Aminoadamantanes containing monoterpene-derived fragments as potent tyrosyl-DNA phosphodiesterase 1 inhibitors

Ponomarev, Konstantin; Суслов, Е. В.; Zakharenko, Alexandra L.; Zakharova, Olga D.; Rogachev, Artem D.; Корчагина, Д. В.; Zafar, Ayesha; Reynisson, Jóhannes; Nefedov, Andrey A.; Волчо, К. П.; Salakhutdinov, N. F.; Lavrik, Olga I.

doi:10.1016/j.bioorg.2017.12.005

Cited by 38 publications

(41 citation statements)

References 47 publications

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“…Bile acid amide 21 inhibited Tdp1 with IC 50 = 0.47 µM [44], whilst octahydro-2H-chromen-4-ol derivative 22 IC 50 was 1.24 µM (see Figure 2) [45]. It was also demonstrated that compounds combining adamantane/heteroadamantane and monoterpene fragments are active against Tdp1 [46,47]. Moderate activity at micromolar concentrations (IC 50~1 5 µM) was demonstrated for diazaadamantanes containing citronellal and citral moieties 23 and 24 ( Figure 2) [46].…”

Section: Introductionmentioning

confidence: 95%

The Development of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges

et al. 2019

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Eleven amide and thioamide derivatives with monoterpene and adamantine substituents were synthesised. They were tested for their activity against the tyrosyl-DNA phosphodiesterase 1 DNA (Tdp1) repair enzyme with the most potent compound 47a, having an IC50 value of 0.64 M. When tested in the A-549 lung adenocarcinoma cell line, no or very limited cytotoxic effect was observed for the ligands. However, in conjunction with topotecan, a well-established Topoisomerase 1 (Top1) poison in clinical use against cancer, derivative 46a was very cytotoxic at 5 M concentration, displaying strong synergism. This effect was only seen for 46a (IC50—3.3 M) albeit some other ligands had better IC50 values. Molecular modelling into the catalytic site of Tdp1 predicted plausible binding mode of 46a, effectively blocking access to the catalytic site.

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Section: Introductionmentioning

confidence: 95%

The Development of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges

et al. 2019

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“…Introducing an adamantyl moiety into biologically active molecules often decreases their toxicity and improves their therapeutic efficacy. These compounds inhibit Tdp1 at medium concentrations; their IС 50 values vary between 3.5 and 16 μM (Figure B, Table ). Monoterpenoid‐substituted aminoadamantane derivatives were found to enhance the cytotoxic effect of topotecan .…”

Section: Tdp1 Inhibitors: Sensitizing Tumors To Camptothecin and Its mentioning

confidence: 99%

“…These compounds inhibit Tdp1 at medium concentrations; their IС 50 values vary between 3.5 and 16 μM (Figure B, Table ). Monoterpenoid‐substituted aminoadamantane derivatives were found to enhance the cytotoxic effect of topotecan . This ability, combined with their own low toxicity, makes this class of compounds very promising for further in vivo studies.…”

Section: Tdp1 Inhibitors: Sensitizing Tumors To Camptothecin and Its mentioning

confidence: 99%

“…A, Structure of 7‐Hydroxycoumarin ( + )− 25c. B , Aminoadamantane 4a . Tdp1, tyrosyl‐DNA phosphodiesterase 1…”

Section: Tdp1 Inhibitors: Sensitizing Tumors To Camptothecin and Its mentioning

confidence: 99%

“…Monoterpenoid-substituted aminoadamantane derivatives were found to enhance the cytotoxic effect of topotecan. 76 This ability, combined with their own low toxicity, makes this class of compounds very promising for further in vivo studies.…”

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Dual DNA topoisomerase 1 and tyrosyl‐DNA phosphodiesterase 1 inhibition for improved anticancer activity

Zakharenko

Dyrkheeva

Lavrik

2019

Medicinal Research Reviews

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Tyrosyl‐DNA phosphodiesterase 1 (Tdp1) is a DNA repair enzyme that catalyzes the hydrolysis of the phosphodiester bond in the DNA‐topoisomerase 1 (Top1) covalent complex and repairs some other 3′‐end DNA adducts. Currently, Tdp1 functions as an important target in cancer drug design owing to its ability to break down various DNA adducts induced by chemotherapeutics. Tdp1 inhibitors may sensitize tumor cells to the action of Top1 poisons, thereby potentiating their effects. This mini‐review summarizes findings from studies reporting the combined inhibition of Top1 and Tdp1. Two different approaches have been considered for developing such drug precursors.

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Antiproliferative in Vitro Evaluation of Terpenic Amines Synthesized via a Rhodium‐catalyzed Hydroaminomethylation

Pérez Alonso,

Gibot,

Favier

et al. 2024

Chemistry & Biodiversity

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Terpene‐derived alkaloids show a variety of biological activities, including antioxidant, anti‐inflammatory, antimicrobial and cytotoxicity effects. In this work, homologated monoterpene amines have been prepared via a rhodium‐catalyzed hydroaminomethylation of biomass‐based alkenes, such as (R)‐limonene, linalool, myrcene and camphene, in combination with secondary amines of aliphatic and aromatic nature, namely morpholine and N‐methylaniline, leading to highly chemo‐ and regioselective processes. The as‐prepared amines were obtained in 50‐99% overall yields, and in vitro tested on a human colon cancer cell line (HCT‐116) to evaluate their cytotoxic potential. The lead compound of the series (3a) showed cytotoxicity in the micromolar range (IC50 52.46 µM) via the induction of cell death by apoptosis, paving the way towards further structure‐activity relationship studies.

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Aminoadamantanes containing monoterpene-derived fragments as potent tyrosyl-DNA phosphodiesterase 1 inhibitors

Cited by 38 publications

References 47 publications

The Development of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges

The Development of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors. Combination of Monoterpene and Adamantine Moieties via Amide or Thioamide Bridges

Dual DNA topoisomerase 1 and tyrosyl‐DNA phosphodiesterase 1 inhibition for improved anticancer activity

Antiproliferative in Vitro Evaluation of Terpenic Amines Synthesized via a Rhodium‐catalyzed Hydroaminomethylation

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