Abstract
A series of symmetric molecules incorporating aryl or pyridyl moieties as central core and 1,4-substituted triazoles as a side bridge was synthesised. The new compounds were investigated as lactate dehydro-genase (LDH, EC 1.1.1.27) inhibitors. The cancer associated LDHA isoform was inhibited with IC50 = 117–174 µM. Seven compounds exhibited better LDHA inhibition (IC50 117–136 µM) compared to known LDH inhibitor – galloflavin (IC50 157 µM).
Highlights
The lactate dehydrogenase (LDH, EC 1.1.1.27) is one of the most abundant proteins and it is expressed in all tissues[1]
Three LDH isoforms are present in humans – LDHA, LDHB and LDHC
LDHA and LDHB are expressed in all cells, whereas LDHC is produced only in testis[1]
Summary
The lactate dehydrogenase (LDH, EC 1.1.1.27) is one of the most abundant proteins and it is expressed in all tissues[1]. In contrast to LDHB, LDHA has a higher affinity for pyruvate, that is, LDHA and LDH5 tetramer in particular predominantly converts pyruvate to lactate with consumption of one NADH molecule to produce NADþ which in turn is essential in glycolysis[3]. Utilising NMR and SPR (surface plasmon resonance) fragment based hit identification technique and further optimisation of structure a series with low- and submicromolar LDHA inhibition was obtained with best lead A (IC50 1⁄4 0.27 lM)[10]. Using fragment-based hit identification, series of new LDHA inhibitors was obtained. In this series, IC50 values ranged from 59 to 0.12 lM, where the best inhibition was observed for compound B.11. One of the compounds identified (C) showed very good LDHA inhibition potency in vitro with an IC50 value of 0.33 lM.[12]
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