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Review
. 2023 Mar 17;24(6):5781.
doi: 10.3390/ijms24065781.

Natural Products and Their Derivatives as Inhibitors of the DNA Repair Enzyme Tyrosyl-DNA Phosphodiesterase 1

Alexandra L Zakharenko  1 , Olga A Luzina  2 , Arina A Chepanova  1 , Nadezhda S Dyrkheeva  1 , Nariman F Salakhutdinov  2 , Olga I Lavrik  1
Affiliations
Review

Natural Products and Their Derivatives as Inhibitors of the DNA Repair Enzyme Tyrosyl-DNA Phosphodiesterase 1

Alexandra L Zakharenko et al. Int J Mol Sci. .

Abstract

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an important repair enzyme that removes various covalent adducts from the 3' end of DNA. Particularly, covalent complexes of topoisomerase 1 (TOP1) with DNA stabilized by DNA damage or by various chemical agents are an examples of such adducts. Anticancer drugs such as the TOP1 poisons topotecan and irinotecan are responsible for the stabilization of these complexes. TDP1 neutralizes the effect of these anticancer drugs, eliminating the DNA adducts. Therefore, the inhibition of TDP1 can sensitize tumor cells to the action of TOP1 poisons. This review contains information about methods for determining the TDP1 activity, as well as describing the inhibitors of these enzyme derivatives of natural biologically active substances, such as aminoglycosides, nucleosides, polyphenolic compounds, and terpenoids. Data on the efficiency of combined inhibition of TOP1 and TDP1 in vitro and in vivo are presented.

Keywords: TDP1 inhibitors; TOP1 inhibitors; anticancer therapy; derivative; natural compound.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Crystal structure of the complex of TDP1 with the vanadate oxoanion VO43− [6]. (A) Red depicts a negative partial charge on the surface, blue depicts positive partial charge. The yellow V indicates the position of the vanadate residue in the active site. The DNA moiety extends above the active site, bound in the narrow, positively charged half of the substrate-binding groove. The peptide moiety is located below the active site, in a relatively neutral part of the wider substrate-binding cleft (Protein Data Bank (PDB) ID: 1NOP). (B) Detailed view of contacts between the substrate and amino acid residues in the catalytic site of TDP1. H-bonds between DNA and amino acid residues of TDP1 are indicated.
Figure 2
Figure 2
TDP1′s catalytic cycle. (A) The nucleophilic attack of the phosphodiester backbone by the imidazole N2 atom of H263. H493 donates a proton to the tyrosyl moiety of the leaving group. (B) The phosphohistidine covalent intermediate. (C) The second nucleophilic attack mediated by a water molecule activated by H493. (D) The emergence of the final 3′-phosphate product and free TDP1. (E) The SCAN1 mutation (H493R) leads to the accumulation of the TDP1–DNA intermediate and a fall in the TDP1 turnover rate.
Figure 3
Figure 3
Aminoglycosides as inhibitors of TDP1.
Figure 4
Figure 4
Nucleosides as inhibitors of TDP1.
Figure 5
Figure 5
Natural phenolic compounds that inhibit TDP1.
Figure 6
Figure 6
Natural polyphenols as TDP1 inhibitors.
Figure 7
Figure 7
Coumarin derivatives as inhibitors of TDP1.
Figure 8
Figure 8
Enamine derivatives of usnic acid as inhibitors of TDP1.
Figure 9
Figure 9
Cyano and furanone derivatives of usnic acid as inhibitors of TDP1.
Figure 10
Figure 10
Thiazole derivatives of usnic acid as inhibitors of TDP1.
Figure 11
Figure 11
Usnic acid thioether derivatives as TDP1 inhibitors.
Figure 12
Figure 12
Camptothecin and its analogs that are potential TDP1 inhibitors.
Figure 13
Figure 13
Berberine derivatives that are inhibitors of TDP1.
Figure 14
Figure 14
Monoterpenoid derivatives as inhibitors of TDP1.
Figure 15
Figure 15
Terpenyl adamantane compounds that are inhibitors of TDP1.
Figure 16
Figure 16
Dehydroabiethylamine derivatives that are inhibitors of TDP1.
Figure 17
Figure 17
TDP1 inhibitors based on steroid derivatives.
Figure 18
Figure 18
TDP1 inhibitors based on deoxycholic acid amides.
See this image and copyright information in PMC

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