Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy

Khomenko, T. M.; Zakharenko, Alexandra L.; Chepanova, Arina A; Ilina, E. S.; Zakharova, Olga D.; Каледин, В. И.; Николин, В. П.; Попова, Н. А.; Корчагина, Д. В.; Reynisson, Jóhannes; Raina, Chand; Ayine-Tora, Daniel Moscoh; Patel, Jinal; Leung, Ivanhoe K. H.; Волчо, К. П.; Salakhutdinov, N. F.; Lavrik, Olga I.

doi:10.3390/ijms21010126

Cited by 38 publications

(44 citation statements)

References 79 publications

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“…Some of these derivatives exhibit analgesic, antiviral, neuroprotective, and antitumor properties [ 14 ]. Moreover, new classes of TDP1 inhibitors with submicromolar half maximal inhibitory concentration (IC 50 ) values have been developed that contain monoterpene moieties; for example, coumarin [ 16 ], 4-arylcoumarin [ 17 ], and adamantane [ 18 , 19 , 20 , 21 ] derivatives as well as octahydro-2 H -chromenes 3 (see Figure 1 ) synthesized from p -menthane monoterpenoid (-)-isopulegol [ 22 ]. Their ability to enhance the Tpc cytotoxic potential was demonstrated for several of these derivatives.…”

Section: Introductionmentioning

confidence: 99%

“…Their ability to enhance the Tpc cytotoxic potential was demonstrated for several of these derivatives. For example, 7-hydroxycoumarin derivative 4 ( Figure 1 ) with a pinene-type fragment reduced the CC 50 (median cytotoxic concentration causing 50% cell death) of camptothecin eight-fold for the human breast adenocarcinoma cell line MCF-7 [ 16 ] while the hybrid molecule 5 , comprising of (4-fluorophenyl)-coumarin and geraniol moieties, showed a significant increase in the antitumor effect of Tpc on Krebs-2 ascites in an in vivo tumor model [ 17 ]. Among the adamantane derivatives, strong synergism was found for 6 and 7 ( Figure 1 ), both containing the acyclic monoterpene substituents, when lung adenocarcinoma cells A549 were treated in combination with Tpc [ 18 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1

et al. 2020

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Two novel structural types of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors with hexahydroisobenzofuran 11 and 3-oxabicyclo [3.3.1]nonane 12 scaffolds were discovered. These monoterpene-derived compounds were synthesized through preliminary isomerization of (+)-3-carene to (+)-2-carene followed by reaction with heteroaromatic aldehydes. All the compounds inhibit the TDP1 enzyme at micro- and submicromolar levels, with the most potent compound having an IC50 value of 0.65 μM. TDP1 is an important DNA repair enzyme and a promising target for the development of new chemosensitizing agents. A panel of isogenic clones of the HEK293FT cell line knockout for the TDP1 gene was created using the CRISPR-Cas9 system. Cytotoxic effects of topotecan (Tpc) and non-cytotoxic compounds of the new structures were investigated separately and jointly in the TDP1 gene knockout cells. For two TDP1 inhibitors, 11h and 12k, a synergistic effect was observed with Tpc in the HEK293FT cells but was not found in TDP1 −/− cells. Thus, it is likely that the synergistic effect is caused by inhibition of TDP1. Synergy was also found for 11h in other cancer cell lines. Thus, sensitizing cancer cells using a non-cytotoxic drug can enhance the efficacy of currently used pharmaceuticals and, concomitantly, reduce toxic side effects.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1

et al. 2020

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“…Also, natural products of various types have been found to inhibit Tdp1, including derivatives of bile acids 4 [ 10 , 11 ], of lichen metabolite usnic acid 5a , b [ 12 , 13 ] and 6 [ 14 ], monoterpenoid derivatives 7 [ 15 , 16 , 17 , 18 ] and oxinitidine 8 [ 19 ] with inhibitory activity in the micro- or submicromolar range. Importantly, the hydrazinothiazole derivative of usnic acid 5a [ 13 , 20 ] and monoterpene-substituted 4-arylcoumarin 7a [ 21 ] significantly increased topotecan efficacy in vivo.…”

Section: Introductionmentioning

confidence: 99%

The First Berberine-Based Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), an Important DNA Repair Enzyme

Gladkova

Nechepurenko

Bredikhin

et al. 2020

IJMS

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A series of berberine and tetrahydroberberine sulfonate derivatives were prepared and tested against the tyrosyl-DNA phosphodiesterase 1 (Tdp1) DNA-repair enzyme. The berberine derivatives inhibit the Tdp1 enzyme in the low micromolar range; this is the first reported berberine based Tdp1 inhibitor. A structure–activity relationship analysis revealed the importance of bromine substitution in the 12-position on the tetrahydroberberine scaffold. Furthermore, it was shown that the addition of a sulfonate group containing a polyfluoroaromatic moiety at position 9 leads to increased potency, while most of the derivatives containing an alkyl fragment at the same position were not active. According to the molecular modeling, the bromine atom in position 12 forms a hydrogen bond to histidine 493, a key catalytic residue. The cytotoxic effect of topotecan, a clinically important topoisomerase 1 inhibitor, was doubled in the cervical cancer HeLa cell line by derivatives 11g and 12g; both displayed low toxicity without topotecan. Derivatives 11g and 12g can therefore be used for further development to sensitize the action of clinically relevant Topo1 inhibitors.

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“…As already mentioned, we have previously shown that various Tdp1 inhibitors enhanced the cytotoxic and antitumor effects of topotecan [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. In this work, we also tested the ability of the berberrubine sultones to sensitize cells to the action of topotecan.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, Tdp1 is a promising therapeutic target, and its inhibitors are expected to significantly synergize the effects of current anti-tumor therapies, including topoisomerase poisons and other DNA damaging agents. Indeed, it was found that combined treatment of tumor cells with Tdp1 inhibitors and anticancer drugs camptothecin or topotecan greatly increased the activity of these pharmaceuticals in in vitro [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ] and in vivo [ 29 , 30 ] experiments. Nevertheless, to the best of our knowledge, no Tdp1 inhibitors have reached human clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors

et al. 2021

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A new type of berberine derivatives was obtained by the reaction of berberrubine with aliphatic sulfonyl chlorides. The new polycyclic compounds have a sultone ring condensed to C and D rings of a protoberberine core. The reaction conditions were developed to facilitate the formation of sultones with high yields without by-product formation. Thus, it was shown that the order of addition of reagents affects the composition of the reaction products: when sulfochlorides are added to berberrubine, their corresponding 9-O-sulfonates are predominantly formed; when berberrubine is added to pre-generated sulfenes, sultones are the only products. The reaction was shown to proceed stereo-selectively and the cycle configuration was confirmed by 2D NMR spectroscopy. The inhibitory activity of the synthesized sultones and their 12-brominated analogs against the DNA-repair enzyme tyrosyl-DNA phosphodiesterase 1 (Tdp1), an important target for a potential antitumor therapy, was studied. All derivatives were active in the micromolar and submicromolar range, in contrast to the acyclic analogs and 9-O-sulfonates, which were inactive. The significance of the sultone cycle and bromine substituent in binding with the enzyme was confirmed using molecular modeling. The active inhibitors are mostly non-toxic to the HeLa cancer cell line, and several ligands show synergy with topotecan, a topoisomerase 1 poison in clinical use. Thus, novel berberine derivatives can be considered as candidates for adjuvant therapy against cancer.

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Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy

Cited by 38 publications

References 79 publications

Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1

Design, Synthesis, and Biological Investigation of Novel Classes of 3-Carene-Derived Potent Inhibitors of TDP1

The First Berberine-Based Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), an Important DNA Repair Enzyme

Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors

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