- Identification of Hypoxic Cells Using an Organotellurium Tag Compatible with Mass Cytometry
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Mass cytometry (MC) offers unparalleled potential for the development of highly parameterized assays for characterization of single cells within heterogeneous populations. Current reagents compatible with MC analysis employ antibody-metal-chelating polymer conjugates to report on the presence of biomarkers. Here, we expand the utility of MC by developing the first activity-based probe designed specifically for use with the technology. A compact MC-detectable telluroether is linked to a bioreductively sensitive 2-nitroimidazole scaffold, thereby generating a probe sensitive to cellular hypoxia. The probe exhibits low toxicity and is able to selectively label O2-deprived cells. A proof-of-concept experiment employing metal-bound DNA intercalators demonstrates that a heterogeneous mixture of cells with differential exposure to O2 can be effectively discriminated by the quantity of tellurium-labeling. The organotellurium reagents described herein provide a general approach to the development of a large toolkit of MC-compatible probes for activity-based profiling of single cells.
- Edgar, Landon J.,Vellanki, Ravi N.,Halupa, Adrienne,Hedley, David,Wouters, Bradly G.,Nitz, Mark
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- Oxazolidine Formation, or Loss of Acid, from Attempted Fluorination of Amide Side-Chain in 2-Nitroimidazoles
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Reaction of Etanidazole (a 2-nitroimidazole derivative with an amide side-chain containing a hydroxyethyl group) with triflic anhydride gives, depending on conditions, a trifluoromethyl(sulfonyl)oxazolidine via a cyclization reaction, or a fluorine-free formate derivative; reaction with tosyl chloride gives only a chloroethyl derivative. An attempt to replace a Br-atom in a related propyl-containing amide side-chain by a F-atom forms instead a propylene derivative via loss of HBr. The studies stem from interest in use of 2-nitroimidazoles with fluorine-containing amide side-chains as hypoxia markers.
- Baird, Ian R.,Patrick, Brian O.,Skov, Kirsten A.,James, Brian R.
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- KRAS G12D INHIBITORS
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The present invention relates to compounds that inhibit KRas G12D. In particular, the present invention relates to compounds that inhibit the activity of KRas G12D, pharmaceutical compositions comprising the compounds and methods of use therefor.
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Paragraph 0631
(2021/03/05)
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- Targeting tumor hypoxia: A third generation 2-nitroimidazole-indocyanine dye-conjugate with improved fluorescent yield
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Tumor hypoxia is associated with the rapid proliferation and growth of malignant tumors, and the ability to detect tumor hypoxia is important for predicting tumor response to anti-cancer treatments. We have developed a class of dye-conjugates that are related to indocyanine green (ICG, 1) to target tumor hypoxia, based on in vivo infrared fluorescence imaging using nitroimidazole moieties linked to indocyanine fluorescent dyes. We previously reported that linking 2-nitroimidazole to an indocyanine dicarboxylic acid dye derivative (2) using an ethanolamine linker (ethanolamine-2-nitroimidazole-ICG, 3), led to a dye-conjugate that gave promising results for targeting cancer hypoxia in vivo. Structural modification of the dye conjugate replaced the ethanolamine unit with a piperazineacetyl unit and led a second generation dye conjugate, piperzine-2-nitroimidazole-ICG (4). This second generation dye-conjugate showed improved targeting of tumor hypoxia when compared with 3. Based on the hypothesis that molecules with more planar and rigid structures have a higher fluorescence yield, as they could release less absorbed energy through molecular vibration or collision, we have developed a new 2-nitroimidazole ICG conjugate, 12, with two carbon atoms less in the polyene linker. Dye-conjugate 12 was prepared from our new dye (8), and coupled to 2-nitroimidazole using a piperazine linker to produce this third-generation dye-conjugate. Spectral measurements showed that the absorption/emission wavelengths of 657/670 were shifted ~100 nm from the second-generation hypoxia dye of 755/780 nm. Its fluorescence quantum yield was measured to be 0.467, which is about 5 times higher than that of 4 (0.083). In vivo experiments were conducted with balb/c mice and 12 showed more than twice the average in vivo fluorescence intensity in the tumor beyond two hours post retro-orbital injection as compared with 4. These initial results suggest that 12 may significantly improve in vivo tumor hypoxia targeting.
- Zhou, Feifei,Zanganeh, Saeid,Mohammad, Innus,Dietz, Christopher,Abuteen, Akram,Smith, Michael B.,Zhu, Quing
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p. 11220 - 11227
(2015/12/01)
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- Synthesis and fluorescent characteristics of imidazole-indocyanine green conjugates
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We have successfully synthesized imidazole-dye conjugates by linking imidazole and nitroimidazoleacetic acids to an indocyanine green (ICG) carboxylic acid derivative, using an ethanolamine linker. These dye-conjugates show absorbance peaks at 754-756 nm and fluorescence peaks at 780 nm. The dye-conjugates show a blue shift of 25 nm and 30 nm in the absorption and fluorescence spectra respectively when compared to that of standard cardiogreen. There is no change in absorption and fluorescence spectral profiles between the ICG derivative and imidazole conjugates. The extinction coefficients of new ICG derivative and imidazole conjugates are 1.8 times higher than that of standard ICG. The relative quantum yields of the new compounds are 4.5-5.5 times higher than that of the Sigma-Aldrich's ICG. The dyes are tested for hypoxia in-vitro with 4T1 luc cell lines and it is found that the cells treated with 2-nitroimidazole ICG show a contrast of fluorescence signal of 2.5-3.0 for the cells under hypoxic to that of cells under normoxic. However pure ICG shows no significant difference between hypoxic and normoxic cells.
- Pavlik, Christopher,Biswal, Nrusingh C.,Gaenzler, Faith Corbo,Morton, Martha D.,Kuhn, Liisa T.,Claffey, Kevin P.,Zhu, Quing,Smith, Michael B.
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experimental part
p. 9 - 15
(2011/07/07)
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- Design, synthesis, and radiosensitizing activities of sugar-hybrid hypoxic cell radiosensitizers
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We have designed sugar-hybrid TX-1877 derivatives conjugated with sugar moieties including β-glucose (β-Glc), β-galactose (β-Gal), α-mannose (α-Man) and N-acetyl-β-galactosamine (β-GalNAc). Compound 1 (TX-1877) was glycosylated with appropriate peracetylated sugars using BF3-OEt2 to give acetylated sugar-hybrids, 5 (TX-2244), 6 (TX-2245), 7 (TX-2246), and 10 (TX-2243). Removal of the acetyl groups afforded the sugar-hybrids having free hydroxyl groups, 11 (TX-2141), 12 (TX-2218), 13 (TX-2217) and 14 (TX-2068). We evaluated their radiosensitizing activities by an in vitro radiosensitization assay. All free hydroxyl hybrids have lower enhancement ratio (ER) values (ER ≤ 1.43) and lower n-octanol/water partition coefficient (Poct) values (Poct -2) than does 1 (TX-1877, ER = 1.75, Poct: 5.60 × 10-2). All acetylated hybrids have similar Poct values (3.55 × 10-2-1.05 × 10-1) to 1 (TX-1877) and have improved ER values (ER ≥ 1.47) compared to the hybrids having free hydroxyl groups. Among these, 5 (TX-2244) is the most active radiosensitizer (ER = 2.30). We found a good correlation (r = 0.866) between the magnitude of Poct (logPoct) and the ER value of 5 (TX-2244), 6 (TX-2245), 7 (TX-2246), 10 (TX-2243) and 1 (TX-1877), suggesting that increasing the hydrophobicity is reflected in increased in vitro radiosensitizing activity. In the present study, we have succeeded in producing sugar-hybrid hypoxic cell radiosensitizers that have an increased radiosensitizing activity that does not depend on increased hydrophobicity.
- Nakae, Takashi,Uto, Yoshihiro,Tanaka, Motoko,Shibata, Haruna,Nakata, Eiji,Tominaga, Masahide,Maezawa, Hiroshi,Hashimoto, Toshihiro,Kirk, Kenneth L.,Nagasawa, Hideko,Hori, Hitoshi
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p. 675 - 682
(2008/09/17)
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- New antimetastatic hypoxic cell radiosensitizers: Design, synthesis, and biological activities of 2-nitroimidazole-acetamide, TX-1877, and its analogues
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We designed, based on the molecular orbital (MO) calculation, synthesized, and evaluated the biological activities of the new antimetastatic hypoxic cell radiosensitizer, 2-nitroimidazole-acetamide, TX-1877, and its analogues. Each analogue has an electron-affinic imidazole group, an acetamide group and a certain hydrophilic group to control its biological effect, toxicity, and pharmacokinetics. In in vitro radiosensitization assay, most TX-1877 analogues, which have an electron affinity (EA) of more than 0.9 eV and partition coefficient (P) of more than 0.021, showed satisfactory enhancement ratios (ER > 1.60) at doses of 1 mM. On the other hand, imidazole analogues, such as TX-1908 (EA = 0.67 eV), TX-1910 (EA = -0.34 eV) and TX-1931 (EA = -0.37 eV), which have low electron affinities, had an ER of 1.31 or less. TX-1877 and KIN-806 effectively inhibited tumor regrowth when administered with irradiation in vivo at a dose of 0.4 mg/g. Tumor lung metastasis was inhibited by treatment with either TX-1877 or KIN-806 without irradiation at a dose of 0.4 mg/g. TX-1877 reduced markedly the mean number of metastatic lung nodules in comparison with KIN-806. Moreover, TX-1877 and KIN-806 enhanced macrophage and helper T lymphocyte infiltration for 3 weeks after drug treatment. TX-1877 shows a high EA value and has the C2 of HOMO localizing on N-methylamide and the C2 of LUMO localizing on 2-nitroimidazole group. The MO data might be useful for designing a bifunctional hypoxic cell radiosensitizer. TX-1877 and its analogues are potential antimetastatic hypoxic cell radiosensitizers, which would improve the efficiency of radiotherapy and quality of life in cancer treatment.
- Kasai, Soko,Nagasawa, Hideko,Yamashita, Mao,Masui, Mie,Kuwasaka, Hideki,Oshodani, Tomoko,Uto, Yoshihiro,Inomata, Taisuke,Oka, Shigenori,Inayama, Seiichi,Hori, Hitoshi
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p. 453 - 464
(2007/10/03)
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- An efficient procedure for the 1-alkylation of 2-nitroimidazoles and the synthesis of a probe for hypoxia in solid tumours
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The N-alkylation of 2-nitroimidazole through its 'naked' anion, formed from its alkali metal salts in the presence of crown ethers and in homogeneous solution, is shown to be a useful preparative procedure. The reactions of α,ω-dihaloalkanes can be controlled to afford either the mono- or diheteroarylalkane. The procedure has been used to alkylate theophylline and to prepare a compound of use as a probe to identify, locate and quantify hypoxia in sections from solid tumours.
- Long,Parrick,Hodgkiss
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p. 709 - 713
(2007/10/02)
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- Nitroimidazoles of low toxicity and high activity as radiosensitizers of hypoxic tumor cells
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Two compounds represented by the formula STR1 wherein R is hydrogen or a 2-hydroxyethyl radical are reported to have minimum penetration into the brain and nerve tissues combined with maximum penetration into hypoxic tumor cells. This combination of properties makes these compounds the optimal radiosensitizers among electron-affinic 1-substituted 2-nitroinidazoles.
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