Alex M. Nadzan

Malonyl Coenzyme A Decarboxylase Inhibition Protects the Ischemic Heart by Inhibiting Fatty Acid Oxidation and Stimulating Glucose Oxidation

Abnormally high rates of fatty acid oxidation and low rates of glucose oxidation are important contributors to the severity of ischemic heart disease. Malonyl coenzyme A (CoA) regulates fatty acid oxidation by inhibiting mitochondrial uptake of fatty acids. Malonyl CoA decarboxylase (MCD) is involved in the decarboxylation of malonyl CoA to acetyl CoA. Therefore, inhibition of MCD may decrease fatty acid oxidation and protect the ischemic heart, secondary to increasing malonyl CoA levels. Ex vivo working rat hearts aerobically perfused in the presence of newly developed MCD inhibitors showed an increase in malonyl CoA levels, which was accompanied by both a significant decrease in fatty acid oxidation rates and an increase in glucose oxidation rates compared with controls. Using a model of demand-induced ischemia in pigs, MCD inhibition significantly increased glucose oxidation rates and reduced lactate production compared with vehicle-treated hearts, which was accompanied by a significant increase in cardiac work compared with controls. In a more severe rat heart global ischemia/reperfusion model, glucose oxidation was significantly increased and cardiac function was significantly improved during reperfusion in hearts treated with the MCD inhibitor compared with controls. Together, our data show that MCD inhibitors, which increase myocardial malonyl CoA levels, decrease fatty acid oxidation and accelerate glucose oxidation in both ex vivo rat hearts and in vivo pig hearts. This switch in energy substrate preference improves cardiac function during and after ischemia, suggesting that pharmacological inhibition of MCD may be a novel approach to treating ischemic heart disease.

A convenient solution and solid-phase synthesis of Δ5-2-oxopiperazines via N-acyliminium ions cyclization

An extremely efficient synthesis of Δ5-2-oxopiperazines in solution phase and on solid support has been established via a Ugi four-component condensation reaction (U-4CC) followed by N-acyliminium ion cyclization between the aldehyde (acetal) functionality and the newly formed amide bond. The desired Δ5-2-oxopiperazines are obtained in excellent yields and purity.

Retinoic acid receptor ligands based on the 6-cyclopropyl-2,4-hexadienoic acid

A series of novel cyclopropanyl methyl hexadienoic acid retinoids was designed and prepared. These compounds exhibited either selective activity as RXR agonists or pan-agonists on one or more of each of the RAR and RXR isoforms. The most potent pan-agonist 5a (RARs EC(50)=17-59 nM; RXRs EC(50)=6-14 nM) showed good antiproliferative properties in the in vitro cancer cell lines, ME 180 and RPMI 8226.

A traceless solid-phase synthesis of 2-imidazolones

A traceless solid-phase synthesis of 2-imidazolones has been developed. Polymer-bound glycerol resin was reacted with bromoacetaldehyde diethyl acetal to give the cyclic acetal bromide on the solid support. Amination of the resin-bound acetal bromide followed by urea formation by reaction with isocyanates afforded the resin-bound urea acetals. The aldehyde urea intermediate, which was released from the resin upon treatment with TFA, immediately cyclized to afford the desired 2-imidazolones in good yield and purity.