263162-13-6Relevant articles and documents
DNA-Targeted 1,2,4-Benzotriazine 1,4-Dioxides: Potent Analogues of the Hypoxia-Selective Cytotoxin Tirapazamine
Hay, Michael P.,Pruijn, Frederik B.,Gamage, Swarna A.,Liyanage, H.D. Sarath,Kovacs, Mary S.,Patterson, Adam V.,Wilson, William R.,Brown, J. Martin,Denny, William A.
, p. 475 - 488 (2004)
Tirapazamine (TPZ, 1,2,4-benzotriazin-3-amine 1,4-dioxide) is a bioreductive hypoxia-selective cytotoxin, currently in phase II/III clinical trials in combination with radiotherapy and with cisplatin-based chemotherapy. We have prepared a series of 1,2,4-benzotriazine 1,4-dioxide (BTO) analogues of TPZ where a DNA-targeting chromophore is attached at the 3-position via a flexible linker. DNA binding affinity was modified through variation of the chromophore or the pKa of the linker chain. The association constants (K DNA) for calf thymus DNA ranged from 1 × 102 to 5.6 × 105 M-1 (ionic strength of 0.01 M). DNA binding affinity was dependent on the presence of a positive charge, either in the linker chain or in the chromophore, and (for a series of 4-acridine carboxamide chromophore analogues) correlated strongly with linker chain pKa. The efficacy of these BTOs in killing aerobic and hypoxic mouse SCCVII tumor cells in vitro was determined by clonogenic survival. Cytotoxicity was measured as the concentration required to reduce plating efficiency to 10% of controls (C10), and the hypoxic cytotoxicity ratio (HCR) for each BTO was calculated as C10(aerobic)/C10(hypoxic). BTOs bearing a positive charge showed increased hypoxic cytotoxicity (1.5-56-fold) compared to TPZ and mostly modest HCRs (8-51), but some excellent (a strong correlation between KDNA and hypoxic cytotoxicity but no correlation between KDNA and HCR. Cytotoxicity in HT-29 human colon carcinoma cells, determined using IC50 assays, showed similar relationships with a correlation between KDNA and hypoxic cytotoxicity but no correlation between KDNA and HCR. In this cell line, a higher proportion of compounds (7 of 11) had HCRs greater than or equal to that of TPZ. The data confirm that DNA targeting is a useful concept for increasing potency while maintaining hypoxic selectivity and provide a direction for the further development of DNA-targeted analogues of TPZ.
Cyclic ferrocenylnaphthalene diimides as a probe for electrochemical telomerase assay
Eguchi, Nao,Fujii, Satoshi,Fujimoto, Kazuhisa,Kaneyoshi, Shuma,Sato, Shinobu,Takenaka, Shigeori
, (2022/02/11)
Novel cyclic naphthalene diimides, 8 and 12, containing ferrocene in the cyclic linker were synthesized as G-quartet (G4) specific electrochemical ligands via the reaction of 1,1′-ferrocenedipropanoic acid and the terminal amine moieties of naphthalene diimides with varying linker lengths. The redox potentials of 8 and 12 were ca. 0.2 V (vs. Ag/AgCl), and the background current in an electrolyte was successfully suppressed. Both 8 and 12 bound to TA-core, representing human telomere G4, with K = 4.4 and 38 × 105 M?1, respectively. The current response of 12 to an electrode immobilized with G4 was the highest among the acyclic derivatives, suggesting its potential application in electrochemical telomerase assays.
A Universal Labeling Strategy for Nucleic Acids in Expansion Microscopy
Wen, Gang,Vanheusden, Marisa,Leen, Volker,Rohand, Taoufik,Vandereyken, Katy,Voet, Thierry,Hofkens, Johan
supporting information, p. 13782 - 13789 (2021/09/11)
Expansion microscopy (ExM) enables the nanoscale imaging of ribonucleic acids (RNAs) on a conventional fluorescence microscope, providing information on the intricate patterns of gene expression at (sub)cellular resolution and within spatial context. To extend the use of such strategies, we examined a series of multivalent reagents that allow the labeling and grafting of deoxyribonucleic acid (DNA) oligonucleotide probes in a unified approach. We show that the reagents are directly compatible with third-generation in situ hybridization chain reaction RNA FISH (fluorescence in situ hybridization) techniques while displaying complete retention of the targeted transcripts. Furthermore, we validate and demonstrate that our labeling method is compatible with multicolor staining. Through oligonucleotide-conjugated antibodies, we demonstrate excellent performance in ×4 ExM and ×10 ExM, achieving a resolution of ~50 nm in ×10 ExM for both pre- and postexpansion labeling strategies. Our results indicate that our multivalent molecules enable the rapid functionalization of DNA oligonucleotides for ExM.
ANTIBODY-DRUG CONJUGATES COMPRISING ANTI-B7-H3 ANTIBODIES
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Page/Page column 123-124, (2022/01/04)
The present disclosure relates to antibody-drug conjugates (ADCs) wherein one or more active agents are conjugated to an anti-B7-H3 antibody through a linker. The linker may comprise a unit that covalently links active agents to the antibody. The disclosure further relates to monoclonal antibodies and antigen binding fragments, variants, multimeric versions, or bispecifics thereof that specifically bind B7-H3, as well as methods of making and using these anti-B7-H3 antibodies and antigen-binding fragments thereof in a variety of therapeutic, diagnostic and prophylactic indications
SMALL MOLECULE INHIBITORS OF AUTOPHAGY AND HISTONE DEACTYLASES AND USES THEREOF
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Page/Page column 42-43, (2021/05/07)
This invention is in the field of medicinal chemistry. In particular, the invention relates to a new class of small-molecules having a quinoline or thioxanthenone (or similar) structure which function as autophagy inhibitors and/or histone deactylase inhibitors, and their use as therapeutics for the treatment of conditions characterized with aberrant autophagy activity and/or aberrant HDAC activity (e.g., cancer, pulmonary hypertension, diabetes, neurodegenerative disorders, aging, heart disease, rheumatoid arthritis, infectious diseases, conditions and symptoms caused by a viral infection (e.g., COVID-19)).
BIFUNCTIONAL COMPOUNDS AS CDK MODULATORS
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Paragraph 0172, (2020/02/16)
The present application provides compounds of formulae I and II that modulate CDK protein function. Methods of making the compounds, compositions containing the compounds, and the compounds for use in a method of treating or ameliorating of diseases, disorders, or conditions associated with CDK proteins, are also disclosed.
SUBSTITUTED THIOXANTHENONE AUTOPHAGY INHIBITORS
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Paragraph 0012; 0111; 0112, (2017/08/23)
Autophagy inhibitors useful for the treatment of cancer and other diseases are described. The autophagy inhibitors are a compound of formula: I wherein R1 is a group selected from lower alkyl, lower alkyl amide, lower alkyl ester, lower alkyl ketone, and lower alkyl ether; R2 and R3 are H or a group selected from cycloalkyl, lower alkyl, lower alkyl amide, lower alkyl ester, lower alkyl ketone, and lower alkyl ether; R4 is a heteroaryl group; and L is a —(CH2)n—X—(CH2)n— group, wherein n is 1, 2, 3, or 4, X is absent, O, S, or N—R5, wherein R5 is H or a lower alkyl group, or a pharmaceutically acceptable salt thereof.
Fatty acid COX inhibitor derivatives and their uses
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Page/Page column 54-56, (2016/01/09)
The invention relates to fatty acid COX inhibitor derivatives; compositions comprising an effective amount of a fatty acid COX inhibitor derivative; and methods for treating or preventing a metabolic, autoimmune, inflammatory, or neurodegenerative disorde
USE OF FATTY ACID NIACIN CONJUGATES FOR TREATING DISEASES
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Paragraph 0332, (2014/07/22)
The invention relates to fatty acid niacin conjugates; compositions comprising an effective amount of a fatty acid niacin conjugate; methods for treating or preventing an metabolic disease comprising the administration of an effective amount of a fatty acid niacin conjugate, and methods for treating or preventing an metabolic disease comprising the administration of an effective amount of a fatty acid niacin conjugate and another therapeutic agent.
METHODS OF LOWERING PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9)
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Paragraph 0244, (2014/01/07)
The invention relates to new methods of modulating cholesterol by inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) with fatty acid derivatives; and new methods for treating or preventing a metabolic disease comprising the administration of an effective amount of a fatty acid derivative. The present invention is also directed to fatty acid bioative derivatives and their use in the treatment of metabolic diseases.