New Hybrid Compounds Combining Fragments of Usnic Acid and Monoterpenoids for Effective Tyrosyl-DNA Phosphodiesterase 1 Inhibition

Usnic acid (UA) is a secondary metabolite of lichens that exhibits wide range biological activities. Previously, we found UA derivatives are effective inhibitors tyrosyl-DNA phosphodiesterase 1 (TDP1). It can remove covalent complex DNA-topoisomerase (TOP1) stabilized by the TOP1 inhibitor topotecan, neutralizing effect drugs. TDP1 removes damage at 3′ end DNA caused other anticancer agents. Thus, promising therapeutic target for development drug combinations with as well drugs cancer treatment. Ten new enamino variation in terpene fragment and substituent backbone were synthesized tested inhibitors. Four compounds, 11a-d, had IC50 values 0.23–0.40 μM range. Molecular modelling showed relatively short aliphatic chains, fit to important binding domains. The intrinsic cytotoxicity 11a-d was on two human cell lines. compounds low CC50 ≥ 60 both 11a 11c high inhibition efficacy cytotoxicity, they enhanced topotecan’s cancerous HeLa cells but reduced it non-cancerous HEK293A cells. This “protective” from topotecan requires further investigation.