Hypoxic tumours, normally resistant to chemotherapy and radiotherapy, are often characterized by a metabolic switch (“Warburg effect”) from normal oxidative phosphorylation to anaerobic glycolysis. This ensures a sufficient energy supply from glucose, even in hypoxic environments. One of the key enzymes of anaerobic glycolysis, the muscle isoform of lactate dehydrogenase (LDH-A), is over-expressed by metastatic cancer cells and is linked to the vitality of tumours in hypoxia. This enzyme constitutes a new target for anticancer agents, since its inhibition leads to a cut in energy supply to cancer, thus reducing its metastatic and invasive potential1. LDH-A is regarded as a safe target since hereditary LDH-A deficiency causes a certain level of myopathy only after intense anaerobic exercise, whereas it does not provoke any symptoms under ordinary circumstances2. Nowadays, only a few LDH inhibitors have been developed, mainly because there was no evidence so far for health benefits deriving from this action3. Some catechol-type derivatives, originally designed as antimalarial agents, have very recently proved that LDH-A inhibition by small molecules represses tumour progression4. We have discovered new carboxy-substituted N-hydroxyheterocycles (NOH), which are efficient and selective LDH-A inhibitors, with minimal inhibition of the heart isoform (LDH-B). Their activity in cells was confirmed by 13C NMR experiments measuring the reduction of the cytoplasmic lactate production in tumour cells, and they also proved to be efficient antiproliferative agents in vitro.
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