Diacylglycerol (DAG) is a lipid second messenger that is produced through phosphoinositol 4,5-bisphosphate (PIP2) hydrolysis following the activation of receptor-coupled phospholipase C or indirectly from phosphatidylcholine via phospholipase D. Increased levels of DAG are transduced into cellular signals by binding to the C1 domains of the various protein kinase C (PKC) isoforms and six other families of proteins. The binding of DAG translocates the target proteins to membranes and may further lead to a conformational change of the protein, as is the case with PKC, leading to enzyme activation. These proteins represent promising therapeutic targets for cancer, dementia, HIV and AIDS, and multiple other disorders.[1] This project will prepare a new class of DAG mimetics using microwave-assisted 1,3 dipolar addition reaction[2] between several oximes (I) and dimethyl methylene glutarate derivatives (II) with diacetoxyiodobenzene (DIB). The resulting isoxazolidines (III) were reduced[3] to give the corresponding 1,3-aminols (IV). The latter, when treated with 6 M HCl under microwave condition, provided the g-lactones (V). These will be reduced to the DAG-lactone mimetic (VI). These DAG-lactone mimetics will be tested for their PKC activity.

Synthesis of diacylglycerol-lactone mimetics using microwave-assisted 1,3-dipolar cycloaddition reaction

ACS Spring 2022

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