- Synthesis, Identification, and Structure-Activity Relationship Analysis of GATA4 and NKX2-5 Protein-Protein Interaction Modulators
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Transcription factors GATA4 and NKX2-5 directly interact and synergistically activate several cardiac genes and stretch-induced cardiomyocyte hypertrophy. Previously, we identified phenylisoxazole carboxamide 1 as a hit compound, which inhibited the GATA4-NKX2-5 transcriptional synergy. Here, the chemical space around the molecular structure of 1 was explored by synthesizing and characterizing 220 derivatives and structurally related compounds. In addition to the synergistic transcriptional activation, selected compounds were evaluated for their effects on transcriptional activities of GATA4 and NKX2-5 individually as well as potential cytotoxicity. The structure-activity relationship (SAR) analysis revealed that the aromatic isoxazole substituent in the southern part regulates the inhibition of GATA4-NKX2-5 transcriptional synergy. Moreover, inhibition of GATA4 transcriptional activity correlated with the reduced cell viability. In summary, comprehensive SAR analysis accompanied by data analysis successfully identified potent and selective inhibitors of GATA4-NKX2-5 transcriptional synergy and revealed structural features important for it.
- Jumppanen, Mikael,Kinnunen, Sini M.,V?lim?ki, Mika J.,Talman, Virpi,Auno, Samuli,Bruun, Tanja,Boije Af Genn?s, Gustav,Xhaard, Henri,Aumüller, Ingo B.,Ruskoaho, Heikki,Yli-Kauhaluoma, Jari
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supporting information
p. 8284 - 8310
(2019/10/11)
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- Thioninium compounds and their use
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This invention pertains generally to processes, uses, methods and materials utilising particular diaminophenothiazinium compounds, specifically, ETC, DEMTC, DMETC, DEETC, MTZ, ETZ, MTI, MTI.HL, ETI, ETI.HL, MTN, and ETN. These compounds are useful as drugs, for example, in the treatment of tauopathies, such as Alzheimer's disease.
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Paragraph 0121; 0122
(2017/12/15)
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- INHIBITORS OF PROTEIN AGGREGATION
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The invention relates generally to the use of diaminophenothiazine compounds to inhibit or reverse the aggregation of synuclein, and for their use in the manufacture of medicaments for this purpose (e.g. for the treatment of Parkinson's Disease). Also provided are related methods of detecting or labelling of aggregated synuclein.
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Page/Page column 40
(2008/06/13)
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- METHODS OF CHEMICAL SYNTHESIS AND PURIFICATION OF DIAMINOPHENOTHIAZINIUM COMPOUNDS INCLUDING METHYLTHIONINIUM CHLORIDE (MTC)
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This invention pertains generally to the field of chemical synthesis and purification, and more specifically to methods of synthesizing and purifying certain 3,7 diamino-phenothiazin-5-ium compounds (referred to herein as "diaminophenothiazinium compounds") including Methythioninium Chloride (MTC) (also known as Methylene Blue). In one embodiment, the method comprises the steps of, in order: nitrosylation (NOS); nitrosyl reduction (NR); thiosulfonic acid formation (TSAF); oxidative coupling (OC); Cr(VI) reduction (CR); isolation and purification of zwitterionic intermediate (IAPOZI); ring closure (RC); chloride salt formation (CSF); one of: sulphide treatment (ST); dimethyldithiocarbamate treatment (DT); carbonate treatment (CT); ethylenediaminetetraacetic acid treatment (EDTAT); organic extraction (OE); and recrystallisation (RX). The present invention also pertains to the resulting (high purity) compounds, compositions comprising them (e.g., tablets, capsules), and their use in methods of inactivating pathogens, and methods of medical treatment and diagnosis, etc., for example, for tauopathies, Alzheimer's disease (AD), skin cancer, melanoma, viral diseases, bacterial diseases, or protozoal diseases.
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Page/Page column 83
(2010/10/20)
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- Aggregated dyes for radiation-sensitive elements
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A dispersion comprising an aqueous medium having dispersed therein an aggregated dye of the Formula (I): wherein X is oxygen or sulfur; R1-R4each independently represent an unsubstituted or substituted alkyl group, an unsubstituted or substituted aryl group or an unsubstituted or substituted heteroaryl group; L1, L2and L3each independently represent substituted or unsubstituted methine groups; M+represents a proton or an inorganic or organic cation; and n is 0, 1, 2 or 3 and wherein the aggregated dye in the dispersion has an absorption halfbandwidth of less than 55 nm.
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- Process for preparing N,N-disubstituted p-phenylenediamine derivatives
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A process for preparing an N,N-disubstituted p-phenylenediamine of the formula STR1 wherein R1 is alkyl of 1-6 C atoms, R2 is alkyl of 1-6 C atoms or alkyl of 1-6 C atoms which is substituted by OH, lower alkoxy, a sulfo group or an alkylsulfonamido group and R3 is hydrogen or lower alkyl or an acid addition salt thereof, comprises adding an alkyl nitrite, as a nitrosation agent, to an aqueous, acid suspension of the corresponding aniline derivative of the formula STR2 thereby forming the corresponding N,N-disubstituted p-nitroso-aniline, and subsequently hydrogenating the latter without isolation thereof from the reaction mixture.
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