TY - JOUR

T1 - Inhibitory Effect of New Semisynthetic Usnic Acid Derivatives on Human Tyrosyl-DNA Phosphodiesterase 1

AU - Dyrkheeva, Nadezhda

AU - Luzina, Olga

AU - Filimonov, Aleksandr

AU - Zakharova, Olga

AU - Ilina, Ekaterina

AU - Zakharenko, Alexandra

AU - Kuprushkin, Maxim

AU - Nilov, Dmitry

AU - Gushchina, Irina

AU - Švedas, Vytas

AU - Salakhutdinov, Nariman

AU - Lavrik, Olga

N1 - Publisher Copyright: © 2019 Georg Thieme Verlag. All rights reserved.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Usnic acid, a lichen secondary metabolite produced by a whole number of lichens, has attracted the interest of researchers owing to its broad range of biological activity, including antiviral, antibiotic, anticancer properties, and it possessing a certain toxicity. The synthesis of new usnic acid derivatives and the investigation of their biological activity may lead to the discovery of compounds with better pharmacological and toxicity profiles. In this context, a series of new usnic acid derivatives comprising a terpenoid moiety were synthesized, and their ability to inhibit the catalytic activity of the human DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 was investigated. The most potent compounds (15a, 15b, 15g, and 16a, 16b, 16g) had IC 50 values in the range of 0.33-2.7 μM. The inhibitory properties were mainly dependent on the flexibility and length of the terpenoid moiety, but not strongly dependent on the configuration of the asymmetric centers. The synthesized derivatives showed low cytotoxicity against human cell lines in an MTT assay. They could be used as a basis for the development of more effective anticancer therapies when combined with topoisomerase 1 inhibitors.

AB - Usnic acid, a lichen secondary metabolite produced by a whole number of lichens, has attracted the interest of researchers owing to its broad range of biological activity, including antiviral, antibiotic, anticancer properties, and it possessing a certain toxicity. The synthesis of new usnic acid derivatives and the investigation of their biological activity may lead to the discovery of compounds with better pharmacological and toxicity profiles. In this context, a series of new usnic acid derivatives comprising a terpenoid moiety were synthesized, and their ability to inhibit the catalytic activity of the human DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 was investigated. The most potent compounds (15a, 15b, 15g, and 16a, 16b, 16g) had IC 50 values in the range of 0.33-2.7 μM. The inhibitory properties were mainly dependent on the flexibility and length of the terpenoid moiety, but not strongly dependent on the configuration of the asymmetric centers. The synthesized derivatives showed low cytotoxicity against human cell lines in an MTT assay. They could be used as a basis for the development of more effective anticancer therapies when combined with topoisomerase 1 inhibitors.

KW - Tdp1 inhibitor

KW - terpenophenols

KW - tyrosyl-DNA phosphodiesterase 1

KW - Usnea barbata

KW - Usneaceae

KW - usnic acid

KW - Phosphoric Diester Hydrolases/drug effects

KW - Escherichia coli

KW - Humans

KW - MCF-7 Cells/drug effects

KW - HEK293 Cells/drug effects

KW - Benzofurans/chemical synthesis

KW - Cell Line, Tumor/drug effects

KW - Microorganisms, Genetically-Modified

KW - Phosphodiesterase Inhibitors/chemistry

KW - Molecular Docking Simulation

KW - REPAIR

KW - BIOLOGICAL EVALUATION

KW - ASSAY

KW - CRYSTAL-STRUCTURE

KW - VANADATE

KW - I INHIBITORS

KW - ANTICANCER

KW - GENE

KW - TDP1

KW - BINDING

UR - http://www.scopus.com/inward/record.url?scp=85060375336&partnerID=8YFLogxK

U2 - 10.1055/a-0681-7069

DO - 10.1055/a-0681-7069

M3 - Article

C2 - 30142660

AN - SCOPUS:85060375336

VL - 85

SP - 103

EP - 111

JO - Planta Medica

JF - Planta Medica

SN - 0032-0943

IS - 2

ER -