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1.
Histone deacetylases inhibitors (HDACis) have gained much attention as a new class of anticancer agents in recent years. Herein, we report a series of fluorescent ruthenium(II) complexes containing N1‐hydroxy‐N8‐(1,10‐phenanthrolin‐5‐yl)octanediamide ( L ), a suberoylanilide hydroxamic acid (SAHA) derivative, as a ligand. As expected, these complexes show interesting chemiphysical properties, including relatively high quantum yields, large Stokes shifts, and long emission lifetimes. The in vitro inhibitory effect of the most effective drug, [Ru(DIP)2 L ](PF6)2 ( 3 ; DIP: 4,7‐diphenyl‐1,10‐phenanthroline), on histone deacetylases (HDACs) is approximately equivalent in activity to that of SAHA, and treatment with complex 3 results in increased levels of the acetylated histone H3. Complex 3 is highly active against a panel of human cancer cell lines, whereas it shows relatively much lower toxicity to normal cells. Further mechanism studies show that complex 3 can elicit cell cycle arrest and induce apoptosis through mitochondria‐related pathways and the production of reactive oxygen species. These data suggest that these fluorescent ruthenium(II)–HDACi conjugates may represent a promising class of anticancer agents for potential dual imaging and therapeutic applications targeting HDACs.  相似文献   

2.
Reversible acetylation of histone and non-histone proteins plays an important role in the regulation of gene expression and cellular homeostasis. A balance between acetylation and deacetylation of these proteins are maintained by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Among different HATs, p300/CBP is the most widely studied chromatin modifying enzymes. p300 is involved in several physiological processes like cell growth, regulation of gene expression, development, and tumor suppressor, and therefore its dysfunction causes different diseases. The autoacetylation of p300 is one of the key regulators of its catalytic activity. Mechanistically, autoacetylation induced structural changes in the p300 HAT domain acts as a master switch. In this report, we have shown that the natural HAT inhibitor garcinol could potently inhibit the autoacetylation activity. Furthermore, for the first time, we demonstrate that indeed autoacetylation induces structural changes in p300 HAT domain, as probed by surface-enhanced Raman scattering. Presumably, SERS will be a very useful tool to find out the structural changes in the other self-modifying enzymes like kinases and methyltransferases.  相似文献   

3.
The development of biomolecular fiber materials with imaging ability has become more and more useful for biological applications. In this work, cationic conjugated polymers (CCPs) were used to construct inherent fluorescent microfibers with natural biological macromolecules (DNA and histone proteins) through the interfacial polyelectrolyte complexation (IPC) procedure. Isothermal titration microcalorimetry results show that the driving forces for fiber formation are electrostatic and hydrophobic interactions, as well as the release of counterions and bound water molecules. Color‐encoded IPC fibers were also obtained based on the co‐assembly of DNA, histone proteins, and blue‐, green‐, or red‐ (RGB‐) emissive CCPs by tuning the fluorescence resonance energy‐transfer among the CCPs at a single excitation wavelength. The fibers could encapsulate GFP‐coded Escherichia coli BL21, and the expression of GFP proteins was successfully regulated by the external environment of the fibers. These multi‐colored fibers show a great potential in biomedical applications, such as biosensor, delivery, and release of biological molecules and tissue engineering.  相似文献   

4.
The development of biomolecular fiber materials with imaging ability has become more and more useful for biological applications. In this work, cationic conjugated polymers (CCPs) were used to construct inherent fluorescent microfibers with natural biological macromolecules (DNA and histone proteins) through the interfacial polyelectrolyte complexation (IPC) procedure. Isothermal titration microcalorimetry results show that the driving forces for fiber formation are electrostatic and hydrophobic interactions, as well as the release of counterions and bound water molecules. Color‐encoded IPC fibers were also obtained based on the co‐assembly of DNA, histone proteins, and blue‐, green‐, or red‐ (RGB‐) emissive CCPs by tuning the fluorescence resonance energy‐transfer among the CCPs at a single excitation wavelength. The fibers could encapsulate GFP‐coded Escherichia coli BL21, and the expression of GFP proteins was successfully regulated by the external environment of the fibers. These multi‐colored fibers show a great potential in biomedical applications, such as biosensor, delivery, and release of biological molecules and tissue engineering.  相似文献   

5.
We propose a binary fluorimetric method for DNA and RNA analysis by the combined use of two probes rationally designed to work cooperatively. One probe is an oligonucleotide (ODN) conjugate bearing a β‐cyclodextrin (β‐CyD). The other probe is a small reporter ligand, which comprises linked molecules of a nucleobase‐specific heterocycle and an environment‐sensitive fluorophore. The heterocycle of the reporter ligand recognizes a single nucleobase displayed in a gap on the target labeled with the conjugate and, at the same time, the fluorophore moiety forms a luminous inclusion complex with nearby β‐CyD. Three reporter ligands, MNDS (naphthyridine–dansyl linked ligand), MNDB (naphthyridine–DBD), and DPDB (pyridine–DBD), were used for DNA and RNA probing with 3′‐end or 5′‐end modified β‐CyD – ODN conjugates. For the DNA target, the β‐CyD tethered to the 3′‐end of the ODN facing into the gap interacted with the fluorophore sticking out into the major groove of the gap site ( MNDS and DPDB ). Meanwhile the β‐CyD on the 5′‐end of the ODN interacted with the fluorophore in the minor groove ( MNDB and DPDB ). The results obtained by this study could be a guideline for the design of binary DNA/RNA probe systems based on controlling the proximity of functional molecules.  相似文献   

6.
We report the design and synthesis of small molecules that exhibit enhanced luminescence in the presence of duplex rather than single‐stranded DNA. The local environment presented by a well‐known [Ru(dipyrido[3,2‐a:2′,3′‐c]phenazine)L2]2+‐based DNA intercalator was modified by functionalizing the bipyridine ligands with esters and carboxylic acids. By systematically varying the number and charge of the pendant groups, it was determined that decreasing the electrostatic interaction between the intercalator and the anionic DNA backbone reduced single‐strand interactions and translated to better duplex specificity. In studying this class of complexes, a single RuII complex emerged that selectively luminesces in the presence of duplex DNA with little to no background from interacting with single‐stranded DNA. This complex shows promise as a new dye capable of selectively staining double‐ versus single‐stranded DNA in gel electrophoresis, which cannot be done with conventional SYBR dyes.  相似文献   

7.
There is considerable interest in the development of novel and more efficient delivery systems for improving the efficacy of photodynamic therapy (PDT). The authors in this highlighted issue describe the synthesis and the photobiological characterizations of two photosensitizer (PS) conjugates based on β‐carboline derivatives covalently conjugated to folic acid (FA) coupled to bovine serum albumin (BSA) as a carrier system specifically targeting cancer cells overexpressing FA receptor alpha (FRα). Accordingly, only the FA–BSA–β‐carboline conjugates are internalized specifically in FRα‐positive cells and are proved to be phototoxic. On the other hand, albumin–β‐carboline conjugates without FA or β‐carboline derivatives alone are not internalized and nontoxic. This conjugate is among the first to produce a conjugate composed of a PS and FA molecules that are directly conjugated to BSA. In addition, the in vitro studies are the first evidence that directly conjugated FA‐BSA can be used as carriers to selectively enhance cytotoxicity by PDT relative to unmodified PS or nontargeted BSA‐PS. This strategy is a positive step forward for the covalent design and construction of a photodynamic nanomedicine for FR‐positive tumors.  相似文献   

8.
《Chemphyschem》2005,6(11):2404-2409
Herein, we continue our investigation of the single‐molecule spectroscopy of the conjugated polymer poly[2‐methoxy,5‐(2‐ethylhexyloxy)‐p‐phenylene‐vinylene] (MEH‐PPV) at cryogenic temperatures. First, the low temperature microsecond dynamics of single MEH‐PPV conjugated polymer molecules are compared to the dynamics at room temperature revealing no detectible temperature dependence. The lack of temperature dependence is consistent with the previous assignment of the dynamics to a mechanism that involves intersystem crossing and triplet–triplet annihilation. Second, the fluorescence spectra of single MEH‐PPV molecules at low temperature are studied as a function of excitation wavelength (i.e. 488, 543, and 568 nm). These results exhibit nearly identical fluorescence spectra for different excitation wavelengths. This strongly suggests that electronic energy transfer occurs efficiently to a small number of low‐energy sites in the multichromophoric MEH‐PPV chains.  相似文献   

9.
A new biomolecular device for investigating the interactions of ligands with constrained DNA quadruplex topologies, using surface plasmon resonance (SPR), is reported. Biomolecular systems containing an intermolecular‐like G‐quadruplex motif 1 (parallel G‐quadruplex conformation), an intramolecular G‐quadruplex 2 , and a duplex DNA 3 have been designed and developed. The method is based on the concept of template‐assembled synthetic G‐quadruplex (TASQ), whereby quadruplex DNA structures are assembled on a template that allows precise control of the parallel G‐quadruplex conformation. Various known G‐quadruplex ligands have been used to investigate the affinities of ligands for intermolecular 1 and intramolecular 2 DNA quadruplexes. As anticipated, ligands displaying a π‐stacking binding mode showed a higher binding affinity for intermolecular‐like G‐quadruplexes 1 , whereas ligands with other binding modes (groove and/or loop binding) showed no significant difference in their binding affinities for the two quadruplexes 1 or 2 . In addition, the present method has also provided information about the selectivity of ligands for G‐quadruplex DNA over the duplex DNA. A numerical parameter, termed the G‐quadruplex binding mode index (G4‐BMI), has been introduced to express the difference in the affinities of ligands for intermolecular G‐quadruplex 1 against intramolecular G‐quadruplex 2 . The G‐quadruplex binding mode index (G4‐BMI) of a ligand is defined as follows: G4‐BMI=KDintra/KDinter, where KDintra is the dissociation constant for intramolecular G‐quadruplex 2 and KDinter is the dissociation constant for intermolecular G‐quadruplex 1 . In summary, the present work has demonstrated that the use of parallel‐constrained quadruplex topology provides more precise information about the binding modes of ligands.  相似文献   

10.
Histone acetyltransferases (HATs) catalyze the acetylation of specific lysine residues in histone and nonhistone proteins. Recent studies showed that acetylation is widely distributed among cellular proteins, suggestive of diverse functions of HATs in cellular pathways. Nevertheless, currently available assays for HAT activity study are still quite limited. Here, we evaluated a series of thiol-sensitive fluorogenic compounds for the detection of the enzymatic activities of different HAT proteins. Upon conjugation to the thiol group of HSCoA, these molecules gain enhanced quantum yields and strong fluorescence, permitting facile quantitation of HAT activities. We investigated and compared the assay performances of these fluorogenic compounds for their capability as HAT activity reporters, including kinetics of reaction with HSCoA, influence on HAT activity, and fluorescence amplification factors. Our data suggest that CPM and coumarin maleic acid ester are excellent HAT probes owing to their fast reaction kinetics and dramatic fluorescence enhancement during the HAT reaction. Further, the microtiter plate measurements show that this fluorescent approach is robust and well suited for adaption to high-throughput screening of small molecule inhibitors of HATs, highlighting the value of this assay strategy in new drug discovery.  相似文献   

11.
Histone deacetylase (HDAC) is a major class of deacetylation enzymes. Many HDACs exist in large protein complexes in cells and their functions strongly depend on the complex composition. The identification of HDAC‐associated proteins is highly important in understanding their molecular mechanisms. Although affinity probes have been developed to study HDACs, they were mostly targeting the direct binder HDAC, while other proteins in the complex remain underexplored. We report a DNA‐based affinity labeling method capable of presenting different probe configurations without the need for preparing multiple probes. Using one binding probe, 9 probe configurations were created to profile HDAC complexes. Notably, this method identified indirect HDAC binders that may be inaccessible to traditional affinity probes, and it also revealed new biological implications for HDAC‐associated proteins. This study provided a simple and broadly applicable method for characterizing protein‐protein interactions.  相似文献   

12.
Efficient violet–blue‐emitting molecules are especially useful for applications in full‐color displays, solid‐state lighting, as well as in two‐photon absorption (TPA) excited frequency‐upconverted violet–blue lasing. However, the reported violet–blue‐emitting molecules generally possess small TPA cross sections. In this work, new 1,8‐diazapyrenes derivatives 3 with blue two‐photon‐excited fluorescence emission were concisely synthesized by the coupling reaction of readily available 1,4‐naphthoquinone O,O‐diacetyl dioxime ( 1 ) with internal alkynes 2 under the [{RhCl2Cp*}2]–Cu(OAc)2 (Cp*=pentamethylcyclopentadienyl ligand) bimetallic catalytic system. Elongation of the π‐conjugated length of 1,8‐diazapyrenes 3 led to the increase of TPA cross sections without the expense of a redshift of the emission wavelength, probably due to the rigid planar structure of chromophores. It is especially noteworthy that 2,3,6,7‐tetra(4‐bromophenyl)‐1,8‐diazapyrene ( 3c ) has a larger TPA cross section than those of other molecules reported so far. These experimental results are explained in terms of the effects of extension of the π‐conjugated system, intramolecular charge transfer, and reduced detuning energy.  相似文献   

13.
Platinum antitumour agents, containing aromatic rings, which are used for targeting DNA in effective therapies for the treatment of cancer. We have synthesized the title metallocomplex with an aromatic ligand and determined its crystal structure. In many cases, complexes of platinum and other metals have a symmetrical structure. In contrast, the platinum(II) complex with pyridine and N‐(9‐anthracenylmethyl)‐1,2‐ethanediamine as ligands (systematic name: cis‐{N‐[(anthracen‐9‐yl)methyl]ethane‐1,2‐diamine‐κ2N ,N ′}bis(pyridine‐κN )platinum(II) dinitrate), [Pt(C5H5N)2(C17H18N2)](NO3)2, is asymmetric. Of the two pyridine ligands, only one is π‐stacked with anthracene, resulting in an asymmetric structure. Moreover, the angle of orientation of each pyridine ligand is variable. Further examination of the packing motif confirms an intermolecular edge‐to‐face interaction.  相似文献   

14.
The synthesis of conjugated polymers with ionic substituents directly bound to their main chain repeat units is a strategy for generating strongly electron‐accepting conjugated polyelectrolytes, as demonstrated through the synthesis of a series of ionic azaquinodimethane (iAQM) compounds. The introduction of cationic substituents onto the quinoidal para‐azaquinodimethane (AQM) core gives rise to a strongly electron‐accepting building block, which can be employed in the synthesis of ionic small molecules and conjugated polyelectrolytes (CPEs). Electrochemical measurements alongside theoretical calculations indicate notably low‐lying LUMO values for the iAQMs. The optical band gaps measured for these compounds are highly tunable based on structure, ranging from 2.30 eV in small molecules down to 1.22 eV in polymers. The iAQM small molecules and CPEs showcase the band gap reduction effects of combining the donor‐acceptor strategy with the bond‐length alternation reduction strategy. As a demonstration of their utility, the iAQM CPEs so generated were used as active agents in photothermal therapy.  相似文献   

15.
The CoII atom in bis(5‐aminotetrazole‐1‐acetato)tetraaquacobalt(II), [Co(C3H4N5O2)2(H2O)4], (I), is octahedrally coordinated by six O atoms from two 5‐aminotetrazole‐1‐acetate (atza) ligands and four water molecules. The molecule has a crystallographic centre of symmetry located at the CoII atom. The molecules of (I) are interlinked by hydrogen‐bond interactions, forming a two‐dimensional supramolecular network structure in the ac plane. The CdII atom in catena‐poly[[cadmium(II)]‐bis(μ‐5‐aminotetrazole‐1‐acetato], [Cd(C3H4N5O2)2]n, (II), lies on a twofold axis and is coordinated by two N atoms and four O atoms from four atza ligands to form a distorted octahedral coordination environment. The CdII centres are connected through tridentate atza bridging ligands to form a two‐dimensional layered structure extending along the ab plane, which is further linked into a three‐dimensional structure through hydrogen‐bond interactions.  相似文献   

16.
The mechanism of N‐dealkylation mediated by cytochrome P450 (P450) has long been studied and argued as either a single electron transfer (SET) or a hydrogen atom transfer (HAT) from the amine to the oxidant of the P450, the reputed iron–oxene. In our study, tertiary anilinic N‐oxides were used as oxygen surrogates to directly generate a P450‐mediated oxidant that is capable of N‐dealkylating the dimethylaniline derived from oxygen donation. These surrogates were employed to probe the generated reactive oxygen species and the subsequent mechanism of N‐dealkylation to distinguish between the HAT and SET mechanisms. In addition to the expected N‐demethylation of the product aniline, 2,3,4,5,6‐pentafluoro‐N,N‐dimethylaniline N‐oxide (PFDMAO) was found to be capable of N‐dealkylating both N,N‐dimethylaniline (DMA) and N‐cyclopropyl‐N‐methylaniline (CPMA). Rate comparisons of the N‐demethylation of DMA supported by PFDMAO show a 27‐fold faster rate than when supported by N,N‐dimethylaniline N‐oxide (DMAO). Whereas intermolecular kinetic isotope effects were masked, intramolecular measurements showed values reflective of those seen previously in DMAO‐ and the native NADPH/O2‐supported systems (2.33 and 2.8 for the N‐demethylation of PFDMA and DMA from the PFDMAO system, respectively). PFDMAO‐supported N‐dealkylation of CPMA led to the ring‐intact product N‐cyclopropylaniline (CPA), similar to that seen with the native system. The formation of CPA argues against a SET mechanism in favor of a P450‐like HAT mechanism. We suggest that the similarity of KIEs, in addition to the formation of the ring‐intact CPA, argues for a similar mechanism of Compound I (Cpd I) formation followed by HAT for N‐dealkylation by the native and N‐oxide‐supported systems and demonstrate the ability of the N‐oxide‐generated oxidant to act as an accurate mimic of the native P450 oxidant.  相似文献   

17.
Recently, metabolic glycoengineering with bioorthogonal click reactions has focused on improving the tumor targeting efficiency of nanoparticles as delivery vehicles for anticancer drugs or imaging agents. It is the key technique for developing tumor‐specific metabolic precursors that can generate unnatural glycans on the tumor‐cell surface. A cathepsin B‐specific cleavable substrate (KGRR) conjugated with triacetylated N‐azidoacetyl‐d ‐mannosamine (RR‐S‐Ac3ManNAz) was developed to enable tumor cells to generate unnatural glycans that contain azide groups. The generation of azide groups on the tumor cell surface was exogenously and specifically controlled by the amount of RR‐S‐Ac3ManNAz that was fed to target tumor cells. Moreover, unnatural glycans on the tumor cell surface were conjugated with near infrared fluorescence (NIRF) dye‐labeled molecules by a bioorthogonal click reaction in cell cultures and in tumor‐bearing mice. Therefore, our RR‐S‐Ac3ManNAz is promising for research in tumor‐specific imaging or drug delivery.  相似文献   

18.
A series of three‐ring analogs of the minor‐groove‐binding molecule Hoechst 33258 ( 1 ), consisting of benzimidazole (B), imidazopyridine (P), and hydroxybenzimidazole (H) monomers, have been synthesized in order to investigate both their sequence specificity and binding modes. MPE⋅FeII Footprinting has revealed the preference of both PBB and BBB ligands for 5′‐WGWWW‐3′ and 5′‐WCWWW‐3′ tracts, as well as A⋅T‐rich sequences. Affinity‐cleavage titrations show no evidence for a 2 : 1 binding mode of these Hoechst analogs. Importantly, all derivatives are oriented in one direction at each of their binding sites. The implications of these results for the design of minor‐groove‐binding small molecules is discussed.  相似文献   

19.
In spite of its importance in cell function, targeting DNA is under‐represented in the design of small molecules. A barrier to progress in this area is the lack of a variety of modules that recognize G ? C base pairs (bp) in DNA sequences. To overcome this barrier, an entirely new design concept for modules that can bind to mixed G ? C and A ? T sequences of DNA is reported herein. Because of their successes in biological applications, minor‐groove‐binding heterocyclic cations were selected as the platform for design. Binding to A ? T sequences requires hydrogen‐bond donors whereas recognition of the G‐NH2 requires an acceptor. The concept that we report herein uses pre‐organized N‐methylbenzimidazole (N‐MeBI) thiophene modules for selective binding with mixed bp DNA sequences. The interaction between the thiophene sigma hole (positive electrostatic potential) and the electron‐donor nitrogen of N‐MeBI preorganizes the conformation for accepting an hydrogen bond from G‐NH2. The compound–DNA interactions were evaluated with a powerful array of biophysical methods and the results show that N‐MeBI‐thiophene monomer compounds can strongly and selectively recognize single G ? C bp sequences. Replacing the thiophene with other moieties significantly reduces binding affinity and specificity, as predicted by the design concept. These results show that the use of molecular features, such as sigma‐holes, can lead to new approaches for small molecules in biomolecular interactions.  相似文献   

20.
Overhanging carboxylic acid porphyrins have revealed promising ditopic ligands offering a new entry in the field of supramolecular coordination chemistry of porphyrinoids. Notably, the adjunction of a so‐called hanging‐atop (HAT) PbII cation to regular PbII porphyrin complexes allowed a stereoselective incorporation of the N‐core bound cation, and an allosterically controlled Newton’s cradle‐like motion of the two PbII ions also emerged from such bimetallic complexes. In this contribution, we have extended this work to other ligands and metal ions, aiming at understanding the parameters that control the HAT PbII coordination. The nature of the N‐core bound metal ion (ZnII, CdII), the influence of the deprotonation state of the overhanging COOH group and the presence of a neutral ligand on the opposite side (exogenous or intramolecular), have been examined through 1H NMR spectroscopic experiments with the help of radiocrystallographic structures and DFT calculations. Single and bis‐strap ligands have been considered. They all incorporate a COOH group hung over the N‐core on one side. For the bis‐strap ligands, either an ester or an amide group has been introduced on the other side. In the presence of a base, the mononuclear ZnII or CdII complexes incorporate the carbonyl of the overhanging carboxylate as apical ligand, decreasing its availability for the binding of a HAT PbII. An allosteric effector (e.g., 4‐dimethylaminopyridine (DMAP), in the case of a single‐strap ligand) or an intramolecular ligand (e.g., an amide group), strong enough to compete with the carbonyl of the hung COO?, is required to switch the N‐core bound cation to the opposite side with concomitant release of the COO?, thereby allowing HAT PbII complexation. In the absence of a base, ZnII or CdII binds preferentially the carbonyl of the intramolecular ester or amide groups in apical position rather than that of the COOH. This better preorganization, with the overhanging COOH fully available, is responsible for a stronger binding of the HAT PbII. Thus, either allosteric or acid–base control is achieved through stereoselective metalation of ZnII or CdII. In the latter case, according to the deprotonation state of the COOH group, the best electron‐donating ligand is located on one or the other side of the porphyrin (COO?>CONHR>COOR>COOH): the lower affinity of COOH for ZnII and CdII, the higher for a HAT PbII. These insights provide new opportunities for the elaboration of innovative bimetallic molecular switches.  相似文献   

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