- Facile functionalization of peptide nucleic acids (PNAs) for antisense and single nucleotide polymorphism detection
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In this report, we show how a convenient on-resin copper-click functionalization of azido-functionalized peptide nucleic acids (PNAs) allows various PNA-based detection strategies. Firstly, a thiazole orange (TO) clicked PNA probe facilitates a binary readout when combined with F/Q labeled DNA, giving increased sensitivity for antisense detection. Secondly, our TO-PNA conjugate also allows single nucleotide polymorphism detection. Since antisense detection is also possible in the absence of the TO label, our sensing platform based on azido-d-ornithine containing PNA even allows for additional and more advanced functionalization and sensing strategies.
- Gahtory, Digvijay,Murtola, Merita,Smulders, Maarten M. J.,Wennekes, Tom,Zuilhof, Han,Str?mberg, Roger,Albada, Bauke
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Read Online
- Inhibitors of heat shock protein 70 (Hsp70) with enhanced metabolic stability reduce tau levels
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The molecular chaperone, Heat Shock Protein 70 (Hsp70), is an emerging drug target for neurodegenerative diseases, because of its ability to promote degradation of microtubule-associated protein tau (MAPT/tau). Recently, we reported YM-08 as a brain penetrant, allosteric Hsp70 inhibitor, which reduces tau levels. However, the benzothiazole moiety of YM-08 is vulnerable to metabolism by CYP3A4, limiting its further application as a chemical probe. In this manuscript, we designed and synthesized seventeen YM-08 derivatives by systematically introducing halogen atoms to the benzothiazole ring and shifting the position of the heteroatom in a distal pyridine. In microsome assays, we found that compound JG-23 has 12-fold better metabolic stability and it retained the ability to reduce tau levels in two cell-based models. These chemical probes of Hsp70 are expected to be useful tools for studying tau homeostasis.
- Bertron, Jeanette L.,Gestwicki, Jason E.,Hayashi, Shigenari,Li, Xiaokai,Schwarz, Daniel M. C.,Shao, Hao,Tang, Benjamin C.
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- Protein Spherical Nucleic Acids for Live-Cell Chemical Analysis
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We report the development of a new strategy for the chemical analysis of live cells based on protein spherical nucleic acids (ProSNAs). The ProSNA architecture enables analyte detection via the highly programmable nucleic acid shell or a functional protein core. As a proof-of-concept, we use an i-motif as the nucleic acid recognition element to probe pH in living cells. By interfacing the i-motif with a forced-intercalation readout, we introduce a quencher-free approach that is resistant to false-positive signals, overcoming limitations associated with conventional fluorophore/quencher-based gold NanoFlares. Using glucose oxidase as a functional protein core, we show activity-based, amplified sensing of glucose. This enzymatic system affords greater than 100-fold fluorescence turn on in buffer, is selective for glucose in the presence of close analogs (i.e., glucose-6-phosphate), and can detect glucose above a threshold concentration of ~5 μM, which enables the study of relative changes in intracellular glucose concentrations.
- Samanta, Devleena,Ebrahimi, Sasha B.,Kusmierz, Caroline D.,Cheng, Ho Fung,Mirkin, Chad A.
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supporting information
p. 13350 - 13355
(2020/09/09)
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- Neutral analogs of the heat shock protein 70 (Hsp70) inhibitor, JG-98
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The heat shock protein 70 (Hsp70) family of molecular chaperones are highly expressed in tumors. Inhibitors containing a pyridinium-modified benzothiazole, such as JG-98, bind to a conserved, allosteric site in Hsp70, showing promising anti-proliferative activity in cancer cells. When bound to Hsp70, the charged pyridinium makes favorable contacts; however, this moiety also increases the inhibitor's fluorescence, giving rise to undesirable interference in biochemical and cell-based assays. Here, we explore whether the pyridinium can be replaced with a neutral pyridine. We report that pyridine-modified benzothiazoles, such as compound 17h (JG2-38), have reduced fluorescence, yet retain promising anti-proliferative activity (EC50 values ~0.1 to 0.07 μM) in breast and prostate cancer cell lines. These chemical probes are expected to be useful in exploring the roles of Hsp70s in tumorigenesis and cell survival.
- Gestwicki, Jason E.,Shao, Hao
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- Nucleic acid dye, and preparation method and application thereof
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The invention discloses a nucleic acid dye, and a preparation method and an application thereof. The nucleic acid dye is used for common gel imaging dyeing of nucleic acid electrophoresis, and concretely is a novel nucleic acid dye which can be simultaneously suitable for agarose gel electrophoresis and polyacrylamide gel electrophoresis, and particularly can be used for blue light imaging. The invention also relates to the preparation and the application of dye. The developed novel nucleic acid dye is good in dyeing effect, high in safety, very low in nucleic acid migration influence rate andwide in applicability and can realize blue light imaging. The defect that an existing nucleic acid dye cannot be applied to polyacrylamide gel electrophoresis due to a poor dyeing effect is effectively overcome, and particularly the problem that tailing is likely to be generated when the existing dye is used for hair dyeing and electrophoresis is solved.
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Paragraph 0018
(2020/07/15)
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- Thiazole orange – Spermine conjugate: A potent human telomerase inhibitor comparable to BRACO-19
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In this report, we synthesized a series of TO conjugates containing different amino side chains and investigated their binding to telomeric G-quadruplex DNA (G4) using several biophysical methods including fluorometric titration and thermal denaturation monitored by fluorescence and circular dichroism. The composition of side chains strongly affects the binding of these molecules to G-quadruplex DNA. Incorporation of amino side chains increases the binding affinity of TO toward G4 but has a minimal effect on its selectivity for G4 over duplex DNA. The plausible binding modes are a synergistic effect of end-stacking and groove interactions as indicated by docking studies. Inhibition of human telomerase activity by TO derivatives was determined in vitro by the TRAP assay. Several derivatives can selectively inhibit the activity of telomerase over DNA polymerase at low concentrations. More significantly, TO-spermine conjugate (16) exhibits a remarkable effect on telomerase inhibition in the submicromolar range, which is comparable to the inhibition effect of a well-known G4 ligand, BRACO-19. Our results here provide guidance of utilizing TO derivatives as a viable scaffold to design novel G4 ligands, G4 probes, and potent telomerase inhibitors.
- Wang, Siwen,Yang, Dazhou,Singh, Mandeep,Joo, Hyun,Rangel, Vanessa M.,Tran, Aaron,Phan, Erich,Xue, Liang
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- POLYMETHINE COMPOUND
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The present invention relates to a polymethine compound which can be useful in a hard coating composition or an adhesive composition. The polymethine compound is represented by chemical formula 1. In chemical formula 1, X and Y are each independently O, S or NR11, and R11 is a C1 to C12 aliphatic hydrocarbon group.COPYRIGHT KIPO 2019
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Paragraph 0072-0075
(2019/10/22)
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- Novel 3-methyl-2-alkylthio benzothiazolyl-based ionic liquids: Synthesis, characterization, and antibiotic activity
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Three series of novel 3-methyl-2-alkylthio benzothiazolyl ionic liquids (ILs) were synthesized for the first time. After structural identification, their melting point, solubility, and thermostability together with antibiotic activity were determined successively. As a result, 3-methyl-2-alkylthio benzothiazolyl p-toluene sulfonate was found to have the highest antibacterial activity among the three series of ILs. Meanwhile, it has a good solubility in water as well. On the basis of comprehensive comparison with similar compounds, the effect of cations and anions of these benzothiazolium ILs on typical physical properties together with antibiotic performance was explored and discussed, which is very beneficial to take the greatest advantage of their structural designability for various purposes. Furthermore, the experiment data preliminarily discovered the relationships of the structure-properties/activities of the above three kinds ILs to a certain extent, which can provide useful references for future research and for the potential application of these new ILs as surfactant antiseptics or agricultural chemicals.
- Zhang, Teng He,He, Hao Xi,Du, Jun Liang,He, Zhi Jian,Yao, Shun
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- Differential array sensing for cancer cell classification and novelty detection
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A series of semi-specific peptides reported in the literature to bind various epitopes on cell surfaces were used in a differential sensing array to pattern cell line identity. The peptides were conjugated to thiazole orange to act as both a fluorescence reporter and a DNA intercalator. Fluorescence data for the peptides exposed to cells, with and without exogenous double stranded DNA (dsDNA), led to chemometric fingerprints for eight cancer cell lines. In contrast to the use of structures meant to act in completely non-specific ways, the use of a limited level of specificity generated linear discriminant score plots with high dimensionality, i.e. several principle components carrying significant variance. The arrays were found to correctly classify the cell lines from 60% to 100% depending upon the cell line. Due to the high dimensionality score plots, the identification of cell lines that were not part of the training set was examined. Support vector machines were used as a novelty detection routine and showed that a cancer line not part of the original training set could be correctly identified as being novel.
- Gade, Alexandra M.,Meadows, Margaret K.,Ellington, Andrew D.,Anslyn, Eric V.
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supporting information
p. 9866 - 9874
(2017/12/12)
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- FLUORESCENT MOLECULAR ROTORS
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The present invention relates to methods and compositions for detecting an interaction between a protein and a ligand, comprising: (i) binding at least one fluorescent molecular rotor to said ligand or protein; and (ii) detecting a change in fluorescence emitted by said fluorescent molecular rotor after contact of the bound fluorescent molecular rotor with the other of said ligand or protein, thereby detecting an interaction between the ligand and the protein, wherein the fluorescent molecular rotor comprises: a rotating ?-bond; an electron-donating moiety; an electron-accepting moiety; and a ?-conjugated linker.
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Paragraph 0302; 0303; 0304
(2016/08/07)
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- Preparation of novel nucleic acid dye for polyacrylamide gel electrophoresis
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The invention provides preparation of a novel nucleic acid dye for polyacrylamide gel electrophoresis. Following reactions are sequentially conducted:, wherein is 4-methylquinoline, and is 6-bromohexanoic acid; , wherein is 2-(methylmercapto)benzothiazole, and is methyl p-toluenesulfonate; , wherein DMF is N,N-dimethyl formamide, Et3N is triethylamine, and HCl(conc.) is concentrated hydrochloric acid; , wherein is 2-succinimido-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), DIPEA is N, N-diisopropyl ethylamine, is taurine, and is a product compound. Improvement is conducted on a molecular structure, therefore, the nucleic acid dye can easily penetrate into a high-density high polymer, the high sensitivity and high stability of the nucleic acid dye are kept, and the technical problem that a fluorescent dye serving as a nucleic acid gel dye is difficult to penetrate into the high polymer and the problem that the nucleic acid dye generally has the high toxicity are solved.
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Paragraph 0071; 0076; 0077; 0078; 0079; 0080; 0081
(2017/01/12)
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- PHARMACEUTICAL COMPOUNDS AND USE OF SAME IN CANCER AND TAUOPATHIES
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Disclosed are compounds of formula (l)-(V): where the substituents are as provided herein. Further disclosed are methods of inhibiting tau aggregation, treating or ameliorating a tauopathy or cancer by administration of such a compound. Tau is a microtubule-binding protein that accumulates in a number of neurodegenerative disorders, including frontotemporal dementia and Alzheimer's disease (AD). The presence of abnormal tau correlates with neuron loss and memory deficits in patients with AD and other neurodegenerative disorders that involve tau accumulation.
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Paragraph 0017; 0054
(2014/09/16)
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- Analogues of the allosteric heat shock protein 70 (Hsp70) inhibitor, MKT-077, as anti-cancer agents
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The rhodacyanine, MKT-077, has antiproliferative activity against cancer cell lines through its ability to inhibit members of the heat shock protein 70 (Hsp70) family of molecular chaperones. However, MKT-077 is rapidly metabolized, which limits its use as either a chemical probe or potential therapeutic. We report the synthesis and characterization of MKT-077 analogues designed for greater stability. The most potent molecules, such as 30 (JG-98), were at least 3-fold more active than MKT-077 against the breast cancer cell lines MDA-MB-231 and MCF-7 (EC50 values of 0.4 ± 0.03 and 0.7 ± 0.2 μM, respectively). The analogues modestly destabilized the chaperone clients, Akt1 and Raf1, and induced apoptosis in these cells. Further, the microsomal half-life of JG-98 was improved at least 7-fold (t1/2 = 37 min) compared to MKT-077 (t1/2 5 min). Finally, NMR titration experiments suggested that these analogues bind an allosteric site that is known to accommodate MKT-077. These studies advance MKT-077 analogues as chemical probes for studying Hsp70s roles in cancer.
- Li, Xiaokai,Srinivasan, Sharan R.,Connarn, Jamie,Ahmad, Atta,Young, Zapporah T.,Kabza, Adam M.,Zuiderweg, Erik. R. P.,Sun, Duxin,Gestwicki, Jason E.
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supporting information
p. 1042 - 1047
(2013/12/04)
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- 2-[3H-THIAZOL-2-YLIDINEMETHYL]PYRIDINES AND RELATED COMPOUNDS AND THEIR USE
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The present invention pertains to certain 2-[3H-thiazol-2-ylidinemethyl]pyridine compounds and analogs thereof, which, inter alia, inhibit cell proliferation, treat cancer, etc., and more specifically to compounds of the following formula, wherein RA1, RA2, RA3, RA4, RB1, RB2, RNA, RNB, and X? are as defined herein: The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit cell proliferation, and in the treatment of proliferative conditions such as cancer, etc.
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Page/Page column 35
(2009/10/06)
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- New cyanine dyes as base surrogates in PNA: Forced intercalation probes (FIT-probes) for homogeneous SNP detection
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Forced intercalation probes (FIT-probes) are nucleic acid probes, in which an intercalator cyanine dye such as thiazole orange (TO) serves as a replacement of a canonical nucleobase. These probes signal hybridization by showing strong increases of fluorescence. TO in FIT-probes responds to adjacent base mismatches by attenuation of fluorescence intensities at conditions where both matched and mismatched target DNA are bound. The interesting features of TO labeled FIT-probes posed the question whether the forced intercalation concept can be extended to other cyanine dyes of the thiazole orange family. Herein, we present the synthesis of three asymmetrical cyanine dyes and their incorporation into PNA-conjugates by means of both divergent and linear solid-phase synthesis. Melting analysis revealed that the DNA affinity of PNA probes remained high irrespective of the replacement of a nucleobase by the cyanines YO (oxazole yellow), MO or JO. Of the three new tested dye-PNA-conjugates, the YO-containing PNA has properties useful for homogeneous SNP detection. YO-PNA is demonstrated to signal the presence of fully complementary DNA by up to 20-fold enhancement of fluorescence. In addition, YO emission discriminates against single base mismatches by attenuation of fluorescence. Oxazole yellow (YO) as a base surrogate in PNA may prove useful in the multiplex detection of single base mutations at non-stringent conditions.
- Bethge, Lucas,Jarikote, Dilip Venkatrao,Seitz, Oliver
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p. 114 - 125
(2008/04/05)
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- Synthesis of three classes of rhodacyanine dyes and evaluation of their in vitro and in vivo antimalarial activity
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Selected members of three classes of rhodacyanine dyes, [0, 0]-, [1, 0]-, and [0, 0, 0]-rhodacyanines, were synthesized and their in vitro antimalarial activities against Plasmodium falciparum K1 (chloroquine-resistant strain) as well as their in vivo activities against P. berghei in mice were determined. The novel [0, 0, 0]-rhodacynines, 3e and 3h, possessing a benzothiazole moiety, were shown to have highly promising antimalarial activities in vivo. Moreover, the [0, 0, 0]-rhodacyanines were found to be orally bioavailable.
- Pudhom, Khanitha,Kasai, Kazuki,Terauchi, Hiroki,Inoue, Hiroshi,Kaiser, Marcel,Brun, Reto,Ihara, Masataka,Takasu, Kiyosei
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p. 8550 - 8563
(2008/02/05)
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- ANTI-LEISHMANIA AGENT
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The present invention is to provide a new anti-leishmania agent with fewer side effects, having a high cell proliferation-inhibiting effect to leishamia protozoa, and also easy to manufacture at a low cost. A compound wherein a heterocycle with a conjugated system and a nitrogen atom and a heterocycle with a nitrogen atom and a sulfur atom are bound by a carbon chain with an ethylene group, that is a compound wherein a specific 5- to 8-membered heterocyclic ring and a specific 5-to 8-membered heterocycle having a conjugated system are bound via a vinylene group, more particularly a specific rhodacyanine dye compound is used as an active ingredient of the anti-leishmania agent.
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Page/Page column 11-12
(2008/06/13)
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- Rhodacyanine dyes as antimalarials. 1. Preliminary evaluation of their activity and toxicity
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The rhodacyanine dye MKT-077 (1), a potent antitumor agent, was found to possess strong in vitro activity against Plasmodium falciparum and a low cytotoxicity. Several new rhodacyanine dyes related to 1, containing a variety of linked heterocyclic moieties, were synthesized, and their antimalarial potencies were evaluated. The synthetic rhodacyanines were found to have EC50 values against P. falciparum in vitro in the range of 4-300 nM. Several compounds in this series have remarkable selective toxicity profiles (> 100).
- Takasu, Kiyosei,Inoue, Hiroshi,Kim, Hye-Sook,Suzuki, Makoto,Shishido, Tadao,Wataya, Yusuke,Ihara, Masataka
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p. 995 - 998
(2007/10/03)
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- Non-fluorescent asymmetric cyanine dye compounds useful for quenching reporter dyes
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The invention provides asymmetric cyanine dye compounds having the general formula: including substituted forms thereof, which are non-fluorescent quencher molecules. The invention further provides reporter-quencher dye pairs, wherein the asymmetric cyanine dyes are the quenchers, polynucleotides incorporating the asymmetric cyanine dyes, and nucleic acid hybridization detection methods utilizing the dye-labeled polynucleotides.
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- Nitro-substituted non-fluorescent asymmetric cyanine dye compounds
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The invention provides an asymmetric cyanine dye compound having the structure including substituted forms thereof, wherein, at least one of R1 and R2 is linking group, X is O, S, or Se, and n ranges from 0 to 2. The invention further provides reporter-quencher dye pairs comprising the asymmetric cyanine dyes, dye-labeled polynucleotides incorporating the asymmetric cyanine dyes, and hybridization detection methods utilizing the dye-labeled polynucleotides.
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- Structure-activity of novel rhodacyanine dyes as antitumor agents
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We have previously reported that rhodacyanine dyes, such as 1 and 2, exhibited a potent inhibitory effect on the growth of several tumor cells and that 4-oxothiazolidine (rhodanine) was an essential moiety for antitumor activity. On the basis of our foregoing work, two types of rhodacyanine dyes, which categorized into class I and II depending on the methine length, were synthesized and evaluated as a novel antitumor agent. Attention was particularly focused on the structure-activity study of two heteroaromatic rings. In class I, where the A rings were conjugated to rhodanine via two methine groups, compounds 1, 20, 23, and 24 were found to be efficacious in tumor-bearing nude mice model study, but they did not have the chemical properties (stability, solubility) suitable for clinical use. In contrast, in class II, where the A rings were directly conjugated to rhodanine, compounds 13 and 25, which possessed a benzothiazole moiety for the A ring, exhibited the favorable biological and chemical properties. Therefore, we decided to have a benzothiazole moiety as the A ring and introduce various heterocyclic groups for the B ring. As a result, the pyridinium ring was selected as the optimal moiety for the B ring (compound 13). Further, the variation of counteranion had a profound effect on solubility in water without influence on antitumor activity. Chloride anion was selected as the favorable anion with respect to synthetic method as well as solubility in water. Our study finally led us to the identification of compound 3 (MKT 077, 1-ethyl-2-[[3- ethyl-5-(methylbenzothiazolin-2-ylidene)-4-oxothiazolidin-2- ylidene]pyridinium chloride) as the candidate for clinical trials and is currently subjected to further investigation as a potent antitumor agent in phase I clinical trial for the treatment of solid tumors.
- Kawakami, Masayuki,Koya, Keizo,Tatsuta, Toshinao,Noriaki, Ukai T.,Ikegawa, Akihiko,Ogawa, Keizo,Shishido, Tadao,Chen, Lan Bo
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p. 130 - 142
(2007/10/03)
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- Substituted unsymmetrical cyanine dyes with selected permeability
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The invention describes the preparation and use of fluorescent stains for nucleic acids derived from unsymmetrical cyanine dyes comprising a substituted benzazolium ring system linked by a methine bridge to a pyridinium or quinolinium ring system having at least one substituent on the pyridinium or quinolinium ring that contains a heteroatom. The presence of the heteroatom-containing substituent results in higher sensitivity to oligonucleotides and larger nucleic acid polymers in a wide range of cells and gels, and for use in analysis of cell structure, membrane integrity or function.
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- Synthesis and evaluation of novel rhodacyanine dyes that exhibit antitumor activity
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Rhodacyanine dyes and several analogous delocalized lipophilic cations (DLCs) were synthesized and evaluated as novel antitumor agents Rhodacyanine dye consists of two heteroaromatic rings such as thiazoles at both termini of the conjugate systems and 4-oxothiazolidine (rhodanine) in the middle of it. Compounds with such a unique double-conjugate structure were found to inhibit the growth of several tumor cell lines, such as colon carcinoma CX-1, and to exhibit relatively low toxicity against normal kidney cell line CV-1 (e.g., IC50(CX-1) = 50 nM, IC50(CV-1) = 17.3 μM; selectivity index = 346 for compound 5). These compounds were also found to be efficacious in the tumor- bearing nude mice model (e.g., against human melanoma LOX; T/C (%) = 168 for compound 5). Structural modifications on rhodacyanine, including deletion of a heteroaromatic ring involved in the merocyanine conjugate system and replacement of rhodanine with a structurally related moiety such as 4- oxoimidazolidine or 4-oxo-1,3-dithiolane, resulted in a loss of the selectivity and/or the activity. Our current structure-activity studies imply that the double-conjugate system with a rhodanine moiety is essential for the selective activity of rhodacyanine dyes, and we find this class of compounds as unique antitumor agent candidates.
- Kawakami, Masayuki,Koya, Keizo,Ukai, Toshinao,Tatsuta, Noriaki,Ikegawa, Akihiko,Ogawa, Keizo,Shishido, Tadao,Chen, Lan Bo
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p. 3151 - 3160
(2007/10/03)
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- Specific Molecular Orbital Contributions to Nucleophilicity. The Thiocarbonyl Group as Privileged Monitor To Pinpoint Active and Less Active Molecular Orbitals in Reactions with Methylating Agents
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The rate constants for 41 compounds bearing a C=S function reacting with MeX (X = I, Tos) span 7 orders of magnitude.The PES spectra of these compounds display two very low energy peaks, which stand clearly apart from the other peaks.These two peaks correspond to the ? orbitals of the C-S group; one is its CS ? bonding orbital oriented out of the molecular plane (?CS) and the other its p-type in-plane lone pair orbital (?S).For some of the compounds, the HOMO is the ?CS orbital and for others the HOMO is the ?S lone pair orbital.The best correlation (R = 0.96) between rate constants k and PES data is obtained when ln(k) is plotted against the inverse of PES energy of the ?S lone pair orbital.Whether this lone pair orbital is the HOMO or the next lower HOMO has no importance.A modest correlation (R = 0.78) is obtained when ln(k) is plotted against the inverse of PES energy of the ?CS bonding orbital.An attempt to correlate the calculated energy of the third highest occupied orbital (from AM1 calculations) with ln(k) provides a complete scattering of data (R S (ca. 90 kcal mol-1 deeper than the HOMO) correlates reasonably with ln(k) (R = 0.88).The energies of the S 2s and 2p core orbitals (calculated for 13 cyclic compounds with the HF/3-21G technique to be 4000 to 5500 kcal mol-1 deeper than HOMO) correlate with ln(k) (R = 0.86) as well as does that of the second lone pair orbital ?S.These results are the first where both frontier orbitals and core orbitals display correlation with overall reactivity.They are discussed in terms of direct (perturbational) versus indirect (nonperturbational) concepts.
- Arbelot, M.,Allouche, A.,Purcell, K. F.,Chanon, M.
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p. 2330 - 2343
(2007/10/02)
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