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1-Iodonaphthalene-2,4-diamines in trifluoroacetic acid/chloroform give stable Wheland-like tetrahedral cationic species observable by NMR, through an initial intramolecular protonation. Dynamic equilibria allow proton-deuterium exchange of aromatic protons and provide a mechanism for deiodination of 1-iodonaphthalene-2,4-diamines. The Royal Society of Chemistry.

Provided herein are isoquinolidinobenzodiazepine (IQB)-1(chloromethyl)-2,3-dihydro-1H-benzo[e]indole (CBI) dimers, antibody-drug conjugates comprising them and methods of use for killing cells and treating disease.

Basicity constants, pKa, for a wide range of mono-protonated diaminobenzenes and diaminonaphthalenes, including dimethylamino derivatives were for the first time uniformly measured in 20% aqueous ethanol (29 compounds) and 80% aqueous dioxane (39 compounds) spanning from aniline to 1,8-bis(dimethylamino)naphthalene (‘proton sponge’). The dioxane system proved to be more versatile and because of better solubility of N-alkylated polyaminoarenes allowed to add to the same scale some superbasic bis(dialkylamino)-, tetrakis(dialkylamino)-, and hexakis(dialkylamino)naphthalenes, thus extending the scale for almost 10 pKa units, revealing possible limits of basicity changes in aromatic amines. The basicity of reference bases, pyridine and triethylamine, was also measured in these solvent systems. A group of N-alkylated compounds was found to be less basic in aqueous dioxane when compared with their NH2-analogs. This anomaly was not observed in aqueous ethanol. Other basicity trends and correlations between different basicity scales were also discussed. Copyright

Activation of the transcription factor Nrf2 has been posited to be a promising therapeutic strategy in a number of inflammatory and oxidative stress diseases due to its regulation of detoxifying enzymes. In this work, we have developed a comprehensive structure-activity relationship around a known, naphthalene-based non-electrophilic activator of Nrf2, and we report highly potent non-electrophilic activators of Nrf2. Computational docking analysis of a subset of the compound series demonstrates the importance of water molecule displacement for affinity, and the X-ray structure of di-amide 12e supports the computational analysis. One of the best compounds, acid 16b, has an IC50 of 61 nM in a fluorescence anisotropy assay and a Kd of 120 nM in a surface plasmon resonance assay. Additionally, we demonstrate that the ethyl ester of 16b is an efficacious inducer of Nrf2 target genes, exhibiting ex vivo efficacy similar to the well-known electrophilic activator, sulforaphane.

Abstract Cyclopropabenzaindoles (CBIs) are exquisitely potent cytotoxins which bind and alkylate in the minor groove of DNA. They are not selective for cancer cells, so prodrugs are required. CBIs can be formed at physiological pH by Winstein cyclisation of 1-chloromethyl-3-substituted-5-hydroxy-2,3-dihydrobenzo[e]indoles (5-OH-seco-CBIs). Corresponding 5-NH2-seco-CBIs should also undergo Winstein cyclisation similarly. A key triply orthogonally protected intermediate on the route to 5-NH2-seco-CBIs has been synthesised, via selective monotrifluoroacetylation of naphthalene-1,3-diamine, Boc protection, electrophilic iodination, selective allylation at the trifluoroacetamide and 5-exo radical ring-closure with TEMPO. This intermediate has potential for introduction of peptide prodrug masking units (deactivating the Winstein cyclisation and cytotoxicity), addition of diverse indole-amide side-chains (enhancing non-covalent binding prior to alkylation) and use of different leaving groups (replacing the usual chlorine, allowing tuning of the rate of Winstein cyclisation). This key intermediate was elaborated into a simple model 5-NH2-seco-CBI with a dimethylaminoethoxyindole side-chain. Conversion to a bio-reactive entity and the bioactivity of this system were confirmed through DNA-melting studies (ΔTm = 13°C) and cytotoxicity against LNCaP human prostate cancer cells (IC50 = 18 nM).

The present invention is directed to a compound of formula (I), methods for preparing these compounds, compositions, intermediates and derivatives thereof, and methods for treating inflammatory and serine protease mediated disorders.

The invention provides processes of preparing 3-substituted 1-(chloromethyl)-1,2-dihydro-3H-[ring fused indol-5-yl(amine-derived)] compounds of formula (I) and its analogues, or a physiologically functional derivative thereof, (I), wherein A and B togethe

A new short synthesis of 3-substituted 5-amino-1-(chloromethyl)-1,2-dihydro-3H-benzo[e]indoles from Martius Yellow is disclosed. The key steps of the synthesis were three efficient regioselective reactions (iodination, 5-exo-trig aryl radical-alkene cyclization and carboxylation).