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Biological Activity

walrycin b is an inhibitor of walr [1].walrycin b is screened out from a chemical library. it is proved to be a selective walr inhibitor by measuring egfp fluorescence intensity. in this assay, it is found to strongly increase fluorescence intensity in strain jm109/pfi014 but has no significant effect on the strain jm109/pfi001. walrycin b shows effects on the expression of walr regulon genes in the in vivo assay. the addition of it lowers the expression of ydjm, yoch and yvce and increases the expression of yoeb and yjea rapidly. these effects caused by walrycin b are opposite with which caused by walr suggesting that walrycin b specifically affects the walk/walr system. since walk/walr plays a regulating role in cell wall metabolism and cell division in bacillus subtilis and staphylococcus aureus, walrycin b is found to cause cell death in both of them with strong mics through targeting walr [1].

references

[1] gotoh y, doi a, furuta e, dubrac s, ishizaki y, okada m, igarashi m, misawa n, yoshikawa h, okajima t, msadek t, utsumi r. novel antibacterial compounds specifically targeting the essential walr response regulator. j antibiot (tokyo). 2010 mar;63(3):127-34.

Upstream product

• 1448806-21-0 3-methyl-6-[methyl-[(E)-[4-(trifluoromethyl)phenyl]methyleneamino]amino]-1H-pyrimidine-2,4-dione 
• 4318-56-3 3-methyl-6-chlorouracil 
• 455-19-6 4-Trifluoromethylbenzaldehyde 
• 42747-84-2 3-methyl-6-(1-methylhydrazinyl)pyrimidine-2,4(1H,3H)-dione 

Relevant academic research and scientific papers

Toxoflavins and deazaflavins as the first reported selective small molecule inhibitors of tyrosyl-DNA phosphodiesterase II

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.