Rational design, synthesis and biological profiling of new KDM4C inhibitors

Emerging roles of cystathionine β-synthase in various forms of cancer

“…First of all, toxoflavin not only inhibits CBS-derived H 2 S signals, but, with almost comparable potency, it also inhibits H 2 S signals from chemical H 2 S generators (“H 2 S donors”) suggesting a combined CBS inhibitory and H 2 S decomposing/scavenging mode of action [ 167 ]. Second, toxoflavin is known to have several molecular targets unrelated to CBS or H 2 S, including inhibition of sirtuins, inhibition of KDM4A (lysine demethylase 4A), inhibition of the protein-protein interaction between T cell factor 4 (Tcf4) and β-catenin, inhibition of protein disulfide isomerase, inhibition of tyrosyl-DNA phosphodiesterase II, as well as a significant redox activity that can yield the generation of various pro-oxidant species in biological systems [ [182] , [183] , [184] , [185] , [186] , [187] , [188] , [189] ]. Third, toxoflavin – most likely due to the combination of the above actions – is a known cytotoxic compound, which inhibits the mitochondrial electron transport chain, suppresses cell respiration and exerts antiproliferative and cytotoxic effects in various cell types including several cancer cell lines [ 111 , 167 , [182] , [183] , [184] , [185] , [186] , [187] , [188] , [189] ].…”

Construction of Trisubstituted Hydrazones via Base-Mediated Cascade Condensation N-Alkylation

“…The key intermediate 6-(2-(4-methoxybenzylidene)-1-methylhydrazinyl)-3-methyldihydropyrimidine-2,4­(1 H ,3 H )-dione ( 102d ) could be obtained in high yield under the standard reaction conditions. Furthermore, the KDM4C inhibitor toxoflavin was formed in an acceptable yield via the tandem condensation N -alkylation reaction in two steps with 102d as the substrate …”

The emerging roles of lysine-specific demethylase 4A in cancer: Implications in tumorigenesis and therapeutic opportunities

“…To solve this drawback of compound 58, a set of C3 derivatives of compound 58 were designed and synthesized, and two of them (compounds 59 and 60) showed improved KDM4 inhibitory activity, cell permeability, and metabolic stability. 149 Purpurogallin (compound 61), a natural product with a benzotropolone scaffold and potential anticancer activity, was found to have inhibitory activity against KDM4s. 150 Further optimization showed that the introduction of a carboxylic acid moiety at the C4 position of the benzotropolone scaffold (compounds 62 and 63) and a halogen group in the benzene nucleus could increase the activity of compound 61, but the carboxylic acid in these optimized compounds reduced their cell permeability, while the replacement of the halogen with a phenol group could increase the cell permeability of compound 61 and inhibit the proliferation of several cancer cells.…”