[Show abstract][Hide abstract] ABSTRACT: G-quadruplexes are four-stranded DNA structures formed from G-rich sequences that are built around tetrads of hydrogen-bonded guanine bases. Accumulating studies have revealed that G-quadruplex structures are formed in vivo and play important roles in biological processes such as DNA replication, transcription, recombination, epigenetic regulation, meiosis, antigenic variation, and maintenance of telomeres stability. Mounting evidence indicates that a variety of proteins are capable of binding selectively and tightly to G-quadruplex and play essential roles in G-quadruplex-mediated regulation processes. Some of these proteins promote the formation or/and stabilization of G-quadruplex, while some other proteins act to unwind G-quadruplex preferentially. From a drug discovery perspective, many of these G-quadruplex binding proteins and/or their complexes with G-quadruplexes are potential drug targets. Here, we present a general summary of reported G-quadruplex binding proteins and their biological functions, with focus on those of medicinal research significance. We elaborated the possibility for some of these G-quadruplex binding proteins and their complexes with G-quadruplexes as potential drug targets.
Current topics in medicinal chemistry 05/2015; 15(19). DOI:10.2174/1568026615666150515150803 · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cp*Rh(III) and Cp*Ir(III)-catalysed direct C–H arylation with quinone diazides as efficient coupling partners is disclosed. This redox-neutral protocol offers a facile, operationally simple and environmentally benign access to arylated phenols, which are important in functional molecules. The selective mono- or diarylation was realized by the employment of different catalyst. The reaction represents the first example of Cp*Ir(III)-catalysed C–H direct arylation reaction.
Chemical Communications 05/2015; 51(50). DOI:10.1039/C5CC03187G · 6.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A series of new asymmetric curcumin analogues were synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. Our results showed that most of these synthetic compounds had better inhibitory properties against A aggregation compared with curcumin, and better anti-oxidative properties compared with the reference compound Trolox through the study of oxygen radical absorbance capacity (ORAC). Some compounds showed good properties in selectively chelating metal ions such as copper and iron. Besides, some compounds were found to be able to dissociate A protein which had already aggregated. The structure-activity relationships (SAR) of these synthetic compounds were studied. The present investigation indicated that our synthetic asymmetric curcumin derivatives could be potential multifunctional agents for the treatment of Alzheimer's disease (AD).
Current Alzheimer research 05/2015; 12(5). · 3.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Up-regulation of ADAM10 to prevent the formation of beta-amyloid (Aβ) peptides might be a promising strategy to treat Alzheimer's disease (AD). RNA G-quadruplex motif within the 5'-UTR of the ADAM10 mRNA is an inhibitory element for ADAM10 translation. Thus mitigation of the suppressive effect of this motif using an RNA G-quadruplex-forming G-rich sequence (QGRS) binder might be a new approach for AD therapy. Herein, a series of new methylquinolinium derivatives were synthesized and screened by Surface Plasmon Resonance (SPR) and the dual-luciferase reporter assay. Among them, compound 24 showed selective affinity for the QGRS of ADAM10and could strongly up-regulate the translation of it. Moreover, treatment with 24 led to a significant increase of the secretion of sAPPα, consequently decreasing the Aβ40 in cellular. These results illustrate that the interaction between the RNA QGRS and a small molecule may be a new molecular strategy to modulate the translation of ADAM10.
[Show abstract][Hide abstract] ABSTRACT: A novel series of benzo[a]phenazin derivatives bearing alkylamino side chains were designed, synthesized and evaluated for their topoisomerases inhibitory activity as well as cytotoxicity against four human cancer cell lines (HL-60, K-562, HeLa, and A549). These compounds were found to be dual inhibitors of topoisomerase (Topo) I and Topo II, and exhibited excellent antiproliferative activity, in particular against HL-60 cells with submicromolar IC50 values. Further mechanistic studies showed that this class of compounds acted as Topo I poisons by stabilizing the Topo I-DNA cleavage complexes and Topo II catalytic inhibitors by inhibiting the ATPase activity of hTopo II. Molecular docking studies revealed the binding modes of these compounds for Topo I and Topo II.
European Journal of Medicinal Chemistry 03/2015; 92. DOI:10.1016/j.ejmech.2015.01.024 · 3.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A series of new 2-arylethenylquinoline derivatives (4a(1)-4a(12), 4b(1)-4b(8), 4c(1)-4c(4), 4d(1)-4d(3) and 4e(1)-4e(9)) were designed, synthesized, and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease (AD). In vitro studies showed that these synthetic compounds inhibited self-induced A beta(1-42) aggregation effectively ranged from 23.6% to 83.9% at the concentration of 20 mu M, and acted as potential antioxidants and biometal chelators. Their structure-activity relationships were obtained and discussed. In particular, compound 4b(1), the most active compound, displayed strong inhibitory activity with an IC50 value of 9.7 mu M for self-induced A beta(1-42) aggregation, good antioxidative activity with a value of 3.9-fold of Trolox, potent inhibitory activity for cholinesterase with IC50 values of 0.2 mu M and 64.1 mu M against butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE), respectively. Besides, 4b(1) was also capable of disassembling the self-induced A beta(1-42) aggregation fibrils with a ratio of 59.8% at 20 mu M concentration, and had a good metal chelating activity. Taken together, these results suggest that compound 4b(1) might be a promising lead compound for AD treatment.
European Journal of Medicinal Chemistry 01/2015; 89:349–361. DOI:10.1016/j.ejmech.2014.10.018 · 3.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The sensitive and selective detection of nucleic acids is important for basic research and many applied fields. Herein, a series of new BODIPY-benzofuroquinoline conjugates were designed, synthesized and evaluated as DNA intercalating dyes. All compounds were characterized by using H-1, C-13 NMR, IR, UV-Vis and fluorescence spectroscopy, and DNA binding properties of these conjugates to calf thymus DNA were studied by using fluorescence titration, UV titration, isothermal titration calorimetry and CD analysis. Significant enhancement of the fluorescent quantum yield was observed for all the conjugates in the presence of calf thymus DNA, and one compound showed excellent sensitivity and selectivity offering its potential application as a DNA specific fluorescent probe. Our results showed that these conjugates could intercalate into calf thymus DNA with high binding affinities. The properties of these dyes as fluorescent probes for living cells imaging were also investigated.
Dyes and Pigments 08/2014; 107:97–105. DOI:10.1016/j.dyepig.2014.03.027 · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ferrocene (Fc) tagged peptide nanowires (Fc-PNWs) were synthesized via the self-assemble of Fc coupled diphenylalanine (Phe-Phe, FF) and then utilized as supporting matrix for the immobilization of glucose oxidase (GOx). Scanning electron microscopy (SEM) characterization indicates the Fc-PNWs were twisted together with diameter around 50 nm. The GOx functionalized Fc-PNWs contains both mediator Fc and GOx that necessary for the electrochemical detection of glucose. So, with simply dropping the biocomposite onto electrode surface in one step, the resulting biosensor displays high sensitivity, wide linear range and good stability towards glucose detection. The good performance of the biosensor was originated from the great amount of Fc moieties contained in the nanowire and the facile electron transfer between Fc and GOx. For real sample analysis, the glucose contents in blood samples determined by the biosensor was in good agreement with those obtained using the glucose detection kit. The simplicity of the biosensor preparation process enables mass production of the biosensor with wide potential commercial applications. The synthesized Fc-PNWs can also be used in different sensing and biosensing fields.
[Show abstract][Hide abstract] ABSTRACT: Background: Accelerated proliferation of solid tumor and hematologic cancer cells is related to accelerated transcription of ribosomal DNA by the RNA polymerase I to produce elevated level of ribosomal RNA. Therefore, down-regulation of RNA polymerase I transcription in cancer cells is an important anticancer therapeutic strategy. Methods: A variety of methods were used, including cloning, expression and purification of protein, electrophoretic mobility shift assay (EMSA), circular dichroic (CD) spectroscopy, CD-melting, isothermal titration calorimetry (ITC), chromatin immunoprecipitation (Ch-IP), RNA interference, RT-PCR, Western blot, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) cell assay. Results: Our results showed that 2,4-disubstituted quinazoline derivative Sysu12d could down-regulate c-myc through stabilization of c-myc promoter G-quadruplex, resulting in down-regulation of nucleolin expression. Sysu12d could also disrupt nucleolin/G-quadruplex complex. Both of the above contributed to the down-regulation of ribosomal RNA synthesis, followed by activation of p53 and then cancer cell apoptosis. Conclusions: These mechanistic studies set up the basis for further development of Sysul2d as a new type of lead compound for cancer treatment. General significance: 2,4-Disubstituted quinazoline derivatives may have multi-functional effect for cancer treatment.
Biochimica et Biophysica Acta (BBA) - General Subjects 07/2014; 1840(10). DOI:10.1016/j.bbagen.2014.07.004 · 3.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Telomere is protected by its G-quadruplex, T-loop structure, telomerase, and binding protein complex. Protein POT1 (protection of telomeres 1) is one subunit of telomere binding protein complex Shelterin. POT1 acts as a regulator of telomerase-dependent telomere length, and it can help telomere to form D-loop structure to stabilize telomere. POT1 protects telomere ends from ATR-dependent DNA damage response as well.
Extensive methods were used, including CD, EMSA, ITC, PCR stop assay, luciferase reporter assay, quantitative real-time PCR, Western blot, chromatin immunoprecipitation (Ch-IP), cloning, expression and purification of proteins.
We found a new G-rich 30-base-pair long sequence (P-pot1 G18) located from -165 to -136 base pairs upstream of the translation starting site of protein POT1. This sequence in the promoter region of pot1 gene formed G-quadruplex resulting in down-regulation of pot1 gene transcription. This G-rich sequence is close to a binding site “TCCC” for transcription factor hnRNP K (heterogeneous nuclear ribonucleoprotein K), and its conversion to G-quadruplex prevented the access of hnRNP K to this binding site. The binding of hnRNP K could up-regulate pot1 gene transcription. TMPyP4 (meso-tetra(N-methyl-4-pyridyl)porphine) has been widely used as G-quadruplex binding ligand, which stabilized the G-quadruplex in vitro and in cellulo, resulting in down-regulation of pot1 gene transcription.
This G-quadruplex might become a potentially new drug target for antitumor agents.
Our results first demonstrated that G-quadruplex formation can affect the binding of transcription factor to its nearby binding site, and thus making additional influence to gene transcription.
Biochimica et Biophysica Acta (BBA) - General Subjects 07/2014; DOI:10.1016/j.bbagen.2014.03.001 · 3.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cellular nucleic acid binding protein (CNBP) has been implicated in vertebrate craniofacial development and in myotonic dystrophy type 2 (DM2) and sporadic inclusion body myositis (sIBM) human diseases by controlling cell proliferation and survival to mediate neural crest expansion. CNBP has been found to bind single-stranded nucleic acid and promote rearrangements of nucleic acid secondary structure in an ATP-independent manner, acting as a nucleic acid chaperone.
A variety of methods were used, including cell viability assays, wound-scratch assays, chemotaxis assays, invasion assays, circular dichroic (CD) spectroscopy, NMR spectroscopy, chromatin immunoprecipitation, expression and purification of recombinant human CNBP, electrophoretic mobility shift assay (EMSA), surface plasmon resonance (SPR), fluorescence resonance energy transfer (FRET) analyses, Luciferase reporter assay, Western blotting, isothermal titration calorimetry (ITC).
Up-regulation of CNBP induced human fibrosarcoma cell death and suppressed fibrosarcoma cells motility and invasiveness. It was found that CNBP transcriptionally down-regulated expression of heterogeneous ribonucleoprotein K (hnRNP K) through its conversion of a G-rich sequence into G-quadruplex in the promoter of hnRNP K. G-Quadruplex stabilizing ligand tetra-(N-methyl-4-pyridyl) porphyrin (TMPyP4) could interact with and stabilize the G-quadruplex, resulting in downregulation of hnRNP K transcription.
CNBP overexpression caused increase of cell death and suppression of cell metastasis through its induction of G-quadruplex formation in the promoter of hnRNP K resulting in hnRNP K down-regulation.
The present result provided a new solution for controlling hnRNP K expression, which should shed light on new anticancer drug design and development.
Biochimica et Biophysica Acta (BBA) - General Subjects 07/2014; DOI:10.1016/j.bbagen.2014.02.025 · 3.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the present study, we found that three enzymes, MVK, MDD and FPPS, in the mevalonate pathway (MVP) of cholesterol biosynthesis, can be simultaneously inhibited by two green tea polyphenols ((-)-epicatechin-3-gallate, ECG; (-)-epigallocatechin-3-gallate, EGCG). Molecular dynamics simulations and pharmacophore studies were carried out to elucidate the tri-targeted inhibition mechanisms. Our results indicate that similar triangular binding pockets exist in all three enzymes, which is essential for their binding with polyphenols. Two distinct binding poses for ECG and EGCG were observed in our MD simulations. These results shed light on the potential for further selective and multi-targeted inhibitor design for the treatment of hyperlipidemia.
[Show abstract][Hide abstract] ABSTRACT: A tailor-made colorimetric and red-emitting fluorescent dual probe for G-quadruplex nucleic acids was developed by incorporating a coumarin-hemicyanine fluorophore into an isaindigotone framework. The significant and distinct changes in both the color and fluorescence of this probe enable the label-free and visual detection of G-quadruplex structures.
Chemical Communications 05/2014; 50(52). DOI:10.1039/c4cc01472c · 6.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder that is characterized by dementia, cognitive impairment, and memory loss. Diverse factors are related to the development of AD, such as increased level of β-amyloid (Aβ), acetylcholine, metal ion deregulation, hyperphosphorylated tau protein, and oxidative stress.
The following methods were used: organic syntheses of 1H-phenanthro[9,10-d]imidazole derivatives, inhibition of self-mediated and metal-induced Aβ1-42 aggregation, inhibition studies for acetylcholinesterase and butyrylcholinesterase, anti-oxidation activity studies, CD, MTT assay, transmission electron microscopy, dot plot assay, gel electrophoresis, Western blot, and molecular docking studies.
We synthesized and characterized a new type of 1H-phenanthro[9,10-d]imidazole derivatives as multifunctional agents for AD treatment. Our results showed that most of these derivatives exhibited strong Aβ aggregation inhibitory activity. Compound 9g had 74% Aβ1-42 aggregation inhibitory effect at 10 μM concentration with its IC50 value of 6.5 μM for self-induced Aβ1-42 aggregation. This compound also showed good inhibition of metal-mediated (Cu(2+) and Fe(2+)) and acetylcholinesterase-induced Aβ1-42 aggregation, as indicated by using thioflavin T assay, transmission electron microscopy, gel electrophoresis, and Western blot. Besides, compound 9g exhibited cholinesterase inhibitory activity, with its IC50 values of 0.86 μM and 0.51 μM for acetylcholinesterase and butyrylcholinesterase, respectively. In addition, compound 9g showed good anti-oxidation effect with oxygen radical absorbance capacity (ORAC) value of 2.29.
Compound 9g was found to be a potent multi-target-directed agent for Alzheimer's disease.
Compound 9g could become a lead compound for further development as a multi-target-directed agent for AD treatment.
[Show abstract][Hide abstract] ABSTRACT: Cyanobacterial fructose-1, 6-/sedoheptulose-1, 7-bisphoshatase (cy-FBP/SBPase) is a potential enzymatic target for screening novel inhibitors that can combat harmful algal blooms (HABs). In the present study, we targeted the substrate binding pocket of cy-FBP/SBPase. A series of novel hit compounds from SPECs database were selected by using a pharmacophore-based virtual screening strategy. Most of the compounds tested exhibited moderate inhibitory activities (IC50 = 20.7 -176.9.8 μM) against cy-FBP/SBPase. The compound 2 and its analogues, compounds 10 and 11 exhibited strong inhibitory activities, with IC50 values of 20.7, 13.4, and 19.0 μM against cy-FBP/SBPase in vitro, and with EC50 values of 12.3, 10.9, and 2.9 ppm against cyanobacteria Synechocystis PCC6803 in vivo, respectively. The compound 10 was selected in order to perform the refined docking study to investigate the rational binding mode of inhibitors with cy-FBP/SBPase. Furthermore, the possible interaction of the residues with inhibitors was examined by site-directed mutagenesis, enzymatic assays, and fluorescence spectral analyses. The results provide insight into the binding-mode between the inhibitors and substrate binding pocket. The observed theoretical and experimental results are in concert, indicating that modeling strategies and screening methods employed are appropriate for searching novel lead compounds having both structural diversity and high inhibitory activity against cy-FBP/SBPase.
Journal of Chemical Information and Modeling 02/2014; 54(3). DOI:10.1021/ci4007529 · 4.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In insects, cholesterol is one of the membrane components in cells and a precursor of ecdysteroid biosynthesis. Because insects lack two key enzymes, squalene synthase and lanosterol synthase, in the cholesterol biosynthesis pathway, they cannot autonomously synthesize cholesterol de novo from simple compounds and therefore have to obtain sterols from their diet. Sterol carrier protein (SCP) is a cholesterol-binding protein responsible for cholesterol absorption and transport.
In this study, a model of the three-dimensional structure of SlSCPx-2 in Spodoptera litura, a destructive polyphagous agricultural pest insect in tropical and subtropical areas, was constructed. Docking of sterol and fatty acid ligands to SlSCPx-2 and ANS fluorescent replacement assay showed that SlSCPx-2 was able to bind with relatively high affinities to cholesterol, stearic acid, linoleic acid, stigmasterol, oleic acid, palmitic acid and arachidonate, implying that SlSCPx may play an important role in absorption and transport of these cholesterol and fatty acids from host plants. Site-directed mutation assay of SlSCPx-2 suggests that amino acid residues F53, W66, F89, F110, I115, T128 and Q131 are critical for the ligand-binding activity of the SlSCPx-2 protein. Virtual ligand screening resulted in identification of several lead compounds which are potential inhibitors of SlSCPx-2. Bioassay for inhibitory effect of five selected compounds showed that AH-487/41731687, AG-664/14117324, AG-205/36813059 and AG-205/07775053 inhibited the growth of S. litura larvae.
Compounds AH-487/41731687, AG-664/14117324, AG-205/36813059 and AG-205/07775053 selected based on structural modeling showed binding affinity to SlSCPx-2 protein and inhibitory effect on the growth of S. litura larvae.
PLoS ONE 01/2014; 9(1):e81542. DOI:10.1371/journal.pone.0081542 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cyanobacterial fructose-1,6/sedoheptulose-1,7-bisphosphatase (cy-FBP/SBPase) plays a vital role in gluconeogenesis and in photosynthetic carbon reduction pathway and is thus a potential enzymatic target for inhibition of harmful cyanobacterial blooms. Here, we describe the crystal structure of cy-FBP/SBPase in complex with adenosine monophosphate (AMP) and fructose-1,6-bisphosphate (FBP). The allosteric inhibitor AMP and the substrate FBP exhibit an unusual binding mode when in complex with cy-FBP/SBPase. The binding mode analysis suggests that AMP bound to the allosteric sites near the interface across the up-down subunit pairs C1C4 and C2C3 assembled in the center of the tetramer, while FBP binds opposite to the interface between the horizontal subunit pairs C1C2 or C3C4. We identified a series of residues important for FBP and AMP binding and suggest the formation of a disulfide linkage between Cys 75 and Cys 99. Further analysis indicates that cy-FBP/SBPase may be regulated through ligand binding and changing of the structure of the enzyme complex. The interactions between ligands and cy-FBP/SBPase are different from those of scaffold ligand-bound structures of other FBPase family members and thus provide new insight into the molecular mechanisms of structure and catalysis of cy-FBP/SBPase. Our studies provide novel insight into the evolution of this enzyme family, and may help in the design of inhibitors aimed at preventing toxic cyanobacterial blooms.
cy-FBP/SBPase and cy-FBP/SBPase bind by x-ray crystallography (View interaction) This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Farnesyl pyrophosphate synthase (FPPS) is a key regulatory enzyme in the biosynthesis of cholesterol and in the post-translational modification of signaling proteins. It has been reported that non-bisphosphonate FPPS inhibitors targeting its allosteric binding pocket are potentially important for the development of promising anti-cancer drugs.
The following methods were used: organic syntheses of non-bisphophonate quinoline derivatives, enzyme inhibition studies, fluorescence titration assays, synergistic effect studies of quinoline derivatives with zoledronate, ITC studies for the binding of FPPS with quinoline derivatives, NMR-based HAP binding assays, molecular modeling studies, fluorescence imaging assay and MTT assays.
We report our syntheses of a series of quinoline derivatives as new FPPS inhibitors possibly targeting the allosteric site of the enzyme. Compound 6b showed potent inhibition to FPPS without significant hydroxyapatite binding affinity. The compound showed synergistic inhibitory effect with active-site inhibitor zoledronate. ITC experiment confirmed the good binding effect of compound 6b to FPPS, and further indicated the binding ratio of 1:1. Molecular modeling studies showed that 6b could possibly bind to the allosteric binding pocket of the enzyme. The fluorescence microscopy indicated that these compounds could get into cancer cells.
The traditional FPPS active-site inhibitors bisphosphonates show poor membrane permeability to tumor cells, due to their strong polarity. The development of new non-bisphophonate FPPS inhibitors with good cell membrane permeability is potentially important. Our results showed that quinoline derivative 6b could become a new lead compound for further optimization for cancer treatment.
[Show abstract][Hide abstract] ABSTRACT: A series of pyridophenazine derivatives were synthesized and characterized as DNA intercalating fluorophores. These pyridophenazines showed absorption maxima at ca. 450 nm, and some compounds exhibited strong fluorescence at ca. 530 nm with excellent quantum yields in ethyl acetate solution. DNA binding properties of these pyridophenazines to calf thymus DNA (CT DNA) were studied in phosphate buffered saline at pH 7.4 by means of fluorescence titration. All compounds showed high binding affinity toward CT DNA with binding constant values in the range of 106 M−1, with fluorescence enhancement upon their binding to CT DNA. The fluorescent aminoethylpiperidine substituted pyridophenazine was employed as a sensitive agent for DNA determination with a limit of detection of 65 nM over a linear range of 100–1000 nM. The fluorescence titration and Top1 mediated DNA unwinding assay showed that this derivative exhibited DNA intercalation.
Dyes and Pigments 10/2013; 99(1):82–89. DOI:10.1016/j.dyepig.2013.04.025 · 3.97 Impact Factor