Synthesis of dexrazoxane analogues and iron chelators

This research project started with the foundation of Charles University Research Centre (UNCE 204019/304019/2012): Centre for the Study of Toxic and Protective Effects of Drugs on Cardiovascular System. This center officialy finished in decemebr 2017, but the cooperation between the groups involved in this centre continues.               

Responsible person: Dr. Jaroslav Roh

Iron chelating agents have been long used to the treatment of the iron overload diseases. However, in recent years they have also been thouroughly studied for their other effects such as antiproliferative, cardio- and neuro-protective activities. Our research group has been engaged in a development of aroylhydrazone chelators as cardioprotective and antiproliferative agents. In the field of cardioprotection we  synthesize the derivatives of dexrazoxane and its metabolite ADR-925.

Synthesis of dexrazoxane analogues as potential cardioprotective agents

Anthracycline antineoplastic antibiotics such as doxorubicin or daunorubicin are widely used anticancer drugs. However, the administration of anthracyclines is connected with high risk of cardiotoxicity. Chronic anthracycline cardiotoxicity is characterized by dilated cardiomyopathy, with subsequent development of left ventricular contractile dysfunction and congestive heart failure. It is supposed that the complexation of anthracyclines with intracellular iron leads to the formation of reactive oxygen species, which causes serious tissue damage especially in myocardium. The only clinically used drug preventing anthracycline cardiotoxicity is dexrazoxane (DXZ). It was argued, that its mechanism of action involves iron-chelating properties of ADR-925, main metabolite of DXZ. However, recent studies showed that the mechanism of action is more complex and possibly involved the interaction of DXZ with various isoforms of topoisomerase II.

Schema                      

Daunorubicin                                               Dexrazoxane

Recent results

To date we prepared several analogues of dexrazoxane and ADR-925 and studied their cardioprotective efficiency in vitro on neonatal ventricular cardiomyocytes and in vivo in well-established model of chronic ANT cardiotoxicity in rabbits. First analogs of dexrazoxane (ES-5 and MK-15) as well as ADR-925 analogs (JR-159 and KH-TA4) did not protect heart against anthracycline cardiotoxicity (Figure 1).

A. Jirkovská-Vávrová et al., Toxicol. Res. 2015

Figure 1. Structures of DXZ analogues MK-15 and ES-5 and ADR-925 analogs JR-159 and KH-TA4

Another DXZ analogue, JR-311, showed significant cardioprotective activity in vitro. However, due to its low stability in aqueous media, this compound was not studied in vivo (Figure 2). Due to its synthesis, we developed a large-scale synthesis of piperazine-2,6-dione, a key fragment of DXZ structure (Figure 2).

J. Roh et al. Synthesis 2016; J.Bureš et al.Toxicology 2017

Figure 2. Large-scale synthesis of piperazine-2,6-dione and its use in the synthesis of JR-311

From the very beginning of our research efforts, we focused on the role of a metabolite ADR-925 in the cardioprotective effect of DXZ. We developed the alrge-scale method for the preparation of the racemic form of ADR-925 and prepared more than 150 g of this substance (Figure 3). This was then used in advanced in vivo experiments on the model of chronic ANT cardiotoxicity in rabbits. The result of this long-lasting study is the reversal of the traditional hypothesis about the efficacy of dexrazoxane through its chelating metabolite ADR-925. The first part of this study, which focuses on the pharmacokinetics of dexrazoxane and its metabolite, was published in 2018. The second part of the study, focusing on the pharmacodynamics of dexrazoxane and its metabolite ADR-925, has just been completed.

E. JIrkovský et al. JPET 2018

Figure 3. Large-scale synthesis of racemic form of ADR-925.

 

Synthesis of hydrazone and thiosemicarbazone-type iron chelators

The hypothesis about the effectiveness of the chelating metabolite ADR-925 has led to our greater interest in iron chelators as potential cardioprotective agents but also more generally as protectants against oxidative stress and finally as effective antiproliferative agents. Hence we deals with the synthesis of hydrazone-type iron chelators derived from salicylaldehyde isonicotinoyl hydrazone (SIH) as cytoprotective agents.

SIH

SIH

We are also involved in the research of thiosemicarbazone-type iron chelators as a potent antitumor agents. We prepared several semicarbazone and formamidrazone metabolites of these agents as a standards for pharmacokinetic studies.

In 2018, we prepared a series of 2,6-dihydroxybenzaldehyde analogues of SIH with increased hydrolytic stability and cytoprotective activity against oxidative stress compared to those of SIH. Compound JK-31 (2,6-dihydroxybenzaldehyde 4-chlorobenzohydrazone) showed the best cytoprotective efficiency among the studied compounds including SIH. This compound significantly protected H9c2 cardiomyoblast cells against oxidative stress induced by various pro-oxidants, such as hydrogen peroxide, tert-butyl hydroperoxide, paraquat, epinephrine, N-acetyl-p-benzoquinone imine (a toxic metabolite of paracetamol), and 6-hydroxydopamine.

H. Jansová et al. Chem. Res. Toxicol. 2018

Figure 4. 2,6-Dihydroxydihydroxybenzaldehyde analogues of SIH

 

© Charles University, Faculty of Pharmacy in Hradec Králové, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
Website information | Powered by Kentico