Lactate dehydrogenase A inhibitors with a 2,8-dioxabicyclo[3.3.1]nonane scaffold: A contribution to molecular therapies for primary hyperoxalurias
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Elsevier
Materia
Primary hyperoxaluria Selective lactate dehydrogenase A inhibitors 2,8-Dioxabicyclo[3.3.1]nonane scaffold Flavylium salts Oxalate
Date
2022-09-08Referencia bibliográfica
Alfonso Alejo-Armijo... [et al.]. Lactate dehydrogenase A inhibitors with a 2,8-dioxabicyclo[3.3.1]nonane scaffold: A contribution to molecular therapies for primary hyperoxalurias, Bioorganic Chemistry, Volume 129, 2022, 106127, ISSN 0045-2068, [https://doi.org/10.1016/j.bioorg.2022.106127]
Sponsorship
Spanish Ministerio de Ciencia, Innovacion y Universidades - FEDER funds of the European Union RTI2018-098560-B-C21 RTI2018-098560-B-C22; Centro de Instrumentacion Cientifico-Tecnica (CICT) of the University of Jaen, Spain; University of Jaen; Andalusian Consejeria de Economia y Conocimiento (FEDER program 2014-2020) 1380682; European Youth Guarantee contractAbstract
Human lactate dehydrogenase A (hLDHA) is one of the main enzymes involved in the pathway of oxalate synthesis
in human liver and seems to contribute to the pathogenesis of disorders with endogenous oxalate overproduction,
such as primary hyperoxaluria (PH), a rare life-threatening genetic disease. Recent published results
on the knockdown of LDHA gene expression as a safe strategy to ameliorate oxalate build-up in PH patients are
encouraging for an approach of hLDHA inhibition by small molecules as a potential pharmacological treatment.
Thus, we now report on the synthesis and hLDHA inhibitory activity of a new family of compounds with 2,8-dioxabicyclo[
3.3.1]nonane core (23–42), a series of twenty analogues to A-type proanthocyanidin natural products.
Nine of them (25–27, 29–34) have shown IC50 values in the range of 8.7–26.7 μM, based on a UV spectrophotometric
assay, where the hLDHA inhibition is measured according to the decrease in absorbance of the cofactor
β-NADH (340 nm). Compounds 25, 29, and 31 were the most active hLDHA inhibitors. In addition, the inhibitory
activities of those nine compounds against the hLDHB isoform were also evaluated, finding that all of them were
more selective inhibitors of hLDHA versus hLDHB. Among them, compounds 32 and 34 showed the highest
selectivity. Moreover, the most active hLDHA inhibitors (25, 29, 31) were evaluated for their ability to decrease
the oxalate production by hyperoxaluric mouse hepatocytes (PH1, PH2 and PH3) in vitro, and the relative oxalate
output at 24 h was 16% and 19 % for compounds 25 and 31, respectively, in Hoga1-/- mouse primary hepatocyte
cells (a model for PH3). These values improve those of the reference compound used (stiripentol). Compounds 25
and 31 have in common the presence of two hydroxyl groups at rings B and D and an electron-withdrawing
group (NO2 or Br) at ring A, pointing to the structural features to be taken into account in future structural
optimization.