposited on a perovskite film with controlled thickness via a fast thermal evaporation method at low temperatures and normal pressure, passivating the commonly existing surface halide vacancies without destabilizing the underlying perovskite and sacrificing charge transport in the PSC. Moreover, the fluoride anion in PEAF could undergo a strong interaction with the perovskites due to its high electronegativity, effectively reinforcing the structural stability of the perovskite film. The PEAF-treated PSCs exhibit high power conversion efficiency (PCE) of 23.2% with significantly enhanced stability. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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11. ToF-SIMS characterization of surface chemical evolution on electrode surfaces educed by electrochemical activation.
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Tang, Jilin, Ni, Zhigang, Zhang, Yanyan, Zhao, Yao, Luo, Qun, and Wang, Fuyi
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SURFACE analysis ,SURFACE chemistry ,GOLD electrodes ,AUTOMATIC control systems ,ELECTRODES ,SURFACE contamination - Abstract
Electrode–electrolyte interfaces are the heart of electrochemical reactions. Activation of electrode surfaces by electrochemical pretreatment can endow electrodes with promoted physicochemical properties to facilitate electron-transfer kinetics during electrochemical reactions. However, comprehensive understanding of the activation mechanism, especially in aspects of surface chemical evolution is limited. Herein, we applied ToF-SIMS in combination with SEM imaging to investigate the electrochemical activation in different stages of gold electrode surfaces in hydrochloric acid solution. The results unraveled the complicated activation mechanism, which not only involved the surface reconstruction with formation of an ultra-thin layer of nanoparticles, but also the significantly altered outmost surface chemistry of the electrodes such as the efficient removal of poisonous surface contamination species. We demonstrate that with the virtues of ultra-high surface sensitivity, shallow information depth, and rich molecular characterization information, ToF-SIMS is a powerful technique for characterization of surface chemistry of electrodes/electrocatalysts. The promising applications of ToF-SIMS will advance the fundamental understanding of the surface chemistry-electrochemical/electrocatalytic activity relationship and facilitate the control and engineering of electrochemical interfaces with promoted performance. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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12. Single cell imaging reveals cisplatin regulating interactions between transcription (co)factors and DNA.
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Lin, Yu, Wu, Kui, Jia, Feifei, Chen, Ling, Wang, Zhaoying, Zhang, Yanyan, Luo, Qun, Liu, Suyan, Qi, Luyu, Li, Nan, Dong, Pu, Gao, Fei, Zheng, Wei, Fang, Xiaohong, Zhao, Yao, and Wang, Fuyi
- Published
- 2021
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13. Open-flow microperfusion combined with mass spectrometry for in vivo liver lipidomic analysis.
- Author
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Li, Tuo, Yang, Hui, Li, Xing, Hou, Yinzhu, Zhao, Yao, Wu, Wenjing, Zhao, Lingyu, Wang, Fuyi, and Zhao, Zhenwen
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LIVER analysis ,MASS spectrometry ,MASS transfer ,MICRODIALYSIS ,LIPIDS - Abstract
At present, conventional microdialysis (MD) techniques cannot efficiently sample lipids in vivo, possibly due to the high mass transfer resistance and/or the serious adsorption of lipids onto the semi-permeable membrane of a MD probe. The in vivo monitoring of lipids could be of great significance for the study of disease development and mechanisms. In this work, an open-flow microperfusion (OFM) probe was fabricated, and the conditions for sampling lipids via OFM were optimized. Using OFM, the recovery of lipid standards was improved to more than 34.7%. OFM is used for the in vivo sampling of lipids in mouse liver tissue with fibrosis, and it is then combined with mass spectrometry (MS) to perform lipidomic analysis. 156 kinds of lipids were identified in the dialysate collected via OFM, and it was found that the phospholipid levels, including PC, PE, and SM, were significantly higher in a liver suffering from fibrosis. For the first time, OFM combined with MS to sample and analyze lipids has provided a promising platform for in vivo lipidomic studies. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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14. Photoactivatable diazido Pt(IV) anticancer complex can bind to and oxidize all four nucleosides.
- Author
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Cheng, Yiyu, Zhang, Jishuai, Wu, Kui, Gao, Fang, Cheng, Yang, Zou, Tao, Wu, Xiaoqin, Zhao, Yao, and Wang, Fuyi
- Subjects
NUCLEOSIDES ,VISIBLE spectra ,CANCER cells ,ADENOSINES ,CELL death - Abstract
Photoactivatable diazidodihydroxido Pt(IV) complex trans,trans,trans-[Pt(N
3 )2 (OH)2 (py)2 ] (1; py = pyridine) is a promising anticancer agent which can be activated by visible light to induce cancer cell death. DNA has been thought to be involved in the mechanism of action of this kind of Pt(IV) prodrug. However, the detailed photodecomposition pathways of complex 1 and its interaction modes with DNA are complex. Herein we report that upon light irradiation complex 1 can bind to all four nucleosides covalently with the reduced Pt(II) species. Moreover, apart from the covalent coordination, various oxidation adducts of these four nucleosides induced by the reactive oxidative species (ROS) generated during the photoactivation of the complex 1 have also been identified, especially the induced oxidation of adenosine and cytidine which was firstly reported for this kind of photoactivatable Pt(IV) prodrug. Such dual-action may contribute to the highly potent photo-antiproliferativity of complex 1 towards cancer cells, which may account for the unique mechanism of action of the photoactivatable diazido Pt(IV) anticancer complexes. [ABSTRACT FROM AUTHOR]- Published
- 2020
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15. Reactions of a photoactivatable diazido Pt(IV) anticancer complex with a single-stranded oligodeoxynucleotide.
- Author
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Liang, Zujun, Lin, Jiafan, Gong, Xianxian, Cheng, Yiyu, Huang, Chao, Zhang, Jishuai, Wu, Xiaoqin, Wang, Fuyi, Zhao, Yao, and Wu, Kui
- Subjects
REACTIVE oxygen species ,MASS spectrometry ,BINDING sites ,ANTINEOPLASTIC agents ,DNA adducts - Abstract
Platinum based anticancer agents are widely applied in clinic and their major target is believed to be DNA. Herein, the interaction of a photoactivatable diazido Pt(IV) anticancer prodrug trans,trans,trans-[Pt(N
3 )2 (OH)2 (py)2 ] (py = pyridine; 1) with a 15-mer single-G-containing oligodeoxynucleotide (ODN I: 5′-CT2 CTCTTG8 T9 CT11 TCTC-3′) was investigated by mass spectrometric methods. Up to penta-platinated ODN I adducts were identified from primary mass spectra while the mono- and di-platinated adducts had the highest intensity. Fragmentation of mono-, di- and tri-platinated I adducts in tandem MS revealed that T2 , G8 , T11 and T9 are binding sites. No cytosine sites were identified which may be due to the facile loss of Pt adducts from cytosine during CID. The intensity of {Pt(py)2 }-bound adducts was comparable to that of {Pt(N3 )(py)2 }-bound adducts, indicating that the photo-reduction pathway of complex 1 from Pt(IV) to Pt(II) through two one-electron donations from two azides was substantial. Moreover, no transformation of N3 to NH3 on the {Pt(N3 )(py)2 }-bound adducts was observed, whereas it is very popular during the reactions of complexes with short ODNs or mono-nucleotides. The oxidation on I induced by the reactive oxygen species (ROS) formed by the photodecomposition of complex 1 was significant, and the oxidation of G8 to 8-hydroxyguanine (8-OH-G), spiroiminodihydantoin (Sp) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) was discovered. These results unambiguously revealed a sequence-length-dependent photochemical reactivity of complex 1 when it interacted with different ODNs, providing deeper understanding in the reactivity of photoactivatable diazido anticancer Pt(IV) prodrugs to DNA. [ABSTRACT FROM AUTHOR]- Published
- 2020
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16. A negatively charged Pt(iv) prodrug for electrostatic complexation with polymers to overcome cisplatin resistance.
- Author
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Kang, Xiaoxu, Yu, Yingjie, Chen, Zhigang, Wu, Yixin, Wei, Dengshuai, Zhao, Yao, Wang, Fuyi, and Xiao, Haihua
- Abstract
A negatively charged Pt(iv) prodrug with lipid tails can self-assemble into nanoparticles via electrostatic complexation with a positively charged hydrophilic polymer, which exhibit great potential for clinical application. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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17. Solvent-dependent structural dynamics of an azido-platinum complex revealed by linear and nonlinear infrared spectroscopy.
- Author
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He, Xuemei, Xu, Fengmin, Yu, Pengyun, Wu, Yanzhou, Wang, Fuyi, Zhao, Yao, and Wang, Jianping
- Abstract
The vibrational and anisotropic relaxation dynamics and structural dynamics of a potential anticancer prodrug, trans,trans,trans-[Pt(N
3 )2 (OH)2 (py)2 ], were investigated using time-resolved infrared pump–probe spectroscopy and ultrafast two-dimensional infrared (2D IR) spectroscopy. Herein, two representative bio-friendly solvents, H2 O and DMSO, were used, in which the local structural and dynamical variations were monitored using the antisymmetric linear combination of the two N3 stretching vibrational modes as an infrared probe. It was found that the vibrational relaxation process of the N3 antisymmetric stretching (as) mode in H2 O is two to three times faster than that in DMSO. The anisotropic relaxation process of the anticancer prodrug was observed to be hindered in DMSO; this indicated a tighter solvent environment around the sample molecule in this solvent. The vibrational frequency time correlation of the N3 antisymmetric stretching mode in H2 O decays with a time constant of 1.94 ps, in agreement with the hydrogen bond formation and breaking times of water. In DMSO, the frequency time correlation of the N3 as mode decays on a much longer time scale; this further indicates its sensitivity to the out-layer DMSO structural dynamics, which are relatively static in the experimental time window. [ABSTRACT FROM AUTHOR]- Published
- 2018
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18. Luminescent cyclometallated platinum(ii) complexes: highly promising EGFR/DNA probes and dual-targeting anticancer agents.
- Author
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Zhang, Yang, Luo, Qun, Zheng, Wei, Wang, Zhaoying, Lin, Yu, Zhang, Erlong, Lü, Shuang, Xiang, Junfeng, Zhao, Yao, and Wang, Fuyi
- Published
- 2018
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19. Interface effect of mixed phase Pt/ZrO2 catalysts for HCHO oxidation at ambient temperature.
- Author
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Yang, Xueqin, Yu, Xiaolin, Lin, Mengya, Ge, Maofa, Zhao, Yao, and Wang, Fuyi
- Abstract
A series of high-efficiency Pt/ZrO
2 catalysts were successfully prepared by simple methods on the basis of a ZrO2 support with a mixed monoclinic/tetragonal phase structure. The activity test results showed that the mixed phase catalysts exhibited higher catalytic activity than the pure monoclinic phase, and HCHO can be completely oxidized into CO2 and H2 O at near ambient temperature. XRD, Raman and HRTEM results demonstrated that the monoclinic–tetragonal phase interface with abundant defects was formed due to the introduction of the tetragonal phase. According to the results of TEM, XPS and H2 -TPR, the mixed phase interfacial structure can induce the formation of the active oxygen species, ionic Ptδ+ species, strong metal-support interaction and low-temperature reducibility, which was vital for the significant improvement of the catalytic activity. Furthermore, the specific HCHO reaction rate of the catalysts at 55 °C increased from 0.8 × 10−3 to 10.4 × 10−3 mmol h−1 m−2 and the activation energy decreased remarkably from 213.5 to 24.7 kJ mol−1 with the increase of the biphase interface content. In situ DRIFTS spectra showed that the special interfacial structure can change the reaction pathway of HCHO oxidation and inhibit the formation of inert carbonate species, thus greatly enhancing the HCHO oxidation activity. [ABSTRACT FROM AUTHOR]- Published
- 2017
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20. Deciphering of interactions between platinated DNA and HMGB1 by hydrogen/deuterium exchange mass spectrometry.
- Author
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Wang, Yuanyuan, Du, Zhifeng, Zheng, Wei, Wu, Kui, Xu, Decheng, Luo, Qun, Zhao, Yao, Han, Juanjuan, Liu, Yangzhong, and Wang, Fuyi
- Subjects
PROTEIN crosslinking ,CROSSLINKING (Polymerization) ,CISPLATIN ,ANTINEOPLASTIC agents ,HYDROGEN - Abstract
A high mobility group box 1 (HMGB1) protein has been reported to recognize both 1,2-intrastrand crosslinked DNA by cisplatin (1,2-cis-Pt-DNA) and monofunctional platinated DNA using trans-[PtCl
2 (NH3 )(thiazole)] (1-trans-PtTz-DNA). However, the molecular basis of recognition between the trans-PtTz-DNA and HMGB1 remains unclear. In the present work, we described a hydrogen/deuterium exchange mass spectrometry (HDX-MS) method in combination with docking simulation to decipher the interactions of platinated DNA with domain A of HMGB1. The global deuterium uptake results indicated that 1-trans-PtTz-DNA bound to HMGB1a slightly tighter than the 1,2-cis-Pt-DNA. The local deuterium uptake at the peptide level revealed that the helices I and II, and loop 1 of HMGB1a were involved in the interactions with both platinated DNA adducts. However, docking simulation disclosed different H-bonding networks and distinct DNA-backbone orientations in the two Pt-DNA-HMGB1a complexes. Moreover, the Phe37 residue of HMGB1a was shown to play a key role in the recognition between HMGB1a and the platinated DNAs. In the cis-Pt-DNA-HMGB1a complex, the phenyl ring of Phe37 intercalates into a hydrophobic notch created by the two platinated guanines, while in the trans-PtTz-DNA-HMGB1a complex the phenyl ring appears to intercalate into a hydrophobic crevice formed by the platinated guanine and the opposite adenine in the complementary strand, forming a penta-layer π–π stacking associated with the adjacent thymine and the thiazole ligand. This work demonstrates that HDX-MS associated with docking simulation is a powerful tool to elucidate the interactions between platinated DNAs and proteins. [ABSTRACT FROM AUTHOR]- Published
- 2017
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21. Evaluation of serum phosphopeptides as potential biomarkers of gastric cancer.
- Author
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Zhai, Guijin, Yang, Liping, Luo, Qun, Wu, Kui, Zhao, Yao, Liu, Jianan, Xiong, Shaoxiang, and Wang, Fuyi
- Published
- 2017
- Full Text
- View/download PDF
22. Correlated mass spectrometry and confocal microscopy imaging verifies the dual-targeting action of an organoruthenium anticancer complex.
- Author
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Liu, Suyan, Zheng, Wei, Wu, Kui, Lin, Yu, Jia, Feifei, Zhang, Yang, Wang, Zhaoying, Luo, Qun, Zhao, Yao, and Wang, Fuyi
- Subjects
CELL imaging ,MASS spectrometry ,CELL membranes - Abstract
An addressable single cell imaging strategy combining ToF-SIMS and confocal fluorescence microscopy imaging has been developed, and sucessfully applied to visualize the subcellular distribution of an organoruthenium anticancer complex, [(η
6 -benzene)Ru(N,N-L)Cl]+ (1; L: 4-anilinoquinazoline ligand), showing its accumulation in both cell membrane and nuclei, and verifying its dual-targeting feature. [ABSTRACT FROM AUTHOR]- Published
- 2017
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23. Examining dynamics in a polymer matrix by single molecule fluorescence probes of different sizes.
- Author
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Zhang, Hao, Tao, Kai, Liu, Di, Wu, Kui, Wang, Fuyi, Yang, Jingfa, and Zhao, Jiang
- Published
- 2016
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24. A universal strategy for direct immobilization of intact bioactivity-conserved carbohydrates on gold nanoparticles.
- Author
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Wang, Xiao, Xu, Jiying, Wang, Yuanyuan, Wang, Fuyi, and Chen, Yi
- Published
- 2016
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- View/download PDF
25. Dual-targeting organometallic ruthenium(ii) anticancer complexes bearing EGFR-inhibiting 4-anilinoquinazoline ligands.
- Author
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Zhang, Yang, Zheng, Wei, Luo, Qun, Zhao, Yao, Zhang, Erlong, Liu, Suyan, and Wang, Fuyi
- Subjects
ORGANORUTHENIUM compounds ,ANTINEOPLASTIC agents ,QUINAZOLINE ,APOPTOSIS ,LIGANDS (Chemistry) ,REACTIVITY (Chemistry) - Abstract
We have recently demonstrated that complexation with (η
6 -arene)RuII fragments confers 4-anilinoquinazoline pharmacophores a higher potential for inducing cellular apoptosis while preserving the highly inhibitory activity of 4-anilinoquinazolines against EGFR and the reactivity of the ruthenium centre to 9-ethylguanine (Chem. Commun., 2013, 49, 10224–10226). Reported herein are the synthesis, characterisation and evaluation of the biological activity of a new series of ruthenium(ii) complexes of the type [(η6 -arene)Ru(N,N-L)Cl]PF6 (arene = p-cymene, benzene, 2-phenylethanol or indane, L = 4-anilinoquinazolines). These organometallic ruthenium complexes undergo fast hydrolysis in aqueous solution. Intriguingly, the ligation of (arene)RuII fragments with 4-anilinoquinazolines not only makes the target complexes excellent EGFR inhibitors, but also confers the complexes high affinity to bind to DNA minor grooves while maintaining their reactivity towards DNA bases, characterising them with dual-targeting properties. Molecular modelling studies reveal that the hydrolysis of these complexes is a favourable process which increases the affinity of the target complexes to bind to EGFR and DNA. In vitro biological activity assays show that most of this group of ruthenium complexes are selectively active inhibiting the EGF-stimulated growth of the HeLa cervical cancer cell line, and the most active complex [(η6 -arene)Ru(N,N-L13)Cl]PF6 (4, IC50 = 1.36 μM, L13 = 4-(3′-chloro-4′-fluoroanilino)-6-(2-(2-aminoethyl)aminoethoxy)-7-methoxyquinazoline) is 29-fold more active than its analogue, [(η6 -arene)Ru(N,N-ethylenediamine)Cl]PF6 , and 21-fold more active than gefitinib, a well-known EGFR inhibitor in use clinically. These results highlight the strong promise to develop highly active ruthenium anticancer complexes by ligation of cytotoxic ruthenium pharmacophores with bioactive organic molecules. [ABSTRACT FROM AUTHOR]- Published
- 2015
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26. Visible-light-induced cleavage of 4-α-amino acid substituted naphthalimides and its application in DNA photocleavage.
- Author
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Zhou, Jin, Fang, Canliang, Liu, Ying, Zhao, Yao, Zhang, Nan, Liu, Xiangjun, Wang, Fuyi, and Shangguan, Dihua
- Published
- 2015
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27. Identification and discrimination of binding sites of an organoruthenium anticancer complex to single-stranded oligonucleotides by mass spectrometry.
- Author
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Liu, Suyan, Wu, Kui, Zheng, Wei, Zhao, Yao, Luo, Qun, Xiong, Shaoxiang, and Wang, Fuyi
- Subjects
MASS spectrometry ,ORGANORUTHENIUM compounds ,BINDING sites ,SPECTRUM analysis ,LABORATORY techniques ,WAVELENGTH measurement ,NUCLEOTIDES - Abstract
We here report the identification of the binding sites of an organometallic ruthenium anticancer complex [(η
6 -biphenyl)Ru(en)Cl]+ (1) to single-stranded oligodeoxynucleotides (ODNs) 5′-CCCA4 G5 C6 CC-3′ (I) and 5′-CCC3 G4 A5 CCC-3′ (II) by mass spectrometry. The MS analysis of exonuclease ladders demonstrated that the 5′-exonuclease bovine spleen phosphodiesterase digestion of I and II mono-ruthenated by complex 1 was arrested solely at A4 and partially at C3 and G4 , respectively, and that the 3′-exonuclease snake venom phosphodiesterase digestion of the ruthenated ODNs was arrested solely at G5 and G4 , respectively, due to the ruthenation. These results did not allow unambiguous identification of ruthenation sites on the metallated ODNs. In contrast, tandem mass spectrometry analysis with CID fragmentation of the mono-ruthenated ODNs provided sequential and complementary [ai − B]/wi fragments, leading to unambiguous identification of G5 in I and G4 in II as the ruthenation sites on the ODN adducts, which is in line with the high selectivity of the complex towards guanine base as reported previously. These findings suggest that caution should be raised with regard to the identification of the binding sites of metal complexes, in particular complexes with bulky ligands, like biphenyl in complex 1, to DNA by MS analysis of exonuclease ladders of the metallated adducts, because the bulky ligands may adopt such an orientation that they block the exonuclease cleavage of the 5′- or 3′-side phosphodiester bonds adjacent to the binding sites, leading to digestion stalling at the nucleotides before the binding sites. [ABSTRACT FROM AUTHOR]- Published
- 2014
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28. Reactions of an organoruthenium anticancer complex with 2-mercaptobenzanilide—a model for the active-site cysteine of protein tyrosine phosphatase 1BElectronic supplementary information (ESI) available: HPLC, UV-Vis and LC-ESI-MS data, Figure S1–S11. CCDC reference numbers 821489–821492. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c1dt11189b
- Author
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Han, Yumiao, Luo, Qun, Hao, Xiang, Li, Xianchan, Wang, Fuyi, Hu, Wenbing, Wu, Kui, Lü, Shuang, and Sadler, Peter J.
- Subjects
ORGANORUTHENIUM compounds ,ANTINEOPLASTIC agents ,COMPLEX compounds ,ETHYLENEDIAMINE ,THIOLS ,CYSTEINE proteinases ,PROTEIN-tyrosine phosphatase ,SULFINATES - Abstract
The organometallic anticancer complex [(η6-p-cymene)Ru(en)Cl]PF6(1, en = ethylenediamine) readily reacts with thiols and forms stable sulfenate/sulfinate adducts which may be important for its biological activity. Protein tyrosine phosphatase 1B (PTP1B), a therapeutic target, contains a catalytic cysteinyl thiol and is involved in the regulation of insulin signaling and the balance of protein tyrosine kinase activity. On oxidation, the catalytic Cys215 can form an unusual sulfenyl-amide intermediate which can subsequently be reduced by glutathione. Here we study reactions of 1with 2-mercaptobenzanilide, 2, a recognized model for the active site of PTP1B. We have characterized crystallographically compound 2and its oxidized sulfenyl-amide derivative 2-phenyl-1,2-benzisothiazol-3(2H)-one (4), which shows a close structural similarity to the sulfenyl-amide in oxidized PTP1B. At pH 7.4 and 5.3, 1reacted with 2, affording a mono-ruthenium thiolato complex [(η6-cym)Ru(en)(S-RS)]+(7+, R = (C6H4)CONH(C6H5)) and a triply-S-bridged thiolato complex [((η6-cym)Ru)2(μ-S-RS)3]+(8+), respectively. Coordination of Ru to the S atom in 7allows formation of a strong H-bond (2.02 Å) between the en-NH and the carbonyl oxygen. To assess the possible effect of ruthenium coordination on the redox regulation of PTP1B, reactions of these thiolato products with H2O2and/or GSH were then investigated, demonstrating that coordination to Ru largely retards both the oxidation (deactivation) of the thiol in compound 2by H2O2and the subsequent reduction (reactivation) of the sulfenyl-amide by GSH, implying that the inhibition of complex 1on PTP1B (IC50of 19 μM) may be attributed to coordination to its catalytic cysteine. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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29. Copper binding promotes the interaction of cisplatin with human copper chaperone Atox1.
- Author
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Xi, Zhaoyong, Guo, Wei, Tian, Changlin, Wang, Fuyi, and Liu, Yangzhong
- Subjects
COPPER binding proteins ,CELLULAR control mechanisms ,MOLECULE-molecule collisions ,CISPLATIN ,PROTEIN binding ,CHEMICAL reactions - Abstract
Cu(i) binding promotes the platination of Atox1, although cisplatin binds to the copper coordination sites. In addition, Cu(i) binding enhances the competition of Atox1 with DTT in the reaction of cisplatin. These results indicate that cuprous ions could regulate the cellular trafficking of cisplatin. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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30. Complexation with organometallic ruthenium pharmacophores enhances the ability of 4-anilinoquinazolines inducing apoptosis.
- Author
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Zheng, Wei, Luo, Qun, Lin, Yu, Zhao, Yao, Wang, Xiuli, Du, Zhifeng, Hao, Xiang, Yu, Yang, Lü, Shuang, Ji, Liyun, Li, Xianchan, Yang, Ling, and Wang, Fuyi
- Subjects
ORGANOMETALLIC compounds ,RUTHENIUM ,QUINAZOLINE ,AROMATIC compounds ,HETEROCYCLIC compounds - Abstract
The complexation with organoruthenium fragments confers 4-anilinoquinazoline pharmacophores with higher potential for inducing cellular apoptosis while the highly inhibitory activity of 4-anilinoquinazolines against EGFR and the reactivity of the ruthenium centre to 9-ethylguanine are well preserved. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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31. The anticancer drug cisplatin can cross-link the interdomain zinc site on human albuminElectronic supplementary information (ESI) available: Experimental details of HPLC and ESI-MS/MS analysis, tryptic digestion and molecular modeling; Table S1 and Fig. S1–S7. See DOI: 10.1039/c1cc11627d
- Author
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Hu, Wenbing, Luo, Qun, Wu, Kui, Li, Xianchan, Wang, Fuyi, Chen, Yi, Ma, Xiaoyan, Wang, Jianping, Liu, Jianan, Xiong, Shaoxiang, and Sadler, Peter J.
- Subjects
CISPLATIN ,ALBUMINS ,BINDING sites ,ZINC ,MOLECULAR models ,HIGH performance liquid chromatography - Abstract
Cisplatin, cis-[Pt(Cl2(NH3)2], can crosslink residues His67 of domain I and His247 of domain II in human albumin, occupying the major binding site for the essential metal zinc on the protein. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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32. Correction: Open-flow microperfusion combined with mass spectrometry for in vivo liver lipidomic analysis.
- Author
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Li T, Yang H, Li X, Hou Y, Zhao Y, Wu W, Zhao L, Wang F, and Zhao Z
- Abstract
Correction for 'Open-flow microperfusion combined with mass spectrometry for in vivo liver lipidomic analysis' by Tuo Li et al. , Analyst , 2021, 146 , 1915-1923, https://doi.org/10.1039/D0AN02189J.
- Published
- 2024
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33. Adenine-adenine, adenine-cytosine and cytosine-cytosine intrastrand crosslinks induced by a photoactivatable Pt(IV) anticancer prodrug.
- Author
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Lin J, Huang J, Zhang J, Qin X, Ma Z, Wu X, Wang F, Zhao Y, and Wu K
- Subjects
- Organoplatinum Compounds pharmacology, Organoplatinum Compounds chemistry, Adenine, Cisplatin, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Prodrugs pharmacology, Prodrugs chemistry
- Abstract
Four trinucleotides 5'-ATA-3' (I), 5'-ATC-3' (II), 5'-CTA-3' (III) and 5'-CTC-3' (IV) were introduced to interact with a diazido-based photoactivatable anticancer prodrug trans , trans , trans -[Pt
IV (N3 )2 (OH)2 (py)2 ] (py = pyridine; 1) upon light irradiation. Using electrospray ionization mass spectrometry (ESI-MS), we aimed to investigate the possibility of 1,3-intrastrand crosslinks at adenine and/or cytosine in the trinucleotides via the bi-functional trans -[PtII (py)2 ]2+ species generated by photodecomposition of complex 1. The primary mass spectrometry results showed that although mono- and di-platinated trinucleotides bound by mono-functional trans -[PtII (N3 )(py)2 ]+ species were the major platinated adducts, comparable amounts of bifunctional trans -[PtII (py)2 ]2+ -bound trinucleotides were also observed. Further tandem mass spectrometry of the trans -[PtII (py)2 ]2+ -bound trinucleotides showed the formation of 1,3-crosslinks between adenine-adenine, adenine-cytosine and cytosine-cytosine bases in the trinucleotides. The formation of such unique structures is not only distinct from the action modes of cisplatin with DNA but also an important complement to the acknowledged 1,3-GNG intrastrand crosslink by trans -Pt species, which may support the promising and distinct anticancer activities of such photoactivatable diazido Pt(IV) anticancer prodrugs and deserve further studies.- Published
- 2023
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34. Ruthenium(II) polypyridyl complexes with visible light-enhanced anticancer activity and multimodal cell imaging.
- Author
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Kang Y, Zhao Y, Wei Y, Zhang Y, Wang Z, Luo Q, Du J, and Wang F
- Subjects
- Humans, Ligands, Light, ErbB Receptors, Ruthenium, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms
- Abstract
Ruthenium(II) polypyridyl complexes have drawn growing attention due to their photophysical properties and anticancer activity. Herein we report four ruthenium(II) polypyridyl complexes [(N^N)
2 RuII (L)]2+ (1-4, L = 4-anilinoquinazoline derivatives, N^N = bidentate ligands with bis-nitrogen donors) as multi-functional anticancer agents. The epidermal growth factor receptor (EGFR) is overexpressed in a broad range of cancer cells and related to many kinds of malignance. EGFR inhibitors, such as gefitinib and erlotinib, have been approved as clinical anticancer drugs. The EGFR-inhibiting 4-anilinoquinazoline ligands greatly enhanced the in vitro anticancer activity of these ruthenium(II) polypyridyl complexes against a series of human cancer cell lines compared to [Ru(bpy)2 (phen)], but interestingly, these complexes were actually not potent EGFR inhibitors. Further mechanism studies revealed that upon irradiation with visible light, complexes 3 and 4 generated a high level of singlet oxygen (1 O2 ), and their in vitro anticancer activities against human non-small-cell lung (A549), cervical (HeLa) and squamous (A431) cancer cells were significantly improved. Specifically, complex 3 displayed potent phototoxicity upon irradiation with blue light, of which the photo-toxicity indexes (PIs) against HeLa and A431 cells were 11 and 8.3, respectively. These complexes exhibited strong fluorescence emission at ca. 600 nm upon excitation at about 450 nm. A subcellular distribution study by fluorescence microscopy imaging and secondary ion mass spectrometry imaging (ToF-SIMS) demonstrated that complex 3 mainly localized at the cytoplasm and complex 4 mainly localized in the nuclei of cells. Competitive binding with ctDNA showed that complex 4 was more favorable to bind to the DNA minor groove than complex 3. These differences support that complex 3 possibly exerts its anticancer activities majorly by photo-induced1 O2 generation and complex 4 by binding to DNA.- Published
- 2023
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35. Reaction of human telomeric unit TTAGGG and a photoactivatable Pt(IV) anticancer prodrug.
- Author
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Lin J, Zhang J, Ma Z, Wu X, Wang F, Zhao Y, Wu K, and Liu Y
- Subjects
- Humans, Organoplatinum Compounds pharmacology, Organoplatinum Compounds chemistry, DNA chemistry, DNA Adducts, Guanine chemistry, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Prodrugs chemistry
- Abstract
The interaction of a photoactivatable diazidodihydroxido Pt(IV) prodrug, trans,trans,trans -[Pt(N
3 )2 (OH)2 (py)2 ] (py = pyridine; 1), with a hexamer straight human telomeric DNA unit sequence (5'-T1 T2 A3 G4 G5 G6 -3', I) upon light irradiation was investigated by electrospray ionization mass spectroscopy (ESI-MS). In the primary mass spectrum, two major mono-platinated I adducts with the bound Pt moieties, trans -[PtII (N3 )(py)2 ]+ (1') and trans -[PtII (py)2 ]2+ (1''), respectively, were detected. It is rare to observe such high abundance and nearly equal intensity platinated DNA adducts formed by these two PtII species because 1' is usually the only major reduced Pt(II) species produced by the photodecomposition of complex 1 in the presence of DNA while 1'' was rarely detected as the major reduced PtII species reported previously. Subsequent tandem mass spectrometric analysis by collision-induced dissociation (CID) showed that in the former adduct {I + 1'}2+ , G6 and A3 were the platination sites. While in the latter adduct {I + 1''}2+ , a potential intrastrand crosslink was speculated after G4 and G6 sites were identified. Additionally, other minor platinated adducts like di-platinated I adduct by 1' with platination sites at G4 and G6 and mono-platinated I adducts containing base oxidation were also detected by mass spectrometry. Due to the rich guanines and their sensitivity to oxidation, the oxidation induced by 1 most probably occurred at guanine. The oxidation adducts were proposed as 8-hydroxyl guanine, spiroiminodihydantoin (Sp), 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG), 5-guanidinohydantoin (Gh), and/or dehydroguanidinohydantoin (DGh) referring to previous reports. The obtained results provide useful chemical information about the photoreaction between photoactivatable Pt(IV) anticancer prodrugs and human telomeric DNA. Such special damages of Pt(IV) prodrugs on human telomeric DNA implicate its active role in the mechanism of Pt(IV) prodrugs and further support the unique sequence-dependent photointeraction profile of complex 1 reacting with DNA.- Published
- 2023
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36. Differentiated oxidation modes of guanine between CpG and 5m CpG by a photoactivatable Pt(IV) anticancer prodrug.
- Author
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Ma Z, Zhang J, Lin J, Li W, Wu X, Wang F, Zhao Y, and Wu K
- Subjects
- Organoplatinum Compounds pharmacology, Guanine, Cytosine, DNA Adducts, Antineoplastic Agents pharmacology, Prodrugs pharmacology
- Abstract
CpG and its cytosine-methylated counterpart (
5m CpG) are a unique reversible pair of sequences in regulating the expression of genes epigenetically. As DNA is the potential target of Pt-based anticancer metallodrugs, herein, we comparatively investigate the interactions of 5'-CpG and 5'-5m CpG with a photoactivatable anticancer Pt(IV) prodrug, trans , trans , trans -[PtIV (N3 )2 (OH)2 (py)2 ] (1; py = pyridine), to explore the effects of methylation on the platination and ROS-induced oxidation of the CpG motif. Mono-platinated dinucleotides were demonstrated by ESI-MS to be the main products for both 5'-CpG and 5'-5m CpG with the bound Pt moiety as [PtII (N3 )(py)2 ] generated by the photodecomposition of complex 1 under irradiation with blue light, accompanied by the formation of less abundant di-platinated adducts. G-N7 and C-N3/5m C-N3 were shown to be the major and minor platination sites, respectively, with G-N1 as the third and weakest platination site, in particular, in di-platinated products. Moreover, platinated dinucleotides associated with guanine and/or cytosine oxidation were also observed. Apart from 8-oxo-guanine (ox G) and N -formylamidoiminohydantoin (RedSp) reported previously, novel oxidation adducts 5-guanidinohydantoin (Gh) derived from guanine and 1-carbamoyl-4,5-dihydroxy-2-oxoimidazolidine (ImidCyt) derived from cytosine in CpG, and diimino imidazole (DIz) and 2,5-diaminoimidazol-4-one (imidazolone, Iz) derived from guanine and Imid5m Cyt derived from5m C in5m CpG were proposed according to MS information. These results showed that methylation exerted little effects on the platination modes of CpG, but triggered distinct oxidation pathways of CpG, perhaps causing discriminated DNA damage to CpG-rich genes. This work provides novel insights into the role of the anticancer photoactivatable Pt(IV) prodrug through damaging the epigenetically modified DNA sequences.- Published
- 2023
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37. Dual-platination and induced oxidation of uridine by a photoactivatable diazido Pt(IV) anticancer prodrug.
- Author
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Gao F, Zhang J, Wu X, Zhao Y, Wang F, and Wu K
- Subjects
- DNA chemistry, Organoplatinum Compounds chemistry, Organoplatinum Compounds pharmacology, RNA, Uridine, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Prodrugs chemistry
- Abstract
Photoactivatable Pt(IV) anticancer prodrug trans , trans , trans -[Pt(N
3 )2 (OH)2 (pyridine)2 ] (1) has been shown to bind to and induce oxidation of all four DNA nucleobases. Herein, to further render the binding spectrum of complex 1 to nucleic acids, the interaction between complex 1 and uridine, an exclusive RNA component, was investigated by electrospray ionization mass spectrometry (ESI-MS) and NMR spectroscopy. The results showed that complex 1 can bind to uridine through the N3 (major) and O4 (minor) sites upon light irradiation to form the major mono-platinated uridine adduct and the minor di-platinated uridine adduct. Moreover, mono-platinated uridine associated with the oxidation of uridine to 5-hydroxyuridine and 6-hydroxyuridine was also observed. This is the first report that the photoactivatable Pt(IV) prodrug binds to and induces the oxidation of uridine, and also the last piece of the puzzle for the interactions of complex 1 with nucleobases. Combined with our previous results about the interactions between complex 1 and DNA bases, these data showed a wide interaction spectrum of this kind of photoactivatable diazido Pt(IV) prodrugs with nucleobases through such dual-action modes, strongly suggesting that RNA may be a potential target of Pt(IV) prodrugs.- Published
- 2022
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38. Photoactivatable diazido Pt(IV) anticancer complex can bind to and oxidize all four nucleosides.
- Author
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Cheng Y, Zhang J, Wu K, Gao F, Cheng Y, Zou T, Wu X, Zhao Y, and Wang F
- Subjects
- Molecular Structure, Oxidation-Reduction, Photochemical Processes, Spectrometry, Mass, Electrospray Ionization, Antineoplastic Agents chemistry, Azides chemistry, Nucleosides chemistry, Organoplatinum Compounds chemistry, Prodrugs chemistry
- Abstract
Photoactivatable diazidodihydroxido Pt(iv) complex trans,trans,trans-[Pt(N3)2(OH)2(py)2] (1; py = pyridine) is a promising anticancer agent which can be activated by visible light to induce cancer cell death. DNA has been thought to be involved in the mechanism of action of this kind of Pt(iv) prodrug. However, the detailed photodecomposition pathways of complex 1 and its interaction modes with DNA are complex. Herein we report that upon light irradiation complex 1 can bind to all four nucleosides covalently with the reduced Pt(ii) species. Moreover, apart from the covalent coordination, various oxidation adducts of these four nucleosides induced by the reactive oxidative species (ROS) generated during the photoactivation of the complex 1 have also been identified, especially the induced oxidation of adenosine and cytidine which was firstly reported for this kind of photoactivatable Pt(iv) prodrug. Such dual-action may contribute to the highly potent photo-antiproliferativity of complex 1 towards cancer cells, which may account for the unique mechanism of action of the photoactivatable diazido Pt(iv) anticancer complexes.
- Published
- 2020
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39. Reactions of a photoactivatable diazido Pt(iv) anticancer complex with a single-stranded oligodeoxynucleotide.
- Author
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Liang Z, Lin J, Gong X, Cheng Y, Huang C, Zhang J, Wu X, Wang F, Zhao Y, and Wu K
- Subjects
- Antineoplastic Agents chemical synthesis, Molecular Structure, Organoplatinum Compounds chemical synthesis, Photochemical Processes, Prodrugs chemical synthesis, Antineoplastic Agents chemistry, Azides chemistry, Oligodeoxyribonucleotides chemistry, Organoplatinum Compounds chemistry, Prodrugs chemistry
- Abstract
Platinum based anticancer agents are widely applied in clinic and their major target is believed to be DNA. Herein, the interaction of a photoactivatable diazido Pt(iv) anticancer prodrug trans,trans,trans-[Pt(N3)2(OH)2(py)2] (py = pyridine; 1) with a 15-mer single-G-containing oligodeoxynucleotide (ODN I: 5'-CT2CTCTTG8T9CT11TCTC-3') was investigated by mass spectrometric methods. Up to penta-platinated ODN I adducts were identified from primary mass spectra while the mono- and di-platinated adducts had the highest intensity. Fragmentation of mono-, di- and tri-platinated I adducts in tandem MS revealed that T2, G8, T11 and T9 are binding sites. No cytosine sites were identified which may be due to the facile loss of Pt adducts from cytosine during CID. The intensity of {Pt(py)2}-bound adducts was comparable to that of {Pt(N3)(py)2}-bound adducts, indicating that the photo-reduction pathway of complex 1 from Pt(iv) to Pt(ii) through two one-electron donations from two azides was substantial. Moreover, no transformation of N3 to NH3 on the {Pt(N3)(py)2}-bound adducts was observed, whereas it is very popular during the reactions of complexes with short ODNs or mono-nucleotides. The oxidation on I induced by the reactive oxygen species (ROS) formed by the photodecomposition of complex 1 was significant, and the oxidation of G8 to 8-hydroxyguanine (8-OH-G), spiroiminodihydantoin (Sp) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) was discovered. These results unambiguously revealed a sequence-length-dependent photochemical reactivity of complex 1 when it interacted with different ODNs, providing deeper understanding in the reactivity of photoactivatable diazido anticancer Pt(iv) prodrugs to DNA.
- Published
- 2020
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40. Deciphering of interactions between platinated DNA and HMGB1 by hydrogen/deuterium exchange mass spectrometry.
- Author
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Wang Y, Du Z, Zheng W, Wu K, Xu D, Luo Q, Zhao Y, Han J, Liu Y, and Wang F
- Abstract
A high mobility group box 1 (HMGB1) protein has been reported to recognize both 1,2-intrastrand crosslinked DNA by cisplatin (1,2-cis-Pt-DNA) and monofunctional platinated DNA using trans-[PtCl
2 (NH3 )(thiazole)] (1-trans-PtTz-DNA). However, the molecular basis of recognition between the trans-PtTz-DNA and HMGB1 remains unclear. In the present work, we described a hydrogen/deuterium exchange mass spectrometry (HDX-MS) method in combination with docking simulation to decipher the interactions of platinated DNA with domain A of HMGB1. The global deuterium uptake results indicated that 1-trans-PtTz-DNA bound to HMGB1a slightly tighter than the 1,2-cis-Pt-DNA. The local deuterium uptake at the peptide level revealed that the helices I and II, and loop 1 of HMGB1a were involved in the interactions with both platinated DNA adducts. However, docking simulation disclosed different H-bonding networks and distinct DNA-backbone orientations in the two Pt-DNA-HMGB1a complexes. Moreover, the Phe37 residue of HMGB1a was shown to play a key role in the recognition between HMGB1a and the platinated DNAs. In the cis-Pt-DNA-HMGB1a complex, the phenyl ring of Phe37 intercalates into a hydrophobic notch created by the two platinated guanines, while in the trans-PtTz-DNA-HMGB1a complex the phenyl ring appears to intercalate into a hydrophobic crevice formed by the platinated guanine and the opposite adenine in the complementary strand, forming a penta-layer π-π stacking associated with the adjacent thymine and the thiazole ligand. This work demonstrates that HDX-MS associated with docking simulation is a powerful tool to elucidate the interactions between platinated DNAs and proteins.- Published
- 2017
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41. Dual-targeting organometallic ruthenium(II) anticancer complexes bearing EGFR-inhibiting 4-anilinoquinazoline ligands.
- Author
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Zhang Y, Zheng W, Luo Q, Zhao Y, Zhang E, Liu S, and Wang F
- Subjects
- Aniline Compounds chemistry, Aniline Compounds pharmacology, Cell Proliferation drug effects, Drug Screening Assays, Antitumor, ErbB Receptors metabolism, HeLa Cells, Humans, Models, Molecular, Neoplasms drug therapy, Neoplasms metabolism, Organometallic Compounds chemistry, Organometallic Compounds pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, ErbB Receptors antagonists & inhibitors, Quinazolines chemistry, Quinazolines pharmacology, Ruthenium chemistry, Ruthenium pharmacology
- Abstract
We have recently demonstrated that complexation with (η(6)-arene)Ru(II) fragments confers 4-anilinoquinazoline pharmacophores a higher potential for inducing cellular apoptosis while preserving the highly inhibitory activity of 4-anilinoquinazolines against EGFR and the reactivity of the ruthenium centre to 9-ethylguanine (Chem. Commun., 2013, 49, 10224-10226). Reported herein are the synthesis, characterisation and evaluation of the biological activity of a new series of ruthenium(ii) complexes of the type [(η(6)-arene)Ru(N,N-L)Cl]PF6 (arene = p-cymene, benzene, 2-phenylethanol or indane, L = 4-anilinoquinazolines). These organometallic ruthenium complexes undergo fast hydrolysis in aqueous solution. Intriguingly, the ligation of (arene)Ru(II) fragments with 4-anilinoquinazolines not only makes the target complexes excellent EGFR inhibitors, but also confers the complexes high affinity to bind to DNA minor grooves while maintaining their reactivity towards DNA bases, characterising them with dual-targeting properties. Molecular modelling studies reveal that the hydrolysis of these complexes is a favourable process which increases the affinity of the target complexes to bind to EGFR and DNA. In vitro biological activity assays show that most of this group of ruthenium complexes are selectively active inhibiting the EGF-stimulated growth of the HeLa cervical cancer cell line, and the most active complex [(η(6)-arene)Ru(N,N-L13)Cl]PF6 (, IC50 = 1.36 μM, = 4-(3'-chloro-4'-fluoroanilino)-6-(2-(2-aminoethyl)aminoethoxy)-7-methoxyquinazoline) is 29-fold more active than its analogue, [(η(6)-arene)Ru(N,N-ethylenediamine)Cl]PF6, and 21-fold more active than gefitinib, a well-known EGFR inhibitor in use clinically. These results highlight the strong promise to develop highly active ruthenium anticancer complexes by ligation of cytotoxic ruthenium pharmacophores with bioactive organic molecules.
- Published
- 2015
- Full Text
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42. In vivo fluorescence sensing of the salicylate-induced change of zinc ion concentration in the auditory cortex of rat brain.
- Author
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Jiang Q, Guo Z, Zhao Y, Wang F, and Mao L
- Subjects
- Animals, Ions analysis, Male, Molecular Structure, Rats, Rats, Sprague-Dawley, Spectrometry, Fluorescence, Auditory Cortex chemistry, Fluorescence, Salicylates chemistry, Zinc analysis
- Abstract
This study demonstrates a fluorescence method for in vivo sensing of the dynamic change of Zn(2+) concentration in auditory cortex microdialysates induced by salicylate with N'-(7-nitro-2,1,3-benzoxadiazole-4-yl)-N,N,N'-tris(pyridine-2-ylmethyl) ethane-1,2-diamine (NBD-TPEA) as a probe. The excellent properties of the NBD-TPEA probe make it possible to achieve a high selectivity for Zn(2+) sensing with the co-existence of amino acids and other metal ions as well as the species commonly existing in the cerebral system. To validate the method for in vivo fluorescence sensing of Zn(2+) in the rat brain, we pre-mix the microdialysates in vivo sampled from the auditory cortex with the NBD-TPEA probe and then perfuse the mixtures into a fluorescent cuvette for continuous-flow fluorescence detection. The method demonstrated here shows a linear relationship between the signal output and Zn(2+) concentration within the concentration range from 0.5 μM to 4 μM, with a detection limit of 156 nM (S/N = 3). The basal level of extracellular Zn(2+) in auditory cortex microdialysates is determined to be 0.52 ± 0.082 μM (n = 4). This value is increased by the injection of 100 mg mL(-1) of salicylate (1 μL min(-1), 5 min, i.p.), reaches a peak at the time point of 90 min, and levels off with time. Such an increase is attenuated by the injection of MK-801, a potent and specific NMDA receptor antagonist, after the pre-injection of 100 mg mL(-1) salicylate for 5 min. This study offers a fluorescence method for in vivo sensing of Zn(2+) in the rat brain that could be useful for the investigations of chemical processes involved in brain functions.
- Published
- 2015
- Full Text
- View/download PDF
43. Immobilization of trypsin via reactive polymer grafting from magnetic nanoparticles for microwave-assisted digestion.
- Author
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Shen Y, Guo W, Qi L, Qiao J, Wang F, and Mao L
- Abstract
The effort to stabilize enzymes and improve their activity has generated great interest because of their wide application in proteomics research, bioenergy conversion, bioassays and so on. In this work, biocompatible reactive polymer, poly (glycidyl methacrylate), grafted from magnetic nanoparticles by atom transfer radical polymerization method, has been firstly proposed to immobilize enzymes for microwave-assisted digestion. Meanwhile, trypsin was chosen as a model enzyme. Resulting from the increased functionality, the immobilization amount of the enzyme on the magnetic nanoparticle surface has been greatly improved. Furthermore, the enzyme immobilized magnetic nanoparticles have exhibited excellent repeatability and stability. The influence of the polymer chain length on digestion efficiency has been investigated both at 37 °C and under microwave. It has been found that the digestion efficiency increases with the lengthened polymer brushes due to the increased immobilization amount. Utilizing cytochrome C as a model protein for digestion, the performance of this immobilized biocatalyst has been demonstrated and this digestion assisted with microwave could be completed within 15 s. This study offers insight into the design of polymer brushes on the surface of magnetic nanoparticles for high digestion efficiency in the future.
- Published
- 2013
- Full Text
- View/download PDF
44. Competition between glutathione and DNA oligonucleotides for ruthenium(II) arene anticancer complexes.
- Author
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Wang F, Xu J, Wu K, Weidt SK, Mackay CL, Langridge-Smith PR, and Sadler PJ
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents metabolism, Base Sequence, DNA genetics, DNA, Single-Stranded genetics, DNA, Single-Stranded metabolism, Oligodeoxyribonucleotides genetics, Binding, Competitive, DNA metabolism, Glutathione metabolism, Oligodeoxyribonucleotides metabolism, Organometallic Compounds chemistry, Organometallic Compounds metabolism, Ruthenium chemistry
- Abstract
The organometallic anticancer complex [(η(6)-bip)Ru(en)Cl](+) (1; bip = biphenyl, en = ethylenediamine) selectively binds to N7 of guanine bases of oligonucleotides and native DNA. However, under physiologically relevant conditions (micromolar Ru concentrations, pH 7, 22 mM NaCl, 310 K), the tripeptide glutathione (γ-L-Glu-L-Cys-Gly; GSH) is kinetically competitive with guanine (as guanosine 3',5'-cyclic monophosphate, cGMP) for coordination with complex 1, and gives rise to a ruthenium thiolato adduct. This thiolato adduct can subsequently undergo oxidation to a sulfenate intermediate, providing a facile route for the formation of a final cGMP adduct via the displacement of S-bound glutathione by G N7 (F. Y. Wang, J. J. Xu, A. Habtemariam, J. Bella and P. J. Sadler, J. Am. Chem. Soc., 2005, 127, 17734). In this work, the competition between GSH and the single-stranded 14-mer oligonucleotide 5'-TATGTACCATGTAT-3' (I) and duplex III (III = I + II, II = 5'-ATACATGGTACATA) for complex 1 and its analogue [(η(6)-tha)Ru(en)Cl](+) (2, tha = tetrahydroanthracene) under physiologically relevant conditions was investigated using conventional ESI-MS and high resolution ESI-FTICR-MS coupled to conventional HPLC and nanoscale HPLC, respectively. The results indicate that whether there was high excess of GSH or not in the reaction mixtures, the reaction of complex 1 or 2 with single-stranded oligonucleotide I always gave rise to mono-ruthenated oligonucleotide, and the reaction of complex 1 or 2 with duplex III gave rise to the mono-ruthenated duplex oligonucleotide. Furthermore, the ruthenation of duplex III by complex 1 showed no significant discrimination between the complementary strands I and II, but complex 2 appeared to bind preferentially to strand II compared to strand I as revealed by the high resolution FTICR-MS analysis. GSH is highly abundant in cells at millimolar concentrations and is well known to be involved in the deactivation of the clinical drug cisplatin and in platinum resistance. Our findings reveal a potentially contrasting role for GSH in the mechanism of action of these ruthenium anticancer complexes that may contribute to the lack of cross-resistance with platinum drugs.
- Published
- 2013
- Full Text
- View/download PDF
45. Reactions of an organoruthenium anticancer complex with 2-mercaptobenzanilide--a model for the active-site cysteine of protein tyrosine phosphatase 1B.
- Author
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Han Y, Luo Q, Hao X, Li X, Wang F, Hu W, Wu K, Lü S, and Sadler PJ
- Subjects
- Chromatography, High Pressure Liquid, Crystallography, X-Ray, Cysteine chemistry, Organophosphorus Compounds chemistry, Spectrometry, Mass, Electrospray Ionization, X-Ray Diffraction, Anilides chemistry, Antineoplastic Agents chemistry, Organometallic Compounds chemistry, Protein Tyrosine Phosphatase, Non-Receptor Type 1 chemistry, Ruthenium chemistry, Sulfhydryl Compounds chemistry
- Abstract
The organometallic anticancer complex [(η(6)-p-cymene)Ru(en)Cl]PF(6) (1, en = ethylenediamine) readily reacts with thiols and forms stable sulfenate/sulfinate adducts which may be important for its biological activity. Protein tyrosine phosphatase 1B (PTP1B), a therapeutic target, contains a catalytic cysteinyl thiol and is involved in the regulation of insulin signaling and the balance of protein tyrosine kinase activity. On oxidation, the catalytic Cys215 can form an unusual sulfenyl-amide intermediate which can subsequently be reduced by glutathione. Here we study reactions of 1 with 2-mercaptobenzanilide, 2, a recognized model for the active site of PTP1B. We have characterized crystallographically compound 2 and its oxidized sulfenyl-amide derivative 2-phenyl-1,2-benzisothiazol-3(2H)-one (4), which shows a close structural similarity to the sulfenyl-amide in oxidized PTP1B. At pH 7.4 and 5.3, 1 reacted with 2, affording a mono-ruthenium thiolato complex [(η(6)-cym)Ru(en)(S-RS)](+) (7(+), R = (C(6)H(4))CONH(C(6)H(5))) and a triply-S-bridged thiolato complex [((η(6)-cym)Ru)(2)(μ-S-RS)(3)](+) (8(+)), respectively. Coordination of Ru to the S atom in 7 allows formation of a strong H-bond (2.02 Å) between the en-NH and the carbonyl oxygen. To assess the possible effect of ruthenium coordination on the redox regulation of PTP1B, reactions of these thiolato products with H(2)O(2) and/or GSH were then investigated, demonstrating that coordination to Ru largely retards both the oxidation (deactivation) of the thiol in compound 2 by H(2)O(2) and the subsequent reduction (reactivation) of the sulfenyl-amide by GSH, implying that the inhibition of complex 1 on PTP1B (IC(50) of 19 μM) may be attributed to coordination to its catalytic cysteine., (This journal is © The Royal Society of Chemistry 2011)
- Published
- 2011
- Full Text
- View/download PDF
46. The formation of thymidine-based T-tetramers with remarkable structural and metal ion size effects.
- Author
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Luo Q, Wu D, Liu S, Tang D, Huang Y, Liu X, Wang F, Wang R, and Wu G
- Subjects
- Ions chemistry, Models, Molecular, Molecular Structure, Spectrometry, Mass, Electrospray Ionization, Metals chemistry, Oligonucleotides chemistry, Thymidine chemistry
- Abstract
We present direct ESI Q-TOF MS and X-ray evidence for remarkable structural and metal ion size effects on the formation of thymidine-based T-tetramers. The conventional H-bond acceptors on the ribose and deoxyribose may disfavor the formation of T-tetramers, and in the series of alkali metal ions, lithium did not induce T-tetramer due to its small ion size. Sodium, potassium, rubidium and caesium could produce thymidine-based T-tetramers. Furthermore, rubidium and caesium could induce T-pentamers and dimeric T-pentamers probably due to their larger ion sizes.
- Published
- 2011
- Full Text
- View/download PDF
47. Inhibitor screening of protein kinases using MALDI-TOF MS combined with separation and enrichment of phosphopeptides by TiO2 nanoparticle deposited capillary column.
- Author
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Lü S, Luo Q, Li X, Wu J, Liu J, Xiong S, Feng YQ, and Wang F
- Subjects
- Antineoplastic Agents isolation & purification, Antineoplastic Agents pharmacology, Benzamides, Chronic Disease, Drug Screening Assays, Antitumor, Humans, Imatinib Mesylate, Leukemia, Myeloid enzymology, Phosphopeptides isolation & purification, Phosphopeptides pharmacology, Piperazines isolation & purification, Piperazines pharmacology, Protein Kinase Inhibitors isolation & purification, Protein Kinase Inhibitors pharmacology, Protein-Tyrosine Kinases antagonists & inhibitors, Pyrimidines isolation & purification, Pyrimidines pharmacology, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Antineoplastic Agents chemistry, Leukemia, Myeloid drug therapy, Nanoparticles chemistry, Phosphopeptides chemistry, Piperazines chemistry, Protein Kinase Inhibitors chemistry, Pyrimidines chemistry, Titanium chemistry
- Abstract
A MALDI-TOF mass spectrometric method for rapid screening of protein tyrosine kinase (PTK) inhibitors has been developed. To circumvent the ion suppression of phosphorylated substrate peptides caused by the presence of high abundant non-phosphorylated peptides in the enzymatic reaction mixtures, a separation and enrichment process of the phosphorylated peptides from complex mixtures was carried out by using an in-house fabricated TiO(2) nanoparticle-coated capillary column prior to the MS analysis. With a synthetic phosphopeptide (DAIpYAAPFAKKK), of which the sequence is similar to that of the substrate (EAIYAAPFAKKK) of the Abelson tyrosine kinase (Abl), as the internal standard, the signal ratio of the phosphorylated substrate to the standard detected by MALDI-TOF MS is linearly correlated with the molar ratio of the two phosphopeptides over the range of 0.3 to 3 with r(2) = 0.99. We validated the MS method by determining the IC(50) value of imatinib, an Abl inhibitor for clinical treatment of chronic myelogenous leukaemia (CML). The obtained IC(50) value (234 nM) is consistent with that determined by ELISA (291 nM). Then, six analogues of imatinib synthesized in our laboratory were screened using the method, giving rise to inhibitory potential results which are in good agreement with the docking analysis data. The developed method is sensitive, operationally simple, does not require isotope-labelling and is cost/time effective, providing an alterative method for rapid screening of PTK inhibitors as therapeutic agents for tumours.
- Published
- 2010
- Full Text
- View/download PDF
48. Half-sandwich arene ruthenium(II)-enzyme complex.
- Author
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McNae IW, Fishburne K, Habtemariam A, Hunter TM, Melchart M, Wang F, Walkinshaw MD, and Sadler PJ
- Subjects
- Arginine chemistry, Aspartic Acid chemistry, Crystallography, X-Ray, Histidine chemistry, Imidazoles chemistry, Models, Chemical, Muramidase pharmacology, Organometallic Compounds pharmacology, Ruthenium pharmacology, Multienzyme Complexes chemistry, Muramidase chemistry, Organometallic Compounds chemistry, Proteins chemistry, Ruthenium chemistry
- Abstract
The 1.6 [Angstrom] X-ray crystal structure of [(eta(6)-p-cymene)Ru(lysozyme)Cl(2)], the first of a half-sandwich complex of a protein, shows selective ruthenation of Nepsilon of the imidazole ring of His15.
- Published
- 2004
- Full Text
- View/download PDF
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