4,6-Substituted-1,3,5-triazin-2(1H)-ones as monocyclic catalytic inhibitors of human DNA topoisomerase IIα targeting the ATP binding site

Pogorelčnik, Barbara; Janežič, Matej; Sosič, Izidor; Šolmajer, Tom; Perdih, Andrej

doi:10.1016/j.bmc.2015.06.049

Cited by 35 publications

(32 citation statements)

References 63 publications

(75 reference statements)

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“…The results are presented in the succeeding sections. Though we used etoposide ( 1 ) as a standard to contrast the effects between catalytic inhibitors and topoisomerase poisons, we verified these and the following assay conditions to be suitable for catalytic inhibitors in a previous study, using the known catalytic inhibitor ICRF‐193 …”

Section: Resultsmentioning

confidence: 77%

“…In this study we focused on catalytic inhibitors, specifically those targeting the ATP binding site of the htIIα ATPAse domain, as they do not, unlike topoisomerase poisons, transform the enzyme into a cellular toxin so the side effects could potentially be lessened. Our goal was not only to expand the chemical space with novel scaffolds but also to improve the inhibition activity in comparison to our previous studies, both of which we were able to accomplish. Nevertheless, the overall observed solubility properties of the discovered 1 H ‐indazole class and the presence of an ester group in some of the discovered compounds call for further optimization efforts.…”

Section: Discussionmentioning

confidence: 99%

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3‐substituted‐1H‐indazoles as Catalytic Inhibitors of the Human DNA Topoisomerase IIα

et al. 2017

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Catalytic inhibitors represent an attractive possibility of revisiting the established anticancer target human DNA topoisomerase IIa, taking advantage of the many different inhibition steps in its catalytic cycle. In this study we present our efforts to expand the chemical space of inhibitors of the human DNA topoisomerase IIa with a combination of in silico and in vitro methods. Using our previously reported compounds as a base, we constructed a ligand-based pharmacophore and conducted a virtual screening campaign. This led to the discovery of 1Hindazole inhibitors for which the SAR data was subsequently expanded. Additionally, several in vitro methods; cleavage assay, competitive cleavage assay, ATPase assay and microscale thermophoresis (MST) binding studies were employed to study the inhibitory mechanism, and it was confirmed that our compounds are catalytic inhibitors that bind to the ATPase domain. IC 50 values were in the lower micromolar range with multiple compounds showing stronger inhibitory activity than the established topoisomerase poison etoposide. Using in silico methods we proposed a binding mode and evaluated it using molecular dynamics simulation. 1H-indazoles represent a new versatile scaffold that could be utilized for further development of catalytic inhibitors of the human DNA topoisomerase IIa targetting the ATPase domain where ATP binding site is located.

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Section: Resultsmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

3‐substituted‐1H‐indazoles as Catalytic Inhibitors of the Human DNA Topoisomerase IIα

et al. 2017

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“…In turn, ruthenium complexes of triazine-based compounds obtained by Du and co-workers (Du et al 2014 ) exhibited dual inhibition of human topoI and topoII. There were also synthesized such derivatives, including 4-amino-6-phenylamino-1,3,5-triazines and 4,6-disubstituted 1,3,5-triazin-2(1 H )-ones, which catalytically and selectively inhibited htopoIIα through binding to its ATP-dependent subunit (Pogorelčnik et al 2014 , 2015 ). As can be seen from (Table 5 ) compounds 4a – l were characterized by particularly beneficial docking scores for the DNA-dependent subunits of both topoI and topoII enzyme models (1SEU, 3QX3).…”

Section: Resultsmentioning

confidence: 99%

Synthesis, molecular docking, ctDNA interaction, DFT calculation and evaluation of antiproliferative and anti-Toxoplasma gondii activities of 2,4-diaminotriazine-thiazole derivatives

et al. 2018

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Synthesis, characterization, and investigation of antiproliferative activities against human cancer cell lines (MV4-11, MCF-7, and A549) and Toxoplasma gondii parasite of twelve novel 2,4-diaminotriazine-thiazoles are presented. The toxicity of the compounds was studied at three different cell types, normal mouse fibroblast (Balb/3T3), mouse fibroblast (L929), and human VERO cells. The structures of novel compounds were determined using 1H and 13C NMR, FAB(+)-MS, and elemental analyses. Among the derivatives, 4a–k showed very high activity against MV4-11 cell line with IC50 values between 1.13 and 3.21 µg/ml. Additionally, the cytotoxic activity of compounds 4a–k against normal mouse fibroblast Balb/3T3 cells is about 20–100 times lower than against cancer cell lines. According to our results, compounds 4a, 4b, 4d, and 4i have very strong activity against human breast carcinoma MCF-7, with IC50 values from 3.18 to 4.28 µg/ml. Moreover, diaminotriazines 4a–l showed significant anti-Toxoplasma gondii activity, with IC50 values 9–68 times lower than those observed for sulfadiazine. Molecular docking studies indicated DNA-binding site of hTopoI and hTopoII as possible anticancer targets and purine nucleoside phosphorylase as possible anti-toxoplasmosis target. Our UV–Vis spectroscopic results indicate also that diaminotriazine-thiazoles tends to interact with DNA by intercalation. Additionally, the structure and the interaction and binding energies of a model complex formed by compound 4a and two thymine molecules are investigated using quantum mechanical methods.

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“…Moreover, experimental findings can provide clues to the composition of the molecular target for mono-alkylating (2-chloroethyl) triazine derivatives. In the case of 2,4,6-triamino-1,3,5-triazine derivatives with various amino substituents, the proposed mechanism of action represents an interaction with the active cleft of ATPase, DNA topoisomerase IIα or p21-activated kinase 4 [ 19 , 20 , 21 ]. Considering that the suggested activity of 2,4,6-triamine-1,3,5-triazine derivatives is associated in most cases with enzymes/receptors crucial for building blocks of nucleic acids or energy carriers also containing a purine moiety, it is suspected that the 2,4,6-triamine-1,3,5-triazine core may mimic this heterocyclic ring.…”

Section: Introductionmentioning

confidence: 99%

Towards Intelligent Drug Design System: Application of Artificial Dipeptide Receptor Library in QSAR-Oriented Studies

et al. 2018

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The pharmacophore properties of a new series of potential purinoreceptor (P2X) inhibitors determined using a coupled neural network and the partial least squares method with iterative variable elimination (IVE-PLS) are presented in a ligand-based comparative study of the molecular surface by comparative molecular surface analysis (CoMSA). Moreover, we focused on the interpretation of noticeable variations in the potential selectiveness of interactions of individual inhibitor-receptors due to their physicochemical properties; therefore, the library of artificial dipeptide receptors (ADP) was designed and examined. The resulting library response to individual inhibitors was arranged in the array, preprocessed and transformed by the principal component analysis (PCA) and PLS procedures. A dominant absolute contribution to PC1 of the Glu attached to heptanoic gating acid and Phe bonded to the linker m-phenylenediamine/triazine scaffold was revealed by the PCA. The IVE-PLS procedure indicated the receptor systems with predominant Pro bonded to the linker and Glu, Gln, Cys and Val directly attached to the gating acid. The proposed comprehensive ligand-based and simplified structure-based methodology allows the in-depth study of the performance of peptide receptors against the tested set of compounds.

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4,6-Substituted-1,3,5-triazin-2(1H)-ones as monocyclic catalytic inhibitors of human DNA topoisomerase IIα targeting the ATP binding site

Cited by 35 publications

References 63 publications

3‐substituted‐1H‐indazoles as Catalytic Inhibitors of the Human DNA Topoisomerase IIα

3‐substituted‐1H‐indazoles as Catalytic Inhibitors of the Human DNA Topoisomerase IIα

Synthesis, molecular docking, ctDNA interaction, DFT calculation and evaluation of antiproliferative and anti-Toxoplasma gondii activities of 2,4-diaminotriazine-thiazole derivatives

Towards Intelligent Drug Design System: Application of Artificial Dipeptide Receptor Library in QSAR-Oriented Studies

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