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Page 1158 Brettrager et al. Cancer Drug Resist 2019;2:1153-63 I http://dx.doi.org/10.20517/cdr.2019.91

that inhibit Tdp1 catalysis in the low micromolar range while in silico-docking showed that each of these
[64]
six ligands binds Tdp1 in more than one location within the Tdp1 catalytic cavity [Figure 2] . Recently,
Lavrik and colleagues reported 15 monoterpenoid and adamantane fragments, which are able to inhibit
Tdp1 catalysis (0.86-4.08 μmol/L). Of these 15 fragments, 3,7-Dimethyloctyl adamantane-1-carboxylate in
[65]
combination with topotecan induced synergistic toxicity in A549 human lung carcinoma cells .

In addition to arrays of synthesized compounds, Lavrik and co-workers also utilized natural product
scaffolds in their search for potential Tdp1 catalytic inhibitors. They synthesized 29 aryliden- and
hetarylidenfuranone derivatives of usnic acid (a metabolite found in various lichens) that inhibit Tdp1
in the low nanomolar range. These compounds also induced A549 cytotoxicity with IC between 5 and
50
[66]
20 μmol/L and potentiated topotecan toxicity . Their subsequent synthesized hydrazinothiazole usnic
acid derivative (R,E)-2-acetyl-6-(2-(2-(4-bromobenzyliden)hydrazinyl)thiazol-4-yl)-3,7,9-trihydroxy-8,
9b-dimethyldibenzo[b,d]furan-1(9bH)-one is an effective Tdp1 catalytic inhibitor that increased topotecan
toxicity in a Lewis lung carcinoma cell model and was the first potential Tdp1 inhibitor to show, in
combination with topotecan, an anti-tumor and anti-metastatic effect in a mouse model of Lewis Lung
[67]
Carcinoma . This compound is now entering the preclinical trial phase. This group also used semi-
synthetic derivatives of bile acids and disaccharide nucleosides as a scaffold for the development of Tdp1
catalytic inhibitors [68,69] . The bile acid derivatives were tested by in silico-docking and in a catalytic assay
showing inhibition in the 300 to 500 nmol/L ranges with N-(2’’-(3’,5’-Di-tret-buthyl-4’-hydroxyphenyl)-
[69]
ethyl)-3a,12a-diacetoxy-5b-cholan-24-amide as the most promising compound . Disaccharide
nucleosides were explored as Tdp1 inhibitors following reports showing that pyrimidine disaccharide
derivatives including nicotinamide adenine dinucleotide (NAD )-mimetics catalytically inhibited
+
[70]
PARP1 and that PARP1 synthesized free PAR-monomers and -polymers that inhibit, for example, XPC-
[71]
RAD23B . Disaccharide nucleoside analogs inhibited wild type Tdp1 catalysis (low micromolar to high
[68]
nanomolar range) but interestingly not the Tdp1H493R-SCAN1-mutant . Why these compounds do not
show inhibition of the SCAN1-mutant enzyme is unknown and cannot be explained from the reported
experimental results. However, some of these compounds potentiated topotecan induced toxicity in
A549 cells and non-cancerous WI-38 (fibroblasts derived from lung tissue of a three months gestation
female fetus) cells, suggesting to induce “normal” cell toxicity. These active derivatives can be divided
into three classes: (1) (1’-2’)-glycosidic bond (2’-O-pentafuranosyl nucleosides); (2) b(1’-3’)-glycosidic
bond (3’-O-b-D-ribofuranosyl nucleosides); and (3) b(1’-5’)-glycosidic bond (5’-O-β-D-ribofuranosyl
nucleosides). They induce catalytic inhibition in the low micromolar to high nanomolar range, but need
[68]
further development . Quinn and co-workers exploited 3,4-dimethoxyphenol-1-β-D-(6’-O-galloyl)
glucopyranoside and 3-(4-hydroxy-3-methoxyphenyl)propane-1,2-diol2-β-D-(6-O-galloyl) glucopyranoside
from Macropteranthes leichhardtii, and achyrodimer F from the teleomorphic fungus family Cortinariaceae.
[74]
Both compounds inhibit Tdp1 in the low micromolar range [72,73] . Takagi et al. isolated JBIR21 from an
unidentified anamorphic fungus RF-13305 culture that showed catalytic inhibition with IC of 18 μmol/L and
50
induced growth inhibition of cervical carcinoma HeLa cells, malignant mesothelioma NCI-H2052 cells,
colon adenocarcinoma HT-29 cells, and lymphoblastoid namalva cells with an IC range of 3.5-3 μmol/L.
50
JBIR21 also showed an antitumor effect in a HT-29 xenograft model (treatment-to-control ratio of 0.51)
without noticeable toxicity or other adverse effects, suggesting that JBIR21 forms a highly potential scaffold
for further development of a clinically applicable compound. Figure 3 shows examples of structures of
potential Tdp1 inhibitors discussed above.

CONCLUSION
Over the last two decades, the development of Tdp1 catalytic inhibitors has produced active compounds
that showed a high potential to be tested in (pre-)clinical trials. Although these compounds were originally
selected for their ability to inhibit Tdp1 catalysis and modeled-docking of the compounds into the Tdp1
catalytic pocket, the more current and promising compounds were tested in combination with DNA