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The human histone demethylases of the KDM4 family have been related to diseases such as prostate and breast cancer. Majority of currently known inhibitors suffer from the low permeability and low selectivity between the enzyme isoforms. In this study, toxoflavin motif was used to design and synthesize new KDM4C inhibitors with improved biological activity and in vitro ADME properties. Inhibitors displayed good passive cellular permeability and metabolic stability. However, diminishing of redox liability and consequently non-specific influence on cell viability still remains a challenge.

Protein disulfide isomerase (PDI) is overexpressed in glioblastoma, the most aggressive form of brain cancer, and folds nascent proteins responsible for the progression and spread of the disease. Herein we describe a novel nanomolar PDI inhibitor, pyrimidotriazinedione 35G8, that is toxic in a panel of human glioblastoma cell lines. We performed a medium-throughput 20 000-compound screen of a diverse subset of 1 000 000 compounds to identify cytotoxic small molecules. Cytotoxic compounds were screened for PDI inhibition, and, from the screen, 35G8 emerged as the most cytotoxic inhibitor of PDI. Bromouridine labeling and sequencing (Bru-seq) of nascent RNA revealed that 35G8 induces nuclear factor-like 2 (Nrf2) antioxidant response, endoplasmic reticulum (ER) stress response, and autophagy. Specifically, 35G8 upregulated heme oxygenase 1 and solute carrier family 7 member 11 (SLC7A11) transcription and protein expression and repressed PDI target genes such as thioredoxin-interacting protein 1 (TXNIP) and early growth response 1 (EGR1). Interestingly, 35G8-induced cell death did not proceed via apoptosis or necrosis, but by a mixture of autophagy and ferroptosis. Cumulatively, our data demonstrate a mechanism for a novel PDI inhibitor as a chemical probe to validate PDI as a target for brain cancer.

The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure-activity relationship (SAR) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge.

The present disclosure is directed to pyrimidotriazinediones and pyrimidopyrimidinediones having a formula (I), (II), or (III), or a mixture or pharmaceutically acceptable salt or hydrate thereof, and to methods of treating cancer comprising administering

This paper describes a reliable and facile synthesis of 6-azapurines (1,5-dimethyl-1H imidazo[4,5-e][1,2,4]triazin-6(5H)-ones) by treatment of toxoflavins (7-azapteridines) with 10% aqueous sodium hydroxide at 5-25 °C along with a benzilic acid type rearr

The present invention concerns the compounds of formula (I) the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein n represents an integer being 0, 1 or 2; m represents an integer being 0 or 1; R1 represents C I -4alkyl; R2 represents C I -4alkyl; R3 represents CI-4alkyl; or R2 and R3 taken together with the carbon atom to which they are attached form a C3-8cycloalkyl or Het1 wherein said C3-8cycloalkyl or Het1 each independently may optionally be substituted with C1-4alkyloxycarbonyl; R4 represents halo or C I -4alkyloxy; R5 represents C 1-4alkyloxycarbonyl, -O-(mono- or di(C1-4alkyl)aminosulfonyl), CI-4alkyl substituted with one or where possible more substituent being selected from Het3 or NR6R7, C1-4alkyloxy substituted with one or where possible more substituents being selected from amino, Het4or NR8R9; R6 and R7are each independently selected from hydrogen, C I-4alkyl, C I-4alkyloxyC1-4alkyl, -Het5 or CI-4alkyl substituted with one or where possible more substituents being selected from hydroxy, or Het5; R8 and R9 are each independently selected from hydrogen, C,1-4alkyl, -Het7 or mono- or di(C 1-4alkyl)aminosulphonyl; Het3represents a heterocycle selected from piperidinyl, or piperazinyl wherein said monocyclic heterocycles each independently may optionally be substituted with one, or where possible two or three substituents each independently selected from hydroxy, aminosulfonyl, amino, mono-or di(C 1-4 alkyl)aminosulfonyl, hydroxyC 1-4alkyloxyC1-4alkyl or C1-4alkyloxy; Het4represents a heterocycle selected from morpholinyl, piperidinyl or piperazinyl wherein said monocyclic heterocycles each independently may optionally be substituted with one, or where possible two or three substituents each independently selected from C1-4alkyl, C1-4alkyloxycarbonyl or mono- or di(C1-4alkyl)aminosulfonyl; Het5 represents a heterocycle selected from pyridinyl or piperidinyl wherein said monocyclic heterocycles each independently may optionally be substituted with one, or where possible two or three substituents each independently selected from aminosulfonyl, or mono- or di(Cl-4alkyl)aminosulfonyl; Het7 represents piperidinyl.

Regioselective alkylations of reumycin derivatives under alkaline conditions with a dialkyl sulfate or alkyl halide in 1,4-dioxane or DMF to provide 1-alkyltoxoflavin or 8-alkylfervenulin derivatives of biological significance, are described. Namely, the primary and secondary alkylations of reumycin derivatives with appropriate dialkyl sulfates or alkyl bromides under alkaline conditions in 1,4-dioxane gave predominantly 1-alkyltoxoflavin derivatives, while the same alkylations in DMF instead of 1,4-dioxane gave predominantly 8-alkylfervenulin derivatives. In the case of tertiary alkylation, the reumycin derivative with 2-bromo-2-methylpropane in both solvents under the same conditions yielded only the 1-alkyltoxoflavin derivative. Moreover, the rates of transalkylation from 1-alkyltoxoflavin derivatives into nucleophiles, e.g. DMF and n-butylamine, are also described. That is, the toxoflavin derivatives possessing a primary alkyl group at the 1-position were easily dealkylated from the 1-position by heating with DMF, whereupon reumycin (i.e., 1-dealkyltoxoflavin, 8-dealkylfervenulin) derivatives were formed. In other words, transalkylation from the toxoflavin derivatives into DMF took place, However, the transalkylation of 1-alkyltoxoflavin derivatives possessing a secondary or tertiary alkyl group at the 1-position was not observed under such conditions. On the other hand, when heating 1-alkyltoxoflavin derivatives with n-butylamine in 1,4-dioxane, the transalkylations were more easily observed even in the case of 1-alkyltoxoflavin derivatives substituted by a tertiary alkyl group.

Regiospecific alkylation of reumycins (6) under alkaline conditions with a dialkyl sulfate or alkyl halide in dioxane and in DMF to provide 1-alkyltoxoflavins (5) of biological significance and 8-alkylfervenulins (7), respectively, is described.

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