Use of DERA in Development of Novel N-heterocycle-based Statin Precursors

Hypercholesterolemia is a metabolic syndrome characterized by high levels of cholesterol in the blood plasma. Individuals with this condition have a significantly increased risk of developing cardiovascular diseases. Currently, natural or synthetic statins are prescribed to reduce cholesterol levels. In the synthesis of statin precursors, aldolases are often used. These are enzymes that catalyze the reversible and stereospecific aldol addition reaction between carbonyl compounds, forming chiral β-hydroxyketones or β-hydroxyaldehydes.

Among these enzymes, 2-deoxyribose-5-phosphate aldolase (DERA), which is acetaldehyde-dependent, can catalyze two consecutive aldol additions with absolute stereoselectivity, producing chiral 2,4,6-trideoxyhexoses that spontaneously cyclize into 2,4,6-trideoxy-D-erythro-hexapyranoses. However, a limitation of using DERA is that it becomes inhibited at high acetaldehyde concentrations, posing a challenge for large-scale reactions.

To obtain new statin precursors, we tested the activity of a genetically modified variant of DERA from Pectobacterium atrosepticum, showing a high tolerance to high concentrations of acetaldehyde, on crossed aldol addition reactions between acetaldehyde and aldehyde-based scaffolds derived from nitrogen-containing heterocycles, such as benzimidazole and substituted 4-phenyl-imidazoles, synthesized in our laboratory. The obtained products were analyzed using chromatographic and spectroscopic methods.

By replacing the heteroaromatic ring of commercial statins with different scaffolds, it may be possible to develop new hypocholesterolemic drugs that are more effective and have fewer side effects.