- Fit to be tied: Conformation-directed macrocyclization of peptoid foldamers
-
Covalent macrocyclic constraints can be readily installed on N-substituted glycine "peptoid" oligomer substrates. Cu(I)-catalyzed [3+2] cycloaddition reactions were conducted on solid support to ligate peptoid side chain azide and alkyne functionalities. Intramolecular macrocycle formation is facilitated by preorganizing the reactive groups across one turn of the helical secondary structure. These results confirm that conformational ordering can be exploited to assist the macrocyclization of folded oligomers.
- Holub, Justin M.,Jang, Hangjun,Kirshenbaum, Kent
-
-
Read Online
- Amphiphilic peptoid transporters-synthesis and evaluation
-
Cell-penetrating peptoids are an important class of peptidomimetics, which can replace highly biodegradable cell penetrating peptides for enhanced drug delivery. Typically, they contain positively charged amino side chains which are synthesized via their protected analogues. To avoid the use of amine protecting groups a Click-chemistry based modular synthesis of novel hydrophilic as well as amphiphilic cell penetrating peptoids was developed to generate novel structures for drug delivery in cells.
- Vollrath, Sidonie B. L.,Fuerniss, Daniel,Schepers, Ute,Braese, Stefan
-
-
Read Online
- Multivalent peptidomimetic conjugates: A versatile platform for modulating androgen receptor activity
-
We introduce a family of multivalent peptidomimetic conjugates that modulate the activity of the androgen receptor (AR). Bioactive ethisterone ligands were conjugated to a set of sequence-specific peptoid oligomers. Certain multivalent peptoid conjugates enhance AR-mediated transcriptional activation. We identify a linear and a cyclic conjugate that exhibit potent anti-proliferative activity in LNCaP-abl cells, a model of therapy-resistant prostate cancer. The linear conjugate blocks AR action by competing for ligand binding. In contrast, the cyclic conjugate is active despite its inability to compete against endogenous ligand for binding to AR in vitro, suggesting a non-competitive mode of action. These results establish a versatile platform to design competitive and non-competitive AR modulators with potential therapeutic significance.
- Levine, Paul M.,Imberg, Keren,Garabedian, Michael J.,Kirshenbaum, Kent
-
-
Read Online
- Synthesis and PI3 kinase inhibition activity of a Wortmannin-Leucine derivative
-
Wortmannin is a potent covalent inhibitor of PI3K that shows substantial in vivo toxicity and thus is unsuitable for systemic therapeutic applications. One possible approach to minimize systemic toxicity is to generate a latent wortmannin pro-drug that will be selectively activated in target tissues. To test this approach, a wortmannin derivative with a leucine linker attached to C20 has been synthesized and tested for inhibition of PI3K activity in prostate cancer cells. Analysis of PI3K pathway inhibition by Wormannin-Leu (Wn-L) and intact Wortmannin (Wn) showed that attachment of Leu at C-20 decreased potency of PI3K pathway inhibition 10-fold compared to intact wortmannin, yet exceeded the potency of a competitive PI3K inhibitor LY294002.
- Cantrell, William,Huang, Yue,Menchaca, Antonio A.,Kulik, George,Welker, Mark E.
-
-
Read Online
- Synthesis and single enzyme activity of a clicked lipase-BSA hetero-dimer
-
Click chemistry is used to construct a novel lipase-BSA hetero-dimer, in which the latter protein acts as a foot enabling the anchoring of the enzyme onto the surface for single enzyme studies. The Royal Society of Chemistry 2006.
- Hatzakis, Nikos S.,Engelkamp, Hans,Velonia, Kelly,Hofkens, Johan,Christianen, Peter C. M.,Svendsen, Allan,Patkar, Shamkantr A.,Vind, Jesper,Maan, Jan C.,Rowan, Alan E.,Nolte, Roeland J. M.
-
-
Read Online
- Versatile synthesis of asymmetrical dendron-like/dendron-like poly(ε-caprolactone)-b-poly(γ-benzyl- L -glutamate) block copolymers
-
Dendron-like/dendron-like poly(ε-caprolactone)-b-poly(γ-benzyl- L-glutamate) block copolymers with asymmetrical topology (PCL 208-b-PBLG n, both the subscript and the superscript denote the degree of polymerization and the branch number, respectively; n = 1, 2, and 4) were synthesized by combining ring-opening polymerization (ROP) and click chemistry. The dendron-like propargyl focal point PCL 208 precursor with eight branches was synthesized from the controlled ROP of ε-caprolactone, and then click conjugated with azido focal point poly(amido amine) dendrons to generate the PCL 208-dendrons with multiple primary amine groups. The PCL 208-dendrons were further used as macroinitiators for the ROP of γ-benzyl-L-glutamate N-carboxyanhydride to produce the targeted asymmetrical block copolymers. Their molecular structures and physicochemical properties were thoroughly characterized by means of FT-IR, 1H NMR, gel permeation chromatography, differential scanning calorimetry, and wide angle X-ray diffraction. Both the maximal melting temperature and the degree of crystallinity of PCL block within copolymers decreased with increasing the PBLG branches and/or the chain length, demonstrating that the crystallinity of PCL block was progressively suppressed by PBLG block. Meanwhile, the PBLG block within copolymers progressively transformed from β-sheet to α-helical conformation with increasing the PBLG chain length. Consequently, this provides a versatile strategy for the synthesis of biodegradable and biomimetic block copolymers with asymmetrical dendritic topology.
- Liu, Wei,Dong, Chang-Ming
-
-
Read Online
- Hypoxia-Activated and Indomethacin-Mediated Theranostic Prodrug Releasing Drug On-Demand for Tumor Imaging and Therapy
-
A smart theranostic prodrug IMC-FDU-TZBC-NO2, releasing active drug on-demand based on hypoxia-activated and indomethacin-mediated, for solid tumor imaging and efficient therapy was designed. This prodrug was constructed by conjugating chemotherapy drug 5-fluoro-2-deoxyuridine (FDU), targeting moiety indomethacin (IMC), and the hypoxic trigger 4-nitrobenzyl group to a fluorescent dye precursor, which was mediated by IMC and activated by NTR under hypoxic conditions. The fluorescent dye IMC-TZBCM was generated and FDU was released at the same time in tumor cells. The rates and amounts of FDU release and IMC-TZBCM generation were regulated by hypoxia status, and increased with increasing degree of hypoxia. Nevertheless, it is "locked" in normal cells. It combined the advantages of tumor targeting, diagnosis, and chemotherapy functions, showed excellent targeting ability to cancer cells, excellent stability in physiological conditions, high cellular uptake efficiency, and on-demand drug release behavior. The in vitro and in vivo assays demonstrated that IMC-FDU-TZBC-NO2 exhibits enhanced anticancer potency and low side effects. The novel targeted theranostic prodrug activated by hypoxia shows a great potential in cancer therapy.
- Peng, Xiaoran,Gao, Jiaxin,Yuan, Yumeng,Liu, Haitong,Lei, Weiyan,Li, Shenghui,Zhang, Jinchao,Wang, Shuxiang
-
-
Read Online
- Synthesis of a naphthalene-diimide cyclophane for tuning supramolecular interactions by metal ions
-
A new supramolecular species of naphthalene-diimide cyclophane containing triazole units was synthesized, and its fluorescent responses to metal ions were investigated in dichloromethane (DCM). The fluorescence emission of NDI was quenched by intramolecular electron transfer, whereas the appearance of dimer emission of the naphthalene-diimide in the presence of Mg2+, Ba 2+, Hg2+, Ca2+, Zn2+ and Pb 2+ was observed. A new naphthalene-diimide cyclophane was synthesized, and the tuning of photoinduced electronic transfer in this cyclophane by metal ions was investigated. Monomer or dimer emission of naphthalenetetracarboxdiimide (NDI) was observed in the presence of different divalent metal ions. Copyright
- Yu, Yanwen,Li, Yongjun,Chen, Songhua,Liu, Taifeng,Qin, Zhihong,Liu, Huibiao,Li, Yuliang
-
-
Read Online
- Cyclodextrin-/photoisomerization-modulated assembly and disassembly of an azobenzene-grafted polyoxometalate cluster
-
Herein, a mono-lacunary Keggin-type polyoxometalate (POM), [SiW11O39]8?, grafted with an azobenzene group through Sn ion bridging was prepared, and the formed organic-inorganic hybrid cluster was characterized via elemental analysis, NMR, TGA, and IR techniques. A vesicular structure of the hybrid cluster assembly in aqueous media was observed in the TEM image, and it dissociated in the presence of α-/β-, γ-cyclodextrins (α-/β-, γ-CDs); this dissociation was driven by the host-guest interactions. The monodispersed inclusion complex further reassembled into smaller micelles under irradiation with 365 nm light, and this transformation was reversibly controlled by alternating the irradiation with 450 nm light. Moreover, in the case of the POM-Azo/β-CD system, reassembly from the monodispersed state to the vesicular state was achieved by the addition of a competitive guest molecule. Thus, the reversible host-guest interactions combining reversible photoisomerization of the azobenzene group provided multiple ways to modulate the assembly and disassembly of the POM hybrid as well as the changes between different assemblies. The present study inspires the potential use of these kind of hybrid POMs in enhanced catalytic reactions and recycling.
- Li, Hongbo,Jiang, Fengrui,Zhang, Guohua,Li, Bao,Wu
-
-
Read Online
- Dendron conjugation to graphene oxide using click chemistry for efficient gene delivery
-
Owing to its large surface area and rapid cellular uptake, graphene oxide (GO) is emerging as an attractive candidate material for delivery of drugs and genes. The inherent sp2 π-π interaction of GO helps to carry drugs and single stranded RNA (ssRNA) but there is no such interaction with double stranded DNA (dsDNA). In this work, a polyamidoamine (PAMAM) dendron was conjugated with nano GO (nGO) through "click" chemistry to improve the DNA complexation capability of GO as well as its transfection efficiency. The DNA complexation capability of GO was significantly enhanced after dendronization of GO yielding spherical nanosized (250-350 nm) particles of the dendronized GO (DGO)/pDNA complex with a positive zeta potential. The transfection efficiency of GO dramatically increased after conjugation of the PAMAM dendron. Transfection efficiency of 51% in HeLa cells with cell viability of 80% was observed. The transfection efficiency was significantly higher than that of polyethyleneimine 25 kDa (27% efficiency) and also surpassed that of lipofectamine 2000 (47% efficiency). The uptake of the DGO/pDNA complex by the caveolae mediated endocytosis pathway may significantly contribute to the high transfection efficiency. Thus, dendronized GO is shown to be an efficient gene carrier with minimal toxicity and is a promising candidate for use as a nonviral carrier for gene therapy.
- Sarkar, Kishor,Madras, Giridhar,Chatterjee, Kaushik
-
-
Read Online
- MRI-visible poly(ε-caprolactone) with controlled contrast agent ratios for enhanced visualization in temporary imaging applications
-
Hydrophobic macromolecular contrast agents (MMCAs) are highly desirable to provide safe and efficient magnetic resonance (MR) visibility to implantable medical devices. In this study, we report on the synthesis and evaluation of novel biodegradable poly(ε-caprolactone)-based MMCAs. Poly(α- propargyl-ε-caprolactone-co-ε-caprolactone)s containing 2, 5, and 10 mol % of propargyl groups have been prepared by ring-opening copolymerization of ε-caprolactone and the corresponding propargylated lactone. In parallel, a diazido derivative of the clinically used diethylenetriaminepentaacetic acid (DTPA)/Gd3+ complex has been synthesized. Finally, MRI-visible poly(ε-caprolactone)s (PCLs) were obtained by the efficient click ligation of these compounds via a CuI-catalyzed [3 + 2] cycloaddition. ICP-MS analyses confirmed the efficient coupling of the complex on the PCL backbone with the MRI-visible PCLs containing 1.0, 2.6, and 3.6 wt % of Gd3+. The influence of the Gd3+ grafting density on the T1 relaxation times and on the MRI visibility of the novel biodegradable MMCAs was evaluated. Finally, their stability and cytocompatibility were assessed with regard to their potential as innovative MRI-visible biomaterials for biomedical applications.
- El Habnouni, Sarah,Nottelet, Benjamin,Darcos, Vincent,Porsio, Barbara,Lemaire, Laurent,Franconi, Florence,Garric, Xavier,Coudane, Jean
-
-
Read Online
- Fluorine Grafted Cu7S4-Au Heterodimers for Multimodal Imaging Guided Photothermal Therapy with High Penetration Depth
-
We report the multifunctional nanocomposites (NCs) consisting of 19F-moieties grafted Cu7S4-Au nanoparticles (NPs) for negligible background 19F-magnetic resonance imaging (19F-MRI) and computed tomography (CT) imaging guided photothermal therapy. The localized surface plasmon resonance (LSPR) absorption can be reasonably tuned to the in vivo transparent window (800-900 nm) by coupling Au (7S4 (7S4-Au heterodimers. The in vivo photothermal tests show that Cu7S4-Au show deeper light penetration with 808 nm irradiation, better photothermal efficacy, and less damage to normal tissues than Cu7S4 with 1500 nm irradiation. Moreover, compared to traditional 1H-MRI, the 19F-MRI based on these NCs demonstrates much better sensitivity due to the negligible background. This work offers a promising strategy for multimodal imaging guided photothermal therapy of deep tissue with good efficacy.
- Cui, Jiabin,Jiang, Rui,Guo, Chang,Bai, Xilin,Xu, Suying,Wang, Leyu
-
-
Read Online
- Pillar[5]arene as a Co-factor in templating rotaxane formation
-
After the manner in which coenzymes often participate in the binding of substrates in the active sites of enzymes, pillar[5]arene, a macrocycle containing five hydroquinone rings linked through their para positions by methylene bridges, modifies the binding properties of cucurbit[6]uril, such that the latter templates azide-alkyne cycloadditions that do not occur in the presence of only the cucurbit[6]uril, a macrocycle composed of six glycoluril residues doubly linked through their nitrogen atoms to each other by methylene groups. Here, we describe how a combination of pillar[5]arene and cucurbit[6]uril interacts cooperatively with bipyridinium dications substituted on their nitrogen atoms with 2-azidoethyl- to 5-azidopentyl moieties to afford, as a result of orthogonal templation, two [4]rotaxanes and one [5]rotaxane in >90% yields inside 2 h at 55 C in acetonitrile. Since the hydroxyl groups on pillar[5]arene and the carbonyl groups on cucurbit[6]uril form hydrogen bonds readily, these two macrocycles work together in a cooperative fashion to the extent that the four conformational isomers of pillar[5]arene can be trapped on the dumbbell components of the [4]rotaxanes. In the case of the [5]rotaxane, it is possible to isolate a compound containing two pillar[5]arene rings with local C5 symmetries. In addition to fixing the stereochemistries of the pillar[5]arene rings, the regiochemistries associated with the 1,3-dipolar cycloadditions have been extended in their constitutional scope. Under mild conditions, orthogonal recognition motifs have been shown to lead to templation with positive cooperativity that is fast and all but quantitative, as well as being green and efficient.
- Ke, Chenfeng,Strutt, Nathan L.,Li, Hao,Hou, Xisen,Hartlieb, Karel J.,McGonigal, Paul R.,Ma, Zhidong,Iehl, Julien,Stern, Charlotte L.,Cheng, Chuyang,Zhu, Zhixue,Vermeulen, Nicolaas A.,Meade, Thomas J.,Botros, Youssry Y.,Stoddart, J. Fraser
-
-
Read Online
- Synthesis of Amino Terminal Clicked Dendrimers. Approaches to the Application as a Biomarker
-
Herein, we present an easy and efficient synthesis of amino terminal dendrons, combining protection/deprotection reactions with copper-catalyzed azide alkyne cycloaddition in a convergent way. This new approach affords dendrons in gram scale with excellent yields and easy purification. By choosing the appropriate azido-functionalized core, these dendrons lead to a more efficient and controlled convergent synthesis of dendrimers with different sizes and shapes and multivalence. The amino terminal dendrimers were analyzed by diffusion-ordered spectroscopy experiments. The observed dendrimer size is in excellent correlation with the expected size and shape by molecular dynamic simulations. The construction of these kinds of nanostructures, in a simple and efficient way, opens new opportunities for biomedical applications. Moreover, by choosing the appropriate core, these versatile macromolecules become an excellent fluorescent biomarker.
- Molina, Noemi,Nájera, Francisco,Guadix, Juan A.,Perez-Pomares, Jose M.,Vida, Yolanda,Perez-Inestrosa, Ezequiel
-
-
Read Online
- A Novel Estrogen Receptor α-Targeted Near-Infrared Fluorescent Probe for in Vivo Detection of Breast Tumor
-
The ability to detect breast cancer early in its progression is essential to improve patient survival and quality of life. The noninvasive and dynamic imaging and functional assessments of estrogen receptor-alpha (ERα), which is commonly expressed at high levels in breast cancer, are important for effective diagnosis and treatment. Hence, the development of a specific ERα-targeted probe is a major research goal. To that end, in the present study, we created a novel near-infrared (NIR) fluorescent probe, IRDye800CW-E2, for targeted ERα imaging in breast-tumor-bearing mice. IRDye800CW-E2 consisted of a cyanine dye IRDye800CW as the NIR fluorophore and the E2 analogue ethinyl estradiol amine as an ERα targeting ligand. The ethinyl estradiol amine was initially labeled with fluorescein isothiocyanate (FITC) to evaluate the binding specificity to human breast-tumor cells in vitro. Flow chamber and in vitro confocal laser endomicroscopy imaging experiments demonstrated that FITC-E2 was specifically taken up by MCF-7 cells. Furthermore, NIR fluorescence imaging revealed the ability of IRDye800CW-E2 to rapidly target tumors and to achieve good contrast between tumors and background signal 4-48 h postinjection. The fluorescent signal of IRDye800CW-E2 in tumors was successfully blocked by the coinjection of the endogenous ERα-ligand 17β-estradiol (E2) and the probe. Ex vivo fluorescent imaging further confirmed high uptake of the probe by tumors. These results indicated that IRDye800CW-E2 has great potential as an ERα-targeted imaging probe for early breast-tumor detection and has potential for clinical translation.
- Tang, Chu,Du, Yang,Liang, Qian,Cheng, Zhen,Tian, Jie
-
-
Read Online
- EDC/NHS activation mechanism of polymethacrylic acid: Anhydride versus NHS-ester
-
Polymer brushes of polymethacrylic acid (PMAA) and PMAA-associated polymer blends of PMAA/PNIPAM (poly-N-isopropylacrylamide) were prepared on porous silicon for further investigation of the EDC/NHS (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide) activation mechanisms by infrared spectroscopy. When the fragmentation degree of PMAA blocks in PMAA-associated polymer blends is increased, the production of anhydride wanes from dominant to recessive, whereas a complementary product of the NHS-ester waxes from recessive to dominant. The Thorpe-Ingold effect was applied to explain the formation of anhydride: the gem-dialkyl groups of PMAA next to the carboxylic acids compress the acid side chains close to each other; thus, once the intermediate of O-acylisourea forms, it will be attacked by the intramolecular neighboring acid much faster than any other nucleophiles such as NHS and water, and therefore the six-membered ring of the anhydride will be formed. All acid side chains in PMAA standing next to each other will form an anhydride, primarily due to the Thorpe-Ingold effect, unless they are sterically hindered, whereas only isolated acid side chains form the NHS-ester. The EDC/NHS activation results for four small molecules of dicarboxylic acids in aqueous media, namely, glutaric acid and 2,2-dimethyl glutaric acid, which generate disuccinimidyl ester with high yield, and succinic acid and 2,2-dimethyl succinic acid, which remain intact, can also be explained by the Thorpe-Ingold effect. A clear understanding of the EDC/NHS activation mechanisms of PMAA will take us a step closer for resolving the mechanistic ambiguity of the carbodiimide/additive coupling reactions for amide bond formation.
- Yan, Qin,Zheng, Hong-Ning,Jiang, Chuan,Li, Kun,Xiao, Shou-Jun
-
-
Read Online
- Development of Covalent, Clickable Probes for Adenosine A1and A3Receptors
-
Adenosine receptors are attractive therapeutic targets for multiple conditions, including ischemia-reperfusion injury and neuropathic pain. Adenosine receptor drug discovery efforts would be facilitated by the development of appropriate tools to assist in target validation and direct receptor visualization in different native environments. We report the development of the first bifunctional (chemoreactive and clickable) ligands for the adenosine A1receptor (A1R) and adenosine A3receptor (A3R) based on an orthosteric antagonist xanthine-based scaffold and on an existing structure-activity relationship. Bifunctional ligands were functional antagonists with nanomolar affinity and irreversible binding at the A1R and A3R. In-depth pharmacological profiling of these bifunctional ligands showed moderate selectivity over A2Aand A2Badenosine receptors. Once bound to the receptor, ligands were successfully “clicked” with a cyanine-5 fluorophore containing the complementary “click” partner, enabling receptor detection. These bifunctional ligands are expected to aid in the understanding of A1R and A3R localization and trafficking in native cells and living systems.
- Trinh, Phuc N. H.,Chong, Daniel J. W.,Leach, Katie,Hill, Stephen J.,Tyndall, Joel D. A.,May, Lauren T.,Vernall, Andrea J.,Gregory, Karen J.
-
supporting information
p. 8161 - 8178
(2021/06/30)
-
- Sulfonamide rhodamine compound with alkynyl group or azido group derived positions as well as preparation method and application thereof
-
The invention discloses a sulfamide rhodamine compound with an alkynyl or azido derivative site, a preparation method of the compound and an application of the compound, and belongs to the field of fine chemical industries. The sulfamide rhodamine compound with the alkynyl or azido derivative site is prepared by amidation of common rhodamine sulfonate, and overcomes the shortcoming that the commonrhodamine sulfonate cannot be applied due to absence of the derivative site. As alkynyl and azido can be connected through Click reaction under mild conditions, the sulfamide rhodamine compound withan alkynyl or azido group can perform Click reaction with biological macromolecules such as nucleic acid, polypeptides and phospholipid, medicinal molecules or bioactive molecules and the like to synthesize novel molecules which can be applied to the field of life science and have specific functions.
- -
-
Paragraph 0022-0024
(2021/06/21)
-
- Modular Toolkit of Multifunctional Block Copoly(2-oxazoline)s for the Synthesis of Nanoparticles
-
Post-polymerization modification provides an elegant way to introduce chemical functionalities onto macromolecules to produce tailor-made materials with superior properties. This concept was adapted to well-defined block copolymers of the poly(2-oxazoline) family and demonstrated the large potential of these macromolecules as universal toolkit for numerous applications. Triblock copolymers with separated water-soluble, alkyne- and alkene-containing segments were synthesized and orthogonally modified with various low-molecular weight functional molecules by copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) and thiol-ene (TE) click reactions, respectively. Representative toolkit polymers were used for the synthesis of gold, iron oxide and silica nanoparticles.
- Keckeis, Philipp,Zeller, Enriko,Jung, Carina,Besirske, Patricia,Kirner, Felizitas,Ruiz-Agudo, Cristina,Schlaad, Helmut,C?lfen, Helmut
-
supporting information
p. 8283 - 8287
(2021/05/07)
-
- Novel diagnosis and treatment type nano-drug based on molecular shuttle
-
The invention belongs to the technical field of biology, and relates to a novel diagnosis and treatment type nano-drug based on a molecular shuttle. According to the invention, a drug is linked to twoends of a molecular shuttle guest molecule through a click chemical reaction; by utilizing a drug molecule size effect, the molecular shuttle guest is difficultly be identified and penetrated by a molecular shuttle host; and in a tumor reducing microenvironment, the drug is released while the molecular shuttle guest is liberated, so that the molecular shuttle guest can be quickly, precisely and specifically recognized and penetrated by the molecular shuttle host to form a fusiform near-infrared supramolecular probe, wherein the fusiform near-infrared supramolecular probe can be used for real-timely characterizing the release behavior of the drug at an in-vitro cell level or an in-vivo animal level.
- -
-
Paragraph 0101-0106
(2020/05/01)
-
- MACROMOLECULAR PRODRUG-BASED THERMOSENSITIVE INJECTABLE GEL AS A NOVEL DRUG DELIVERY PLATFORM
-
This application discloses prodrug-based thermosensitive gel ("ProGel") comprised of conjugates of dmg molecules with water-soluble polymeric carriers, which are capable of controlled release of the dmg molecules into the tissue of a subject. Use of the ProGel-Drug conjugates for treatment of various diseases or disorders and methods of preparing them are also disclosed.
- -
-
Page/Page column 29
(2020/05/28)
-
- Rational design of ERα targeting hypoxia turn-on fluorescent probes with antiproliferative activity for breast cancer
-
The overexpression of estrogen receptor (ER) α is not only closely related to the development of ER+ breast cancer, but is also an important biomarker for clinical diagnosis and treatment. Herein, we report several ERα targeting hypoxia turn-on fluorescent probes with antitumor activity for breast cancer cells. Among them, probes 3 and 5 displayed good ERα targeting ability and favorable hypoxia turn-on response in MCF-7 cells. Moreover, the probes 3 and 5 exhibited good antiproliferative activity towards MCF-7 cells (IC50 = 8.5 μM, 10.3 μM) and a much lower cytotoxicity to normal cells compared with the positive control. It is expected that these novel fluorescent probes may provide useful tools for the theranostics of ER+ breast cancer.
- Dong, Chune,Hu, Zhiye,Ma, Xiaoyu,Meng, Qiuyu,Xie, Baohua,Zhou, Fuling,Zhou, Hai-Bing
-
supporting information
p. 10493 - 10496
(2020/10/02)
-
- Photolabile Linkers: Exploiting Labile Bond Chemistry to Control Mode and Rate of Hydrogel Degradation and Protein Release
-
Photolabile moieties have been utilized in applications ranging from peptide synthesis and controlled protein activation to tunable and dynamic materials. The photochromic properties of nitrobenzyl (NB) based linkers are readily tuned to respond to cytocompatible light doses and are widely utilized in cell culture and other biological applications. While widely utilized, little is known about how the microenvironment, particularly confined aqueous environments (e.g., hydrogels), affects both the mode and rate of cleavage of NB moieties, leading to unpredictable limitations in control over system properties (e.g., rapid hydrolysis or slow photolysis). To address these challenges, we synthesized and characterized the photolysis and hydrolysis of NB moieties containing different labile bonds (i.e., ester, amide, carbonate, or carbamate) that served as labile crosslinks within step-growth hydrogels. We observed that NB ester bond exhibited significant rates of both photolysis and hydrolysis, whereas, importantly, the NB carbamate bond had superior light responsiveness and resistance to hydrolysis within the hydrogel microenvironment. Exploiting this synergy and orthogonality of photolytic and hydrolytic degradation, we designed concentric cylinder hydrogels loaded with different cargoes (e.g., model protein with different fluorophores) for either combinatorial or sequential release, respectively. Overall, this work provides new facile chemical approaches for tuning the degradability of NB linkers and an innovative strategy for the construction of multimodal degradable hydrogels, which can be utilized to guide the design of not only tunable materials platforms but also controlled synthetic protocols or surface modification strategies.
- Dasgupta, Srimoyee,Kloxin, April M.,Kloxin, Christopher J.,Levalley, Paige J.,Neelarapu, Raghupathi,Sutherland, Bryan P.
-
supporting information
p. 4671 - 4679
(2020/04/10)
-
- Chemical Targeting of Voltage Sensitive Dyes to Specific Cells and Molecules in the Brain
-
Voltage sensitive fluorescent dyes (VSDs) are important tools for probing signal transduction in neurons and other excitable cells. The impact of these highly lipophilic sensors has, however, been limited due to the lack of cell-specific targeting methods in brain tissue or living animals. We address this key challenge by introducing a nongenetic molecular platform for cell- and molecule-specific targeting of synthetic VSDs in the brain. We employ a dextran polymer particle to overcome the inherent lipophilicity of VSDs by dynamic encapsulation and high-affinity ligands to target the construct to specific neuronal cells utilizing only native components of the neurotransmission machinery at physiological expression levels. Dichloropane, a monoamine transporter ligand, enables targeting of dense dopaminergic axons in the mouse striatum and sparse noradrenergic axons in the mouse cortex in acute brain slices. PFQX in conjunction with ligand-directed acyl imidazole chemistry enables covalent labeling of AMPA-type glutamate receptors in the same brain regions. Probe variants bearing either a classical electrochromic ANEP dye or state-of-the-art VoltageFluor-type dye respond to membrane potential changes in a similar manner to the parent dyes, as shown by whole-cell patch recording. We demonstrate the feasibility of optical voltage recording with our probes in brain tissue with one-photon and two-photon fluorescence microscopy and define the signal limits of optical voltage imaging with synthetic sensors under a low photon budget determined by the native expression levels of the target proteins. This work demonstrates the feasibility of a chemical targeting approach and expands the possibilities of cell-specific imaging and pharmacology.
- Fiala, Tomas,Wang, Jihang,Dunn, Matthew,?ebej, Peter,Choi, Se Joon,Nwadibia, Ekeoma C.,Fialova, Eva,Martinez, Diana M.,Cheetham, Claire E.,Fogle, Keri J.,Palladino, Michael J.,Freyberg, Zachary,Sulzer, David,Sames, Dalibor
-
supporting information
p. 9285 - 9301
(2020/06/04)
-
- Site-Selective Modification of Peptides and Proteins via Interception of Free-Radical-Mediated Dechalcogenation
-
The development of site-selective chemistry targeting the canonical amino acids enables the controlled installation of desired functionalities into native peptides and proteins. Such techniques facilitate the development of polypeptide conjugates to advance therapeutics, diagnostics, and fundamental science. We report a versatile and selective method to functionalize peptides and proteins through free-radical-mediated dechalcogenation. By exploiting phosphine-induced homolysis of the C?Se and C?S bonds of selenocysteine and cysteine, respectively, we demonstrate the site-selective installation of groups appended to a persistent radical trap. The reaction is rapid, operationally simple, and chemoselective. The resulting aminooxy linker is stable under a variety of conditions and selectively cleavable in the presence of a low-oxidation-state transition metal. We have explored the full scope of this reaction using complex peptide systems and a recombinantly expressed protein.
- Griffiths, Rhys C.,Smith, Frances R.,Long, Jed E.,Williams, Huw E. L.,Layfield, Robert,Mitchell, Nicholas J.
-
supporting information
p. 23659 - 23667
(2020/10/21)
-
- INTRACELLULAR DELIVERY VEHICLE
-
PROBLEM TO BE SOLVED: To provide a vehicle which can easily deliver a desired component or compound into a cell without preventing cell proliferation. SOLUTION: A intracellular delivery vehicle has its surface covered with positive electric charge. SELECTED DRAWING: None COPYRIGHT: (C)2020,JPOandINPIT
- -
-
Paragraph 0166-0167
(2020/08/13)
-
- Design, synthesis, and evaluation of compounds capable of reducing Pseudomonas aeruginosa virulence
-
Anti-virulence approaches in the treatment of Pseudomonas aeruginosa (PA)-induced infections have shown clinical potential in multiple in vitro and in vivo studies. However, development of these compounds is limited by several factors, including the lack of molecules capable of penetrating the membrane of gram-negative organisms. Here, we report the identification of novel structurally diverse compounds that inhibit PqsR and LasR-based signaling and diminish virulence factor production and biofilm growth in two clinically relevant strains of P. aeruginosa. It is the first report where potential anti-virulent agents were evaluated for inhibition of several virulence factors of PA. Finally, co-treatment with these inhibitors significantly reduced the production of virulence factors induced by the presence of sub-inhibitory levels of ciprofloxacin. Further, we have analyzed the drug-likeness profile of designed compounds using quantitative estimates of drug-likeness (QED) and confirmed their potential as hit molecules for further development.
- Hossain, Mohammad Anwar,Sattenapally, Narsimha,Parikh, Hardik I.,Li, Wei,Rumbaugh, Kendra P.,German, Nadezhda A.
-
supporting information
(2019/11/26)
-
- Fe(III)-Catalyzed Aerobic Intramolecular N-N Coupling of Aliphatic Azides with Amines
-
An Fe(III)-catalyzed intramolecular N-N coupling of aliphatic azidoamines that forms diverse five- and six-membered semisaturated diazoheterocycles using air as an oxidant is reported, providing an alternative to hydrazine-based methods. Mechanistic studies suggest that a N-radical induced intramolecular homolytic substitution (SH2) is involved in ring closure. The power of this N-N bond-forming method is also demonstrated by using it as the final step in a total synthesis of (-)-newbouldine.
- Zhang, Yue,Duan, Dongyu,Zhong, Ying,Guo, Xin-Ai,Guo, Jiawei,Gou, Jing,Gao, Ziwei,Yu, Binxun
-
supporting information
p. 4960 - 4965
(2019/09/03)
-
- A biotin-conjugated photo-Activated CO-releasing molecule (biotinCORM): Efficient CO-release from an avidin-biotinCORM protein adduct
-
Biotinylated pharmaceuticals are of great interest due to the strong interactions between biotinyl-functionality and streptavidin/avidin, which opens up avenues for efficient targeting and localisation. Three new carbon monoxide-releasing molecules (CO-RMs) have been synthesised and characterised using chemical and biological analysis. An alkyne-containing CO-RM 2 was found to be toxic to RAW 264.7 murine macrophages; and thus therapeutically viable CO-RM 1 was employed as the alkyne precursor for [3 + 2] cycloaddition chemistry enabling a new acid-containing CO-RM 4 and biotin-bioconugate-CO-RM (BiotinCORM 5) to be prepared. CO-RM 4 showed significantly improved solubility and BiotinCORM 5 acts as a photo-CO-RM. We have found that an avidin-CORM adduct of 5 is a CO-releasing protein, releasing CO on irradiation with light (400 nm). The avidin-biotinCORM adduct of 5 was found to have a binding energy of 10 kcal mol-1.
- Ward, Jonathan S.,De Palo, Alice,Aucott, Benjamin J.,Moir, James W. B.,Lynam, Jason M.,Fairlamb, Ian J. S.
-
supporting information
p. 16233 - 16241
(2019/11/13)
-
- A DNA-Encoded Chemical Library Incorporating Elements of Natural Macrocycles
-
Here we show a seven-step chemical synthesis of a DNA-encoded macrocycle library (DEML) on DNA. Inspired by polyketide and mixed peptide-polyketide natural products, the library was designed to incorporate rich backbone diversity. Achieving this diversity, however, comes at the cost of the custom synthesis of bifunctional building block libraries. This study outlines the importance of careful retrosynthetic design in DNA-encoded libraries, while revealing areas where new DNA synthetic methods are needed.
- Stress, Cedric J.,Sauter, Basilius,Schneider, Lukas A.,Sharpe, Timothy,Gillingham, Dennis
-
supporting information
p. 9570 - 9574
(2019/06/24)
-
- Carbohydrate-naphthalene diimide conjugates as potential antiparasitic drugs: Synthesis, evaluation and structure-activity studies
-
The neglected tropical diseases Human African Trypanosomiasis and leishmaniasis are caused by infection with trypanosomatid parasites Trypanosoma brucei and Leishmania spp, respectively. The genomes of these organisms contain multiple putative G-quadruplex (G4) forming sequences which have recently been proposed to mediate processes relevant for parasite survival. Therefore, G4 could be considered as potential targets for a novel approach towards the development of antiparasitic drugs. Recently, we have demonstrated that G4 ligands such as carbohydrate naphthalene diimide conjugates (carb-NDIs) possess notable antiparasitic activity. Herein, we have synthesized a new family of carb-NDIs, characterized by significant structural variability, and evaluated their anti-parasitic activity, with special focus on T. brucei. The interaction with relevant G4 sequences was evaluated in vitro through independent biophysical methods (FRET melting assays under competing conditions with double stranded DNA, circular dichroism and fluorescence titrations). Finally, flow cytometry and confocal microscopy experiments demonstrated that the conjugates exhibit excellent uptake into T. brucei parasites, localizing in the nuclei and kinetoplasts. Promising antiparasitic activity and selectivity against control mammalian cells, together with their peculiar mechanism of action, render the carb-NDI conjugates as suitable candidates for the development of an innovative treatment of trypanosomiasis.
- Zuffo,Stucchi,Campos-Salinas,Cabello-Donayre,Martínez-García,Belmonte-Reche,Pérez-Victoria,Mergny,Freccero,Morales,Doria
-
-
- Synthetic Fluorogenic Peptides Reveal Dynamic Substrate Specificity of Depalmitoylases
-
Palmitoylation is a post-translational modification involving the thioesterification of cysteine residues with a 16-carbon-saturated fatty acid. Little is known about rates of depalmitoylation or the parameters that dictate these rates. Here we report a modular strategy to synthesize quenched fluorogenic substrates for the specific detection of depalmitoylase activity and for mapping the substrate specificity of individual depalmitoylases. We demonstrate that human depalmitoylases APT1 and APT2, and TgPPT1 from the parasite Toxoplasma gondii, have distinct specificities that depend on amino acid residues distal to the palmitoyl cysteine. This information informs the design of optimal and non-optimal substrates as well as isoform-selective substrates to detect the activity of a specific depalmitoylase in complex proteomes. In addition to providing tools for studying depalmitoylases, our findings identify a previously unrecognized mechanism for regulating steady-state levels of distinct palmitoylation sites by sequence-dependent control of depalmitoylation rates. Amara et al. describe a method for preparing positional scanning libraries of fluorogenic palmitoylated peptide substrates. This allowed identification of residues that are distal to the palmitoylation site that impact turnover. This information allowed the design of substrates that are selective for a specific depalmitoylating enzyme.
- Amara, Neri,Foe, Ian T.,Onguka, Ouma,Garland, Megan,Bogyo, Matthew
-
p. 35 - 7,47
(2018/10/24)
-
- Chemical Probes Reveal Sirt2's New Function as a Robust "eraser" of Lysine Lipoylation
-
Lysine lipoylation, a highly conserved lysine post-translational modification, plays a critical role in regulating cell metabolism. The catalytic activity of a number of vital metabolic proteins, such as pyruvate dehydrogenase (PDH), depends on lysine lipoylation. Despite its important roles, the detailed biological regulatory mechanism of lysine lipoylation remains largely unexplored. Herein we designed a powerful affinity-based probe, KPlip, to interrogate the interactions of lipoylated peptide/proteins under native cellular environment. Large-scale chemical proteomics analysis revealed a number of binding proteins of KPlip, including sirtuin 2 (Sirt2), an NAD+-dependent protein deacylase. To explore the potential activity of Sirt2 toward lysine lipoylation, we designed a single-step fluorogenic probe, KTlip, which reports delipoylation activity in a continuous manner. The results showed that Sirt2 led to significant delipoylation of KTlip, displaying up to a 60-fold fluorescence increase in the assay. Further kinetic experiments with different peptide substrates revealed that Sirt2 can catalyze the delipoylation of peptide (DLAT-PDH, K259) with a remarkable catalytic efficiency (kcat/Km) of 3.26 × 103 s-1 M-1. The activity is about 400-fold higher than that of Sirt4, the only mammalian enzyme with known delipoylation activity. Furthermore, overexpression and silencing experiments demonstrated that Sirt2 regulates the lipoylation level and the activity of endogenous PDH, thus unequivocally confirming that PDH is a genuine physiological substrate of Sirt2. Using our chemical probes, we have successfully established the relationship between Sirt2 and lysine lipoylation in living cells for the first time. We envision that such chemical probes will serve as useful tools for delineating the roles of lysine lipoylation in biology and diseases.
- Xie, Yusheng,Chen, Lanfang,Wang, Rui,Wang, Jigang,Li, Jingyu,Xu, Wei,Li, Yingxue,Yao, Shao Q.,Zhang, Liang,Hao, Quan,Sun, Hongyan
-
supporting information
p. 18428 - 18436
(2019/11/19)
-
- INTRACELLULAR DELIVERY VEHICLE
-
An intracellular delivery vehicle of which surface is covered by a positive charge, an intracellular delivery complex in which a component or compound desired is loaded in the intracellular delivery vehicle, a temperature-sensitive probe comprising the intracellular delivery complex, and a method for measuring the intracellular temperature by the temperature-sensitive probe are disclosed. The intracellular delivery vehicle is useful on account of its capability of easily delivering the component or compound desired inside the cell without inhibiting cell proliferation.
- -
-
Paragraph 0281; 0282
(2019/05/18)
-
- A Cell-Targeted Non-Cytotoxic Fluorescent Nanogel Thermometer Created with an Imidazolium-Containing Cationic Radical Initiator
-
A cationic fluorescent nanogel thermometer based on thermo-responsive N-isopropylacrylamide and environment-sensitive benzothiadiazole was developed with a new azo compound bearing imidazolium rings as the first cationic radical initiator. This cationic fluorescent nanogel thermometer showed an excellent ability to enter live mammalian cells in a short incubation period (10 min), a high sensitivity to temperature variations in live cells (temperature resolution of 0.02–0.84 °C in the range 20–40 °C), and remarkable non-cytotoxicity, which permitted ordinary cell proliferation and even differentiation of primary cultured cells.
- Uchiyama, Seiichi,Tsuji, Toshikazu,Kawamoto, Kyoko,Okano, Kentaro,Fukatsu, Eiko,Noro, Takahiro,Ikado, Kumiko,Yamada, Sayuri,Shibata, Yuka,Hayashi, Teruyuki,Inada, Noriko,Kato, Masaru,Koizumi, Hideki,Tokuyama, Hidetoshi
-
supporting information
p. 5413 - 5417
(2018/04/09)
-
- A new water soluble copper N-heterocyclic carbene complex delivers mild O6G-selective RNA alkylation
-
We show here that copper carbenes generated from diazo acetamides alkylate single RNAs, mRNAs, or pools of total transcriptome RNA, delivering exclusively alkylation at the O6 position in guanine (O6G). Although the reaction is effective with free copper some RNA fragmentation occurs, a problem we resolve by developing a novel water-stable copper N-heterocyclic carbene complex. Carboxymethyl adducts at O6G are known mutagenic lesions in DNA but their relevance in RNA biochemistry is unknown. As a case-in-point we re-examine an old controversy regarding whether O6G damage in RNA is susceptible to direct RNA repair.
- Rasale, Dnyaneshwar,Patil, Kiran,Sauter, Basilius,Geigle, Stefanie,Zhanybekova, Saule,Gillingham, Dennis
-
supporting information
p. 9174 - 9177
(2018/08/23)
-
- Novel menadione hybrids: Synthesis, anticancer activity, and cell-based studies
-
A series of novel menadione-based triazole hybrids were designed and synthesized by employing copper-catalyzed azide-alkyne cycloaddition (CuAAC). All the synthesized hybrids were characterized by their spectral data (1H NMR, 13C NMR, IR, and HRMS). The synthesized compounds were evaluated for their anticancer activity against five selected cancer cell lines including lung (A549), prostate (DU-145), cervical (Hela), breast (MCF-7), and mouse melanoma (B-16) using MTT assay. The screening results showed that majority of the synthesized compounds displayed significant anticancer activity. Among the tested compounds, the triazoles 5 and 6 exhibited potent activity against all cell lines. In particular, compound 6 showed higher potency than the standard tamoxifen and parent menadione against MCF-7 cell line. Flow cytometric analysis revealed that compound 6 arrested cell cycle at G0/G1 phase and induced apoptotic cell death which was further confirmed by Hoechst staining, measurement of mitochondrial membrane potential (ΔΨm) and Annexin-V-FITC assay. Thus, compound 6 can be considered as lead molecule for further development as potent anticancer therapeutic agent.
- Prasad, Chakka Vara,Nayak, Vadithe Lakshma,Ramakrishna, Sistla,Mallavadhani, Uppuluri Venkata
-
p. 220 - 233
(2017/12/29)
-
- Late-Stage Isotopic Carbon Labeling of Pharmaceutically Relevant Cyclic Ureas Directly from CO2
-
A robust, click-chemistry-inspired procedure for radiolabeling of cyclic ureas was developed. This protocol, suitable for all carbon isotopes (11C, 13C, 14C), is based on the direct functionalization of carbon dioxide: the universal building block for carbon radiolabeling. The strategy is operationally simple and reproducible in different radiochemistry centers, exhibits remarkably wide substrate scope with short reaction times, and demonstrates superior reactivity as compared to previously reported systems. With this procedure, a variety of pharmaceuticals and an unprotected peptide were labeled with high radiochemical efficiency.
- Del Vecchio, Antonio,Caillé, Fabien,Chevalier, Arnaud,Loreau, Olivier,Horkka, Kaisa,Halldin, Christer,Schou, Magnus,Camus, Nathalie,Kessler, Pascal,Kuhnast, Bertrand,Taran, Frédéric,Audisio, Davide
-
supporting information
p. 9744 - 9748
(2018/07/31)
-
- Modular RNA regulators and methods
-
This disclosure describes modular miRNA regulator molecules and methods of using modular miRNA regulator molecules. Generally, the modular miRNA regulator molecules include a recognition module and an inhibition module. Generally, the recognition module includes a polynucleotide in which at least a portion of the polynucleotide recognizes at least a portion of a preselected pre-miRNA. Generally, the inhibition module includes a moiety that inhibits nuclease processing of the preselected pre-RNA to a mature RNA.
- -
-
Page/Page column 23
(2018/10/30)
-
- Optimizing the readout of lanthanide-DOTA complexes for the detection of ligand-bound copper(I)
-
The CuAAC 'click' reaction was used to couple alkyne-functionalized lanthanide-DOTA complexes to a range of fluorescent antennae. Screening of the antenna components was aided by comparison of the luminescent output of the resultant sensors using data normalized to account for reaction conversion as assessed by IR. A maximum 82-fold enhanced signal:background luminescence output was achieved using a Eu(III)-DOTA complex coupled to a coumarin-azide, in a reaction which is specific to the presence of copper(I). This optimized complex provides a new lead design for lanthanide-DOTA complexes which can act as irreversible 'turn-on' catalytic sensors for the detection of ligand-bound copper(I).
- Hanna, Jill R.,Allan, Christopher,Lawrence, Charlotte,Meyer, Odile,Wilson, Neil D.,Hulme, Alison N.
-
supporting information
(2017/06/08)
-
- Low generation PAMAM-based nanomicelles as ROS-responsive gene vectors with enhanced transfection efficacy and reduced cytotoxicity: in vitro
-
Poly(amidoamine)s (PAMAMs) of high-generations (G > 5) exhibit high efficacy in gene transfection, but their high cost and severe cytotoxicity limit their use in biomedicine. In contrast, PAMAMs of low-generations (G w = 3500 Da) via disulfide bonds. This amphiphilic conjugate can self-assemble into stable nanomicelles. The results show that the obtained nanomicelles have a high zeta potential, which can condense DNA tightly. Moreover, the DNA/nanomicelle polyplexes can be fully dissociated by intracellular ROS and easily release the entrapped DNA. As gene vectors, the nanomicelles exhibited high transfection efficacy and fairly low cytotoxicity in vitro.
- Xu, Chen-Tao,Chen, Guang,Nie, Xuan,Wang, Long-Hai,Ding, Sheng-Gang,You, Ye-Zi
-
supporting information
p. 3273 - 3279
(2017/07/12)
-
- Design and synthesis of dendrimers with facile surface group functionalization, and an evaluation of their bactericidal efficacy
-
We report a versatile divergent methodology to construct dendrimers from a tetrafunctional core, utilizing the robust copper(I) catalyzed alkyne-azide cycloaddition (CuAAC, "click") reaction for both dendrimer synthesis and post-synthesis functionalization. Dendrimers of generations 1-3 with 8-32 protected or free OH and acetylene surface groups, were synthesized using building blocks that included acetylene- or azide-terminated molecules with carboxylic acid or diol end groups, respectively. The acetylene surface groups were subsequently used to covalently link cationic amino groups. A preliminary evaluation indicated that the generation one dendrimer with terminal NH3+ groups was the most effective bactericide, and it was more potent than several previously studied dendrimers. Our results suggest that size, functional end groups and hydrophilicity are important parameters to consider in designing efficient antimicrobial dendrimers.
- Ladd, Elizabeth,Sheikhi, Amir,Li, Na,Van De Ven, Theo G.M.,Kakkar, Ashok
-
-
- An ionic liquid-based extraction system using diglycolamide functionalized macrocyclic platforms for the extraction and recovery of lanthanides
-
Solvent extraction of lanthanides Ln(iii) (La, Eu and Yb) with resorcin[4]arene cavitand-triazole-DODGA (CR4-TZ-DODGA) and t-butylcalix[4]arene-triazole-DODGA (C4-TZ-DODGA) has been studied in a room temperature ionic liquid (RTIL), N-octyl-N-ethylpiperidinium bis(trifluoromethylsulfonyl)imide ([EOPip]NTf2). The two macrocyclic platforms were functionalized with four diglycolamide (DGA) moieties thanks to a click reaction and fully characterized by NMR and MS analysis. The effects of acidity as well as the concentration of the ligands were investigated on the extraction and separation properties. The parameters of the extraction processes were determined by the slope method and thermodynamic studies. For both ligands, the extraction efficiency changes along the lanthanoid series with selectivity toward Yb(iii) in regard to La(iii) and Eu(iii). The selective extraction and recovery of lanthanides from a simulated leaching solution of a Nd/Fe/B/Dy magnet has also been investigated.
- Wehbie,Arrachart,Ghannam,Karamé,Pellet-Rostaing
-
p. 16505 - 16515
(2017/12/15)
-
- Discovery of Novel 11-Triazole Substituted Benzofuro[3,2-b]quinolone Derivatives as c-myc G-Quadruplex Specific Stabilizers via Click Chemistry
-
The specificity of nucleic acids' binders is crucial for developing this kind of drug, especially for novel G-quadruplexes' binders. Quindoline derivatives have been developed as G-quadruplex stabilizers with good interactive activities. In order to improve the selectivity and binding affinity of quindoline derivatives as c-myc G-quadruplex binding ligands, novel triazole containing benzofuroquinoline derivatives (T-BFQs) were designed and synthesized by using the 1,3-dipolar cycloaddition of a series of alkyne and azide building blocks. The selectivity toward c-myc G-quadruplex DNA of these novel T-BFQs was significantly improved, together with an obvious increase on binding affinity. Further cellular and in vivo experiments indicated that the T-BFQs showed inhibitory activity on tumor cells' proliferation, presumably through the down-regulation of transcription of c-myc gene. Our findings broadened the modification strategies of specific G-quadruplex stabilizers.
- Zeng, De-Ying,Kuang, Guo-Tao,Wang, Shi-Ke,Peng, Wang,Lin, Shu-Ling,Zhang, Qi,Su, Xiao-Xuan,Hu, Ming-Hao,Wang, Honggen,Tan, Jia-Heng,Huang, Zhi-Shu,Gu, Lian-Quan,Ou, Tian-Miao
-
supporting information
p. 5407 - 5423
(2017/07/22)
-
- Synthesis of new triazole based imidazo[1,2-a]pyrazine-benzimidazole conjugates: H-bonding assisted FRET efficient ratiometric detection of pyrophosphate
-
Triazole tethered imidazo[1,2-a]pyrazine-benzimidazole conjugates 13-38 has been synthesized by click and Suzuki-Miyaura cross coupling reactions at C-8 and C-6 positions, respectively. The research findings clearly predicted that by modification of electronic structure of the receptor, the sensitivity of the recognition process could be modified. Compound 24 with hydroxyphenyl substituent, showed stronger binding to the pyrophosphate than other compounds. Compound 24 has been used as selective probe for ratiometric detection of pyrophosphate amongst the other anions. The binding event of compound 24 toward PPi has been successfully evaluated by absorption and emission spectroscopy as well as NMR titration method. The compound 24 showed H-bonding assisted facilitation of FRET phenomenon in the presence of PPi.
- Goel, Richa,Luxami, Vijay,Paul, Kamaldeep
-
p. 102 - 109
(2017/09/02)
-
- Entirely oligosaccharide-based supramolecular amphiphiles constructed: Via host-guest interactions as efficient drug delivery platforms
-
Entirely oligosaccharide-based supramolecular amphiphiles were constructed via host-guest interactions between ferrocene-terminated acetylated-maltoheptaose (Fc-AcMH) and β-cyclodextrin-terminated four-arm star maltoheptaose (MH4-β-CD). The amphiphiles could self-assemble to form spherical supramolecular nanoparticles to provide efficient drug delivery platforms. The combination of a pH-sensitive covalent acetal group and the oxidation-sensitive noncovalent host-guest interaction of β-CD and ferrocene provided the obtained fully oligosaccharide-based supramolecular amphiphiles. The structures of these amphiphiles could respond to the intracellular microenvironment.
- Shi, Yuting,Li, Hongping,Cheng, Ju,Luan, Tingting,Liu, Di,Cao, Yufei,Zhang, Xiangdong,Wei, Hua,Liu, Yali,Zhao, Guanghui
-
supporting information
p. 12302 - 12305
(2017/11/20)
-
- MODIFIED NUCLEOTIDE REAGENTS
-
Labeled nucleotide analogs comprising at least one avidin protein, at least one dye-labeled compound, and at least one nucleotide compound are provided. The analogs are useful in various fluorescence-based analytical methods, including the analysis of highly multiplexed optical reactions in large numbers at high densities, such as single molecule real time nucleic acid sequencing reactions. The analogs are detectable with high sensitivity at desirable wavelengths. They contain structural components that modulate the interactions of the analogs with DNA polymerase, thus decreasing photodamage and improving the kinetic and other properties of the analogs in sequencing reactions. Also provided are nucleotide and dye-labeled compounds of the subject analogs, as well as intermediates useful in the preparation of the compounds and analogs. Compositions comprising the compounds, methods of synthesis of the intermediates, compounds, and analogs, and mutant DNA polymerases are also provided.
- -
-
Paragraph 0239
(2017/11/29)
-
- Synthesis and self-assembly of amphiphilic and biocompatible poly(vinyl alcohol)-block-poly(L-lactide) copolymer
-
Well-defined amphiphilic and biocompatible poly(vinyl alcohol)-block-poly(L-lactide) copolymers (PVA-b-PLLA) were synthesized by the combination of reversible addition-fragmentation chain transfer (RAFT), ring opening polymerization (ROP), and click chemistry. First, an innovative azide-functionalized xanthate mediated chain transfer agent (CTA) [S-(3-azidopropyl propanamide)-(O-butyl xanthate)] was synthesized and used for vinyl acetate (VAc) polymerization through RAFT. Then, azide-terminated poly(vinyl acetate) (azide-PVAc) was converted to the corresponding azide-terminated poly(vinyl alcohol) (azide-PVA) through hydrolysis. Alkyne-terminated poly (L-lactide) (alkyne-PLLA) was synthesized via ROP using a bifunctional initiator, having an alkyne and a hydroxyl group. Finally, azide-PVA and alkyne-PLLA were coupled by 1,3 cycloaddition click reaction to get PVA-b-PLLA. Synthesized azide-PVAc, azide-PVA, alkyne-PLLA and PVA-b-PLLA were characterized by size exclusion chromatography and 1H NMR spectroscopy. The self-assembly of PVA-b-PLLA in water was investigated by transmission electron microscope, atomic force microscopy, dynamic light scattering and 1H NMR spectroscopy. Spherical micelles in water were clearly observed. The critical micelle concentration of PVA-b-PLLA in water was determined by fluorescence spectroscopy, and it was decreased with increasing the molecular weight of PLLA block. PVA-b-PLLA exhibited low cytotoxicity which could be used in biomedical application.
- Mishra, Avnish Kumar,Park, Jicheol,Joseph, K.L. Vincent,Maiti, Sandip,Kwak, Jongheon,Choi, Chungryong,Hyun, Seung,Kim, Jin Kon
-
-
- MRI-visible polymer based on poly(methyl methacrylate) for imaging applications
-
Macromolecular contrast agents are very attractive to afford efficient magnetic resonance imaging (MRI) visualization of implantable medical devices. In this work, we report on the grafting of a Gd-based DTPA contrast agent onto a poly(methyl methacrylate) derivative backbone by combining free radical polymerization and copper-catalyzed azide-alkyne cycloaddition (CuAAC). Using free radical polymerization, poly(methyl methacrylate-co-propargyl methacrylate) copolymers were prepared with a control of the ratio in propargyl methacrylate monomer units. The synthesis of a new azido mono-functionalized DTPA ligand was also reported and characterized by 1H NMR and mass spectroscopy. After complexation with gadolinium, this ligand has been grafted on the polymer backbone by click chemistry reaction. The obtained macromolecular contrast agent was then coated on a polypropylene mesh using the airbrushing technique and the mesh was assessed for MRI visualization at 7 teslas. The polymeric contrast agent was also tested for cytocompatibility and stability to assess its suitability for biomedical applications.
- Younis, Mira,Darcos, Vincent,Paniagua, Cédric,Ronjat, Pauline,Lemaire, Laurent,Nottelet, Benjamin,Garric, Xavier,Bakkour, Youssef,El Nakat, John Hanna,Coudane, Jean
-
p. 5754 - 5760
(2016/02/05)
-
- Tetra-sensitive graft copolymer gels with high volume changes
-
For the preparation of multi-responsive graft copolymer gels for hydrogel-based microsystem technologies, a poly(4-vinylbenzoic acid) macromonomer was prepared in a three-step synthesis. At first, a chain transfer agent was functionalized with an azide group, followed by a reversible addition fragmentation chain transfer polymerization to give an azide bearing poly(4-vinylbenzoic acid) macromonomer. Subsequently, an acrylamide functionalized macromonomer was prepared by Cu-catalyzed alkyne and azide 1,3-dipolar cycloaddition. With this acrylamide functionalized poly(4-vinylbenzoic acid) macromonomer, various graft copolymer gels composed of a temperature-sensitive poly(N-isopropylacrylamide) backbone and pH-sensitive poly(4-vinylbenzoic acid) graft chains were prepared by radical polymerization. Moreover, the swelling behavior of the hydrogels was investigated with respect to pH, temperature, solvent and salt. It was shown that the graft copolymer gels respond to these stimuli independently with a sharp transition and a high volume change. Additionally, the swelling behavior was reversible over various cycles. This behavior is fundamental for applications of smart gels in microfluidic platforms.
- Gr?fe,Zschoche,Appelhans,Voit
-
p. 34809 - 34817
(2016/05/09)
-
- A click chemistry-based proteomic approach reveals that 1,2,4-trioxolane and artemisinin antimalarials share a common protein alkylation profile
-
In spite of the recent increase in endoperoxide antimalarials under development, it remains unclear if all these chemotypes share a common mechanism of action. This is important since it will influence cross-resistance risks between the different classes. Here we investigate this proposition using novel clickable 1,2,4-trioxolane activity based protein-profiling probes (ABPPs). ABPPs with potent antimalarial activity were able to alkylate protein target(s) within the asexual erythrocytic stage of Plasmodium falciparum (3D7). Importantly, comparison of the alkylation fingerprint with that generated from an artemisinin ABPP equivalent confirms a highly conserved alkylation profile, with both endoperoxide classes targeting proteins in the glycolytic, hemoglobin degradation, antioxidant defence, protein synthesis and protein stress pathways, essential biological processes for plasmodial survival. The alkylation signatures of the two chemotypes show significant overlap (ca. 90 %) both qualitatively and semi-quantitatively, suggesting a common mechanism of action that raises concerns about potential cross-resistance liabilities. Clickable 1,2,4-trioxolane activity-based protein-profiling probes (ABPPs) were designed to retain antimalarial activity and alkylate the molecular targets of the blood stage of Plasmodium falciparum in situ. Comparison of the 1,2,4-trioxolane protein alkylation signature with the corresponding artemisinin ABPPs indicates that both drug classes target key proteins in the glycolytic, hemoglobin degradation, antioxidant defence and protein synthesis pathways.
- Ismail, Hanafy M.,Barton, Victoria E.,Panchana, Matthew,Charoensutthivarakul, Sitthivut,Biagini, Giancarlo A.,Ward, Stephen A.,O'Neill, Paul M.
-
supporting information
p. 6401 - 6405
(2016/06/01)
-
- Synthesis and evaluation of 99mTc-labeled dimeric folic acid for FR-targeting
-
The folate receptor (FR) is overexpressed in a wide variety of human tumors. In our study, the multimeric concept was used to synthesize a dimeric folate derivative via a click reaction. The novel folate derivative (HYNIC-D1-FA2) was radiolabeled with 99mTc using tricine and trisodium triphenylphosphine-3,3′,3″-trisulfonate (TPPTS) as coligands (99mTc-HYNIC-D1-FA2) and its in vitro physicochemical properties, ex vivo biodistribution and in vivo micro-SPECT/CT imaging as a potential FR targeted agent were evaluated. It is a hydrophilic compound (log P = -2.52 ± 0.13) with high binding affinity (IC50 = 19.06 nM). Biodistribution in KB tumor-bearing mice showed that 99mTc-HYNIC-D1-FA2 had high uptake in FR overexpressed tumor and kidney at all time-points, and both of them could obviously be inhibited when blocking with free FA in the blocking studies. From the in vivo micro-SPECT/CT imaging results, good tumor uptake of 99mTc-HYNIC-D1-FA2 was observed in KB tumor-bearing mice and it could be blocked obviously. Based on the results, this new radiolabeled dimeric FA tracer might be a promising candidate for FR-targeting imaging with high affinity and selectivity.
- Guo, Zhide,Gao, Mengna,Song, Manli,Shi, Changrong,Zhang, Pu,Xu, Duo,You, Linyi,Zhuang, Rongqiang,Su, Xinhui,Liu, Ting,Du, Jin,Zhang, Xianzhong
-
supporting information
(2016/07/07)
-
- Development of Bifunctional Inhibitors of Polo-Like Kinase 1 with Low-Nanomolar Activities Against the Polo-Box Domain
-
Polo-like kinase 1 (Plk1), a validated cancer target, harbors a protein-protein interaction domain referred to as the polo-box domain (PBD), in addition to its enzymatic domain. Although functional inhibition either of the enzymatic domain or of the PBD has been shown to inhibit Plk1, so far there have been no reports of bifunctional agents with the potential to target both protein domains. Here we report the development of Plk1 inhibitors that incorporate both an ATP-competitive ligand of the enzymatic domain, derived from BI 2536, and a functional inhibitor of the PBD, based either on the small molecule poloxin-2 or on a PBD-binding peptide. Although these bifunctional agents do not seem to bind both protein domains simultaneously, the most potent compound displays low-nanomolar activity against the Plk1 PBD, with excellent selectivity over the PBDs of Plk2 and Plk3. Our data provide insights into challenges and opportunities relating to the optimization of Plk1 PBD ligands as potent Plk1 inhibitors.
- Scharow, Andrej,Knappe, Daniel,Reindl, Wolfgang,Hoffmann, Ralf,Berg, Thorsten
-
p. 759 - 767
(2016/04/26)
-
- Synthesis of energy transfer cassettes via click and Suzuki-Miyaura cross coupling reactions
-
Novel cassettes capable of energy transfer involving simple synthetic methods viz., copper catalyzed azide-alkyne cycloaddition (click reaction) at the C-8 position and palladium catalyzed Suzuki-Miyaura cross coupling at the C-6 position have been represented. The resulting imidazo[1,2-a]pyrazine-triazole bridged coumarin cassettes are capable of energy transfer from a donor core to an acceptor moiety.
- Goel, Richa,Luxami, Vijay,Paul, Kamaldeep
-
p. 37664 - 37671
(2016/05/19)
-
- SYNTHESIS OF HYPERBRANCHED AMPHIPHILIC POLYESTER AND THERANOSTIC NANOPARTICLES THEREOF
-
A method of making a hyperbranched amphiphilic polyester compound includes drying under vacuum a mixture of 2-(4-hydroxybutyl)-malonic acid and p-toluene sulphonic acid as catalyst. The vacuum is then released with a dry inert gas after drying. The dried mixture is heated under the inert gas at a temperature sufficient for polymerization. The inert gas is evacuated while continuing to heat the mixture. The formed polymer is then dissolved in dimethylformamide and precipitated out by adding methanol. Modifications of the method yield nanoparticles of polyesters having properties suited for coencapsulating fluorescent dyes together with therapeutic drugs, resulting in theranostic nanoparticles, that is, nanoparticles useful in both therapeutic treatments and diagnostic methods.
- -
-
Paragraph 0077; 0078
(2016/09/26)
-
- PEPTIDE-DENDRIMER CONJUGATES AND USES THEREOF
-
The invention relates to dendrimers conjugated to multiple targeting peptides and one or more therapeutic, diagnostic, or imaging agents for delivery of such agents across the blood-brain barrier and into certain cell types including, cells expressing the LRP-1 receptor. Also described are methods of making compounds that comprise dendrimers conjugated to targeting peptides and therapeutic, diagnostic, or imaging agents.
- -
-
Paragraph 0140
(2016/02/10)
-
- Clickable 4-Oxo-β-lactam-Based Selective Probing for Human Neutrophil Elastase Related Proteomes
-
Human neutrophil elastase (HNE) is a serine protease associated with several inflammatory processes such as chronic obstructive pulmonary disease (COPD). The precise involvement of HNE in COPD and other inflammatory disease mechanisms has yet to be clarified. Herein we report a copper-catalyzed alkyne–azide 1,3-dipolar cycloaddition (CuAAC, or ′click′ chemistry) approach based on the 4-oxo-β-lactam warhead that yielded potent HNE inhibitors containing a triazole moiety. The resulting structure–activity relationships set the basis to develop fluorescent and biotinylated activity-based probes as tools for molecular functional analysis. Attaching the tags to the 4-oxo-β-lactam scaffold did not affect HNE inhibitory activity, as revealed by the IC50values in the nanomolar range (56–118 nm) displayed by the probes. The nitrobenzoxadiazole (NBD)-based probe presented the best binding properties (ligand efficiency (LE)=0.31) combined with an excellent lipophilic ligand efficiency (LLE=4.7). Moreover, the probes showed adequate fluorescence properties, internalization in human neutrophils, and suitable detection of HNE in the presence of a large excess of cell lysate proteins. This allows the development of activity-based probes with promising applications in target validation and identification, as well as diagnostic tools.
- Ruivo, Eduardo F. P.,Gon?alves, Lídia M.,Carvalho, Luís A. R.,Guedes, Rita C.,Hofbauer, Stefan,Brito, José A.,Archer, Margarida,Moreira, Rui,Lucas, Susana D.
-
supporting information
p. 2037 - 2042
(2016/10/22)
-
- Fluorescent Probes for Single-Step Detection and Proteomic Profiling of Histone Deacetylases
-
Histone deacetylases (HDACs) play important roles in regulating various physiological and pathological processes. Developing fluorescent probes capable of detecting HDAC activity can help further elucidate the roles of HDACs in biology. In this study, we first developed a set of activity-based fluorescent probes by incorporating the Kac residue and the O-NBD group. Upon enzymatic removal of the acetyl group in the Kac residue, the released free amine reacted intramolecularly with the O-NBD moiety, resulting in turn-on fluorescence. These designed probes are capable of detecting HDAC activity in a continuous fashion, thereby eliminating the extra step of fluorescence development. Remarkably, the amount of turn-on fluorescence can be as high as 50-fold, which is superior to the existing one-step HDAC fluorescent probes. Inhibition experiments further proved that the probes can serve as useful tools for screening HDAC inhibitors. Building on these results, we moved on and designed a dual-purpose fluorescent probe by introducing a diazirine photo-cross-linker into the probe. The resulting probe was not only capable of reporting enzymatic activity but also able to directly identify and capture the protein targets from the complex cellular environment. By combining a fluorometric method and in-gel fluorescence scanning technique, we found that epigenetic readers and erasers can be readily identified and differentiated using a single probe. This is not achievable with traditional photoaffinity probes. In light of the prominent properties and the diverse functions of this newly developed probe, we envision that it can provide a robust tool for functional analysis of HDACs and facilitate future drug discovery in epigenetics.
- Xie, Yusheng,Ge, Jingyan,Lei, Haipeng,Peng, Bo,Zhang, Huatang,Wang, Danyang,Pan, Sijun,Chen, Ganchao,Chen, Lanfang,Wang, Yi,Hao, Quan,Yao, Shao Q.,Sun, Hongyan
-
supporting information
p. 15596 - 15604
(2016/12/16)
-
- PROBE FOR IMAGING PARP-1 ACTIVITY
-
Provided are embodiments of a small molecule tracer for positron emission tomography (PET) imaging of the enzyme activity of PARP-1 that is responsible for DNA-damage sensing and critically involved in radiation therapy and some chemotherapy response mechanisms. These PARP-1 tracers are derivatives of nicotinamide adenine dinucleotide (NAD), which is the natural substrate for PARP-1. Provided are NAD derivatives that include a linker moiety to which may be attached a label moiety such as a PET detectable fluorine to generate a 6N-(triazo-PEG2-18F)-NAD. Especially advantageous for use in PET and MRI scanning detection systems is the attachment of a chelating agent that allows for the formation of a chelator-metal ion complex.
- -
-
Paragraph 0150
(2016/08/03)
-
