Multifunctional Radical Quenchers for the Treatment of Mitochondrial Disorders Exploration of the MRQ B Series Exploration of the MRQ B Series As noted in the attached summary of our studies on multifunctional radical quenchers (MRQs), we have carried out studies of compounds in three structural series. Most of the compounds that we have studied are in the MRQ A and MRQ C series, and these have been characterized largely for their effects on cultured Friedreichs ataxia lymphocytes and fibroblasts, as well as for their biochemical effects on mammalian mitochondria. As a consequence of these studies, which have been supported by the Friedreichs Ataxia Research Alliance (FARA), and using resources available within the Center for BioEnergetics, we have identified a compound in the MRQ A series which we feel is worthy of (pre)clinical development. This compound is currently being evaluated in a mouse model of Friedreichs ataxia, which lacks the mouse homologue of frataxin. Until recently, we had made very few MRQ B analogues due to our observation that these compounds were unstable metabolically when evaluated for cytoprotective effects in mitochondrial function. However, two recent findings have resolved this issue, and identified an unanticipated property of one MRQ B that underscores the potential of optimized MRQ B analogues to function in a superior fashion as mitochondrial therapeutic agents. As shown in Figure 4 of an attached manuscript (Arce et al. Analysis of the structural and mechanistic factors in antioxidants that preserve mitochondrial function and confer cytoprotection, Bioorg. Med. Chem. (2012), doi: http://dx.doi.org/10.1016/j.bmc.2012.07.005), the instability observed for these compounds was shown to be due to the chemical reactivity of an oxidized form of the compounds, and could be remediated completely by the introduction of an alkyl group at the single unsubstituted ring position. It may be noted that the resulting stabilized MRQ B derivative (compound 5 in the paper) had greatly improved properties as a catalytic antioxidant relative to unsubstituted 1, as regards its ability to quench lipid peroxidation (Table 1), confer cytoprotection from oxidative stress (Table 3), and preserve mitochondrial membrane potential (Figure 3) in cultured FRDA lymphocytes. Compound 5 also suppressed ROS more effectively than 1 in cultured CEM leukemia cells (Figure 2). However, because compound 5 strongly inhibited the mitochondrial respiratory chain (Table 4), it was actually less effective than compound 6 (in the MRQ A series) and B-series compound 4 (which was stabilized using a different molecular substitution strategy). It may be noted that compounds 4 and 6 (as well as virtually every other CoQ analogue that we have ever studied) do inhibit complex I; they simply do so less potently than compound 5. Not shown in the attached paper are the results of a limited effort to minimize inhibition of the mitochondrial respiratory chain by altering the alkyl side chain in compound 5. We have identified an analogue with very favorable properties as an MRQ. It is one of the few MRQs that we have ever studied which exhibits no detectable inhibition of the mitochondrial respiratory chain. This MRQ B derivative has properties almost as favorable as the lead compound in the MRQ A series currently being evaluated in an animal model of FRDA (vide supra). In spite of the great promise of the new MRQ B analogue, no work is underway to optimize the structure due to a lack of resources. Optimization would be relatively straightforward, as the synthetic methods are established and the requisite bioassays required for compound characterization are available in our Center. The deliverables include new MRQ B analogues of potential utility for the treatment of mitochondrial disorders, and the development of a better understanding of the structural factors in the MRQ B series that lead to inhibition of the respiratory chain. All of the compounds proposed for preparation will be within the structural series defined by the generalized representation shown below: where R1, R2, R3, R4 and R5 can be identical or different substituents chosen from linear or branched alkyl, aryl, or aralkyl groups, and may also contain one or more heteroatoms (N, O and S) or unsaturation anywhere within the chosen substituents. One or more of the R1, R2, R3, R4 and R5 substituents may also be connected covalently. R1, R2, R3, R4 and R5 can also be functional groups such as (but not limited to) halides or nitriles.
|Effective start/end date||9/17/12 → 12/31/13|
- United Mitochondrial Disease Foundation: $102,836.00
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