Synthesis and <i>h</i>LDH Inhibitory Activity of Analogues to Natural Products with 2,8-Dioxabicyclo[3.3.1]nonane Scaffold
Human lactate dehydrogenase (<i>h</i>LDH) is a tetrameric enzyme present in almost all tissues. Among its five different isoforms, <i>h</i>LDHA and <i>h</i>LDHB are the predominant ones. In the last few years, <i>h</i>LDHA has emerged as a therapeutic...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-06-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/12/9925 |
| Summary: | Human lactate dehydrogenase (<i>h</i>LDH) is a tetrameric enzyme present in almost all tissues. Among its five different isoforms, <i>h</i>LDHA and <i>h</i>LDHB are the predominant ones. In the last few years, <i>h</i>LDHA has emerged as a therapeutic target for the treatment of several kinds of disorders, including cancer and primary hyperoxaluria. <i>h</i>LDHA inhibition has been clinically validated as a safe therapeutic method and clinical trials using biotechnological approaches are currently being evaluated. Despite the well-known advantages of pharmacological treatments based on small-molecule drugs, few compounds are currently in preclinical stage. We have recently reported the detection of some 2,8-dioxabicyclo[3.3.1]nonane core derivatives as new <i>h</i>LDHA inhibitors. Here, we extended our work synthesizing a large number of derivatives (<b>42</b>–<b>70</b>) by reaction between flavylium salts (<b>27</b>–<b>35</b>) and several nucleophiles (<b>36</b>–<b>41</b>). Nine 2,8-dioxabicyclo[3.3.1]nonane derivatives showed IC<sub>50</sub> values lower than 10 µM against <i>h</i>LDHA and better activity than our previously reported compound <b>2</b>. In order to know the selectivity of the synthesized compounds against <i>h</i>LDHA, their <i>h</i>LDHB inhibitory activities were also measured. In particular, compounds <b>58</b>, <b>62a</b>, <b>65b</b>, and <b>68a</b> have shown the lowest IC<sub>50</sub> values against <i>h</i>LDHA (3.6–12.0 µM) and the highest selectivity rate (>25). Structure–activity relationships have been deduced. Kinetic studies using a Lineweaver–Burk double-reciprocal plot have indicated that both enantiomers of <b>68a</b> and <b>68b</b> behave as noncompetitive inhibitors on <i>h</i>LDHA enzyme. |
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| ISSN: | 1661-6596 1422-0067 |