Cardioprotective activity of dexrazoxane (ICRF-187), the only clinically approved drug against anthracycline-induced cardiotoxicity, has traditionally been attributed to its iron-chelating metabolite. However, recent experimental evidence suggested that the inhibition and/or depletion of topoisomerase IIβ (TOP2B) by dexrazoxane could be cardioprotective. Hence, we evaluated a series of dexrazoxane analogues and found that their cardioprotective activity strongly correlated with their interaction with TOP2B in cardiomyocytes, but was independent of their iron chelation ability. Very tight structure–activity relationships were demonstrated on stereoisomeric forms of 4,4′-(butane-2,3-diyl)bis(piperazine-2,6-dione). In contrast to its rac-form 12, meso-derivative 11 (ICRF-193) showed a favorable binding mode to topoisomerase II in silico, inhibited and depleted TOP2B in cardiomyocytes more efficiently than dexrazoxane, and showed the highest cardioprotective efficiency. Importantly, the observed ICRF-193 cardioprotection did not interfere with the antiproliferative activity of anthracycline. Hence, this study identifies ICRF-193 as the new lead compound in the development of efficient cardioprotective agents.
We report herein the discovery of 3,5-dinitrophenyl 1,2,4-triazoles with excellent and selective antimycobacterial activities against Mycobacterium tuberculosis strains, including clinically isolated multidrug-resistant strains. Thorough structure–activity relationship studies of 3,5-dinitrophenyl-containing 1,2,4-triazoles and their trifluoromethyl analogues revealed the key role of the position of the 3,5-dinitrophenyl fragment in the antitubercular efficiency. Among the prepared compounds, the highest in vitro antimycobacterial activities against M. tuberculosis H37Rv and against seven clinically isolated multidrug-resistant strains of M. tuberculosis were found with S-substituted 4-alkyl-5-(3,5-dinitrophenyl)-4H-1,2,4-triazole-3-thiols and their 3-nitro-5-(trifluoromethyl)phenyl analogues. The minimum inhibitory concentrations of these compounds reached 0.03 μM, which is superior to all the current first-line anti-tuberculosis drugs. Furthermore, almost all compounds with excellent antimycobacterial activities exhibited very low in vitro cytotoxicities against two proliferating mammalian cell lines. The docking study indicated that these compounds acted as the inhibitors of decaprenylphosphoryl-β-d-ribofuranose 2′-oxidase enzyme, which was experimentally confirmed by two independent radiolabeling experiments.
Abstract The bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 has been previously identified as a more potent analog of dexrazoxane (ICRF-187), a drug used in clinical practice against anthracycline cardiotoxicity. However, the poor aqueous solubility of ICRF-193 has precluded its further in vivo development as a cardioprotective agent. To overcome this issue, water-soluble prodrugs of ICRF-193 were prepared, their abilities to release ICRF-193 were investigated using a novel UHPLC-MS/MS assay, and their cytoprotective effects against anthracycline cardiotoxicity were tested in vitro in neonatal ventricular cardiomyocytes (NVCMs). Based on the obtained results, the bis(2-aminoacetoxymethyl)-type prodrug GK-667 was selected for advanced investigations due to its straightforward synthesis, sufficient solubility, low cytotoxicity and favorable ICRF-193 release. Upon administration of GK-667 to NVCMs, the released ICRF-193 penetrated well into the cells, reached sufficient intracellular concentrations and provided effective cytoprotection against anthracycline toxicity. The pharmacokinetics of the prodrug, ICRF-193 and its rings-opened metabolite was estimated in vivo after administration of GK-667 to rabbits. The plasma concentrations of ICRF-193 reached were found to be adequate to achieve cardioprotective effects in vivo. Hence, GK-667 was demonstrated to be a pharmaceutically acceptable prodrug of ICRF-193 and a promising drug candidate for further evaluation as a potential cardioprotectant against chronic anthracycline toxicity.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
Anthracyclines (ANT; e.g. doxorubicin, epirubucin or daunorubicin) are still indispensable part of modern chemotherapy regiments, despite of their well-known risk to induce cardiotoxicity leading even to heart failure. Thus, there is a need for effective cardioprotective strategy. Dexrazoxane (DEX) is the only clinically approved drug clearly effective both in clinics and clinically relevant experimental models. However, mechanisms of ANT-cardiotoxicity induction as well as DEX protection are not elucidated yet. Traditionally, ANTs have been believed to induce iron-catalyzed oxidative damage to cardiomyocytes. DEX should prevent this via its metal-chelating metabolite ADR-925, but direct evidence is missing. This paradigm has been recently challenged by topoisomerase IIβ (TOP2B) hypothesis of ANT cardiotoxicity. Hence, the aims of this study were to examine if ADR-925 is really the protective agent in DEX-afforded cardioprotection against daunorubicin (DAU) cardiotoxicity, along with the involvement of TOP2B interaction in this process.
Methods
Firstly, a pharmacokinetic studies were employed to set up ADR-925 doses ensuring same or even higher exposition of isolated rat neonatal ventricular cardiomyocytes (NVCMs) and rabbits' heart than after endogenously formed ADR-925 after DEX administration. Cardioprotective effectcs of DEX and ADR-925 (both in 10–100 uM) were compared using NVCMs treated with DAU (1.2 uM). In rabbits (n=50), cardiotoxicity was induced with DAU (3 mg/kg IV, once weekly/10 weeks). Prior to each DAU dose, ADR-925 was administered in two schedules (60 mg/kg 30-min-infusion alone or with additional the same s.c. bolus dose after 2 hrs). Cardiotoxicity markers, LV function and interaction with TOP2B were compared to effects of DEX pre-treatment (60 mg/kg IP).
Results
ADR-925 administration did not provide any meaningful cardioprotection against ANT cardiotoxicity in NVCMs. Regardless various administration schedule in rabbits, ADR-925 did not protect against DAU-induced mortality due to end-stage heart failure, decrease of LV function (dP/dtmax and LVFS), increase of cTnT levels, ANP or BNP mRNA as well as histopathological changes. This sharply contrasted with remarkable cardioprotective effects of DEX. Further experiments documented that the parent compound can inhibit and deplete TOP2B and prevent DAU-induced genotoxic damage in cardiomyocytes in contrast to ADR-925.
Conclusion
The present investigation strongly encourages the shift of mechanistic paradigm in clinically translatable cardioprotection against anthracycline cardiotoxicity - from metal chelation and protection from direct oxidative damage towards a TOP2B interaction. This study was supported by the Czech Science Foundation [Grant n. 18–08169S], the Charles University Research Program PROGRES [Grant n. Q40/5] and by the project EFSA-CDN (No. CZ.02.1.01/0.0/0.0/16_019/0000841) co-funded by ERDF.
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