- Inhibition of topoisomerase II by ICRF-193, the meso isomer of 2,3-bis(2,6-dioxopiperazin-4-yl)butane: Critical dependence on 2,3-butanediyl linker absolute configuration
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The bis(2,6-dioxopiperazine)s are a structurally and mechanistically unique class of topoisomerase II inhibitors that do not bind DNA and that do not stabilize topoisomerase II-DNA strand passing intermediates ("cleavable complexes"). The most effective topoisomerase II inhibitor in the bis(2,6-dioxopiperazine) series is ICRF-193 (meso or S*, R* isomer), with a meso 2,3-butanediyl linker connecting the dioxopiperazine rings. The two enantiomeric diastereomers, (R,R) and (S,S), of ICRF-193 possessing the two optically active 2,3-butanediyl linkers have been prepared from their respective optically pure 2,4-diaminobutanes via 2,3-diaminobutane-N,N,N′,N′-tetraacetic acid, esterification, and imide formation. Both in vivo and in vitro assays for catalytic inhibition of topoisomerase II were employed to show that the (S,S)-and (R,R)-isomers are almost inactive as topoisomerase II inhibitors. The data indicate that the meso stereochemistry of the alkanediyl linker is crucial for activity and provides additional evidence that the cytotoxicity of the bis(2,6-dioxopiperazine)s is due to their ability to inhibit topoisomerase II. Copyright
- Snapka, Robert M.,Woo, Sung Ho,Blokhin, Andrei V.,Witiak, Donald T.
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- Structure-Activity Relationship Study of Dexrazoxane Analogues Reveals ICRF-193 as the Most Potent Bisdioxopiperazine against Anthracycline Toxicity to Cardiomyocytes Due to Its Strong Topoisomerase IIβ Interactions
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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.
- Jirkovská, Anna,Karabanovich, Galina,Kube?, Jan,Skalická, Veronika,Melnikova, Iuliia,Korábe?ny, Jan,Ku?era, Tomá?,Jirkovsky, Eduard,Nováková, Lucie,Bavlovi? Piská?ková, Hana,?koda, Josef,?těrba, Martin,Austin, Caroline A.,?im?nek, Tomá?,Roh, Jaroslav
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p. 3997 - 4019
(2021/05/04)
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- Pharmaceutical compositions
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Compounds of formula II: wherein n is 0, 1 or 2, R1, R2, R3 and R4 are each separately selected from hydrogen, unsubstituted acyclic aliphatic hydrocarbon groups having a maximum of six carbon atoms and C1 6 alkyl groups substituted by a hydroxy group or a C1 6 alkoxy group, or one of R1 and R2 and one of R3 and R4 is hydrogen and the others are a trimethylene, tetramethylene or pentamethylene bridging group, and R5 as hydrogen or an unsubstituted acyclic aliphatic hydrocarbon group having a maximum of six carbon atoms, but with the provisos that (a) when n is 0 the combinations R1 = R2 = R3 = R4 = R5 = H and R1 = R2 = R3 = R5 = H, R4 = methyl are excluded, and (b) when n is 0, R1, R3 and R5 are each hydrogen, and each of R2 and R4 is other than hydrogen the compound is in other than the mesoor erythroconfiguration, or a salt thereof formed with a physiologically acceptable inorganic or organic acid, are of use in therapy, particularly as cardioprotective agents.
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- Bis diketopiperazines
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A pharmaceutical composition useful for aiding regression and palliation of cancer in mammals comprises a therapeutically effective amount of a compound of formula EQU1 wherein R1 and R2 are each separately selected from hydrogen and methyl or together represent an ethylene bridging group, with the proviso that when both of the groups R1 and R2 are methyl they are disposed in the meso configuration, or a non-toxic salt thereof with a physiologically acceptable inorganic or organic acid, in combination with a physiologically acceptable diluent or carrier.
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