Research output: Contribution to journal › Article › peer-review
Usnic Acid Conjugates with Monoterpenoids as Potent Tyrosyl-DNA Phosphodiesterase 1 Inhibitors. / Luzina, Olga; Filimonov, Alexander; Zakharenko, Alexandra et al.
In: Journal of Natural Products, Vol. 83, No. 8, 28.08.2020, p. 2320-2329.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Usnic Acid Conjugates with Monoterpenoids as Potent Tyrosyl-DNA Phosphodiesterase 1 Inhibitors
AU - Luzina, Olga
AU - Filimonov, Alexander
AU - Zakharenko, Alexandra
AU - Chepanova, Arina
AU - Zakharova, Olga
AU - Ilina, Ekaterina
AU - Dyrkheeva, Nadezhda
AU - Likhatskaya, Galina
AU - Salakhutdinov, Nariman
AU - Lavrik, Olga
N1 - Publisher Copyright: Copyright © 2020 American Chemical Society and American Society of Pharmacognosy. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/8/28
Y1 - 2020/8/28
N2 - Hybrid molecules created from different pharmacophores of natural and synthetic equivalents are successfully used in pharmaceutical practice. One promising target for anticancer therapy is tyrosyl-DNA phosphodiesterase 1 (Tdp1) because it can repair DNA lesions caused by DNA-topoisomerase 1 (Top1) inhibitors, resulting in drug resistance. In this study, new hybrid compounds were synthesized by combining the pharmacophoric moiety of a set of natural compounds with inhibitory properties against Tdp1, particularly, phenolic usnic acid and a set of different monoterpenoid fragments. These fragments were connected through a hydrazinothiazole linker. The inhibitory properties of the new compounds mainly depended on the structure of the terpenoid moieties. The two most potent compounds, 9a and 9b, were synthesized from citral and citronellal, which contain acyclic fragments with IC50 values in the range of 10-16 nM. Some synthesized derivatives showed low cytotoxicity against HeLa cells and increased the effect of the Top1 inhibitor topotecan in vitro by three to seven times. These derivatives may be considered as potential agents for the development of anticancer therapies when combined with Top1 inhibitors.
AB - Hybrid molecules created from different pharmacophores of natural and synthetic equivalents are successfully used in pharmaceutical practice. One promising target for anticancer therapy is tyrosyl-DNA phosphodiesterase 1 (Tdp1) because it can repair DNA lesions caused by DNA-topoisomerase 1 (Top1) inhibitors, resulting in drug resistance. In this study, new hybrid compounds were synthesized by combining the pharmacophoric moiety of a set of natural compounds with inhibitory properties against Tdp1, particularly, phenolic usnic acid and a set of different monoterpenoid fragments. These fragments were connected through a hydrazinothiazole linker. The inhibitory properties of the new compounds mainly depended on the structure of the terpenoid moieties. The two most potent compounds, 9a and 9b, were synthesized from citral and citronellal, which contain acyclic fragments with IC50 values in the range of 10-16 nM. Some synthesized derivatives showed low cytotoxicity against HeLa cells and increased the effect of the Top1 inhibitor topotecan in vitro by three to seven times. These derivatives may be considered as potential agents for the development of anticancer therapies when combined with Top1 inhibitors.
KW - BIOLOGICAL-ACTIVITY
KW - NATURAL-PRODUCTS
KW - DERIVATIVES
KW - ANTICANCER
KW - ENAMINES
KW - ENHANCE
KW - TDP1
UR - http://www.scopus.com/inward/record.url?scp=85089825639&partnerID=8YFLogxK
U2 - 10.1021/acs.jnatprod.9b01089
DO - 10.1021/acs.jnatprod.9b01089
M3 - Article
C2 - 32786885
AN - SCOPUS:85089825639
VL - 83
SP - 2320
EP - 2329
JO - Journal of Natural Products
JF - Journal of Natural Products
SN - 0163-3864
IS - 8
ER -
ID: 25094429