- DNA-Targeted 1,2,4-Benzotriazine 1,4-Dioxides: Potent Analogues of the Hypoxia-Selective Cytotoxin Tirapazamine
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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.
- 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.
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Read Online
- Cyclic ferrocenylnaphthalene diimides as a probe for electrochemical telomerase assay
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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.
- Eguchi, Nao,Fujii, Satoshi,Fujimoto, Kazuhisa,Kaneyoshi, Shuma,Sato, Shinobu,Takenaka, Shigeori
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- A Universal Labeling Strategy for Nucleic Acids in Expansion Microscopy
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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.
- Wen, Gang,Vanheusden, Marisa,Leen, Volker,Rohand, Taoufik,Vandereyken, Katy,Voet, Thierry,Hofkens, Johan
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supporting information
p. 13782 - 13789
(2021/09/11)
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- ANTIBODY-DRUG CONJUGATES COMPRISING ANTI-B7-H3 ANTIBODIES
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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
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Page/Page column 123-124
(2022/01/04)
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- SMALL MOLECULE INHIBITORS OF AUTOPHAGY AND HISTONE DEACTYLASES AND USES THEREOF
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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)).
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Page/Page column 42-43
(2021/05/07)
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- BIFUNCTIONAL COMPOUNDS AS CDK MODULATORS
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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.
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Paragraph 0172
(2020/02/16)
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- SUBSTITUTED THIOXANTHENONE AUTOPHAGY INHIBITORS
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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.
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Paragraph 0012; 0111; 0112
(2017/08/23)
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- Fatty acid COX inhibitor derivatives and their uses
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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
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Page/Page column 54-56
(2016/01/09)
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- USE OF FATTY ACID NIACIN CONJUGATES FOR TREATING DISEASES
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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.
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Paragraph 0332
(2014/07/22)
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- METHODS OF LOWERING PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9)
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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.
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Paragraph 0244
(2014/01/07)
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- FATTY ACID NON-FLUSHING NIACIN DERIVATIVES AND THEIR USES
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The invention relates to fatty non-flushing acid niacin derivatives; compositions comprising an effective amount of a fatty acid non-flushing niacin derivative; and methods for treating or preventing an metabolic disease comprising the administration of an effective amount of a fatty acid non-flushing niacin derivative.
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Page/Page column 32
(2012/10/08)
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- FATTY ACID GUANIDINE AND SALICYLATE GUANIDINE DERIVATIVES AND THEIR USES
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The invention relates to fatty acid guanidine or salicylate guanidine derivatives; compositions comprising an effective amount of a fatty acid guanidine or salicylate guanidine derivative; and methods for treating or preventing a metabolic disease compris
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Page/Page column 36
(2012/11/08)
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- BIS-FATTY ACID CONJUGATES AND THEIR USES
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The invention relates to bis-fatty acid conjugates; compositions comprising an effective amount of a bis-fatty acid conjugate; and methods for treating or preventing cancer, a metabolic disease or a neurodegenerative disease comprising the administration of an effective amount of a bis-fatty acid conjugate.
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Page/Page column 78-79
(2012/09/11)
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- FATTY ACID NIACIN CONJUGATES AND THEIR USES
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The invention relates to fatty acid niacin conjugates; compositions comprising 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.
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Page/Page column 19-20
(2011/04/14)
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- FATTY ACID FIBRATE DERIVATIVES AND THEIR USES
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The invention relates to fatty acid fibrate derivatives; compositions comprising an effective amount of a fatty acid fibrate derivative; and methods for treating or preventing an metabolic disease comprising the administration of an effective amount of a
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Page/Page column 36
(2011/04/24)
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- FATTY ACID ACIPIMOX DERIVATIVES AND THEIR USES
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The invention relates to fatty acid acipimox derivatives; compositions comprising an effective amount of a fatty acid acipimox derivative; and methods for treating or preventing an metabolic disease comprising the administration of an effective amount of a fatty acid acipimox derivative.
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Page/Page column 19-20
(2011/04/24)
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- FATTY ACID FUMARATE DERIVATIVES AND THEIR USES
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The invention relates to Fatty Acid Fumarate Derivatives; compositions comprising an effective amount of a Fatty Acid Fumarate Derivative; and methods for treating or preventing cancer, a metabolic disorder or neurodegenerative disorder comprising the adm
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Page/Page column 38
(2011/08/03)
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- LIPOIC ACID ACYLATED SALICYLATE DERIVATIVES AND THEIR USES
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The invention relates to lipoic acid acylated salicylate derivatives; compositions comprising an effective amount of a lipoic acid acylated salicylate derivative; and methods for treating or preventing an metabolic disease comprising the administration of
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Page/Page column 30
(2011/04/24)
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- BIS-FATTY ACID CONJUGATES AND THEIR USES
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The invention relates to bis-fatty acid conjugates; compositions comprising an effective amount of a bis-fatty acid conjugate; and methods for treating or preventing cancer, a metabolic disease or a neurodegenerative disease comprising the administration of an effective amount of a bis-fatty acid conjugate.
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Page/Page column 74
(2011/09/30)
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- FATTY ACID MYCOPHENOLATE DERIVATIVES AND THEIR USES
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The invention relates to fatty acid mycophenolate derivatives; compositions comprising an effective amount of a fatty acid mycophenolate derivative; and methods for treating and preventing organ rejection and autoimmune diseases such as systemic lupus erythematosus, psoriasis and multiple sclerosis comprising the administration of an effective amount of a fatty acid mycophenolate derivative.
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Page/Page column 30-31
(2011/09/20)
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- Synthesis of new diaryl and dialkyl diselenides as potential virucides and antimicrobials
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The synthesis of three new groups of alkyl and aryl diselenides: 2,2′-diselenobisbenzamides, 4,4′-diselenobisbutyramides and 2,2′-di(selenomethyl)bisbenzamides designed as potential virucides and bacteriocides was elaborated. It was based on acylation of
- Palus,Chojnacka,Piasecki,Zboinska,Mlochowski
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p. 2117 - 2126
(2007/10/03)
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- DNA-TARGETED BENZOTRIAZINE 1,4-DIOXIDES AND THEIR USE IN CANCER THERAPY
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The present invention relates to DNA-targeted 1,2,4-benzotriazine- 1,4-dioxides and related analogues, to their preparation, and to their use as hypoxia-selective drugs and radiosensitizers for cancer therapy, both alone or in combination with radiation and/or other anticancer drugs.
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