Work

(±)-2-Cyclohexyl-5-methoxy-2H-chromene, a Synthetic 5-Methoxyflavone Derivative, Is a Selective DNA Polymerase-β Inhibitor with Neuroprotective Activity against β-Amyloid Toxicity

Year: 2025

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide DNA polymerase-β (DNA pol-β) plays a critical role in β-amyloid-induced neurodegeneration by mediating aberrant DNA replication in postmitotic neurons. In previous work, we demonstrated that 5-methoxyflavone inhibits DNA pol-β, though computational analyses suggested potential binding to the primase p58 subunit. Through molecular modeling, here, we designed ( S )-2-cyclohexyl-5-methoxy-2 H -chromene ( S -chromene), a novel flavone-derived inhibitor exhibiting strong electrostatic complementarity with DNA pol-β but weak interaction with primase p58, suggesting enhanced selectivity. ( R )-2-cyclohexyl-5-methoxy-2 H -chromene ( R -chromene) exhibited indistinguishable binding properties from S -chromene. The compound was obtained as a racemic mixture (chromene). Since the separated enantiomers were unstable, all biological assays used the racemate. DNA polymerase activity assay confirmed that chromene inhibited selectively DNA pol-β without affecting the primase/DNA pol-α complex activity. Also, the compound amplified methylmethanesulfonate toxicity in wild-type but not DNA pol-β-null fibroblasts, validating target-engagement. In cultured neurons, chromene effectively prevented β-amyloid-induced DNA replication and apoptosis. Ours is the first demonstration of a chromene acting as a selective DNA pol-β inhibitor endowed with a unique mechanism of neuroprotection.

Source: ACS Chemical Neuroscience

DOI: 10.1021/acschemneuro.5c00712