Synthesis of 13C-Labelled 2-Pyrones: Towards Imaging in Biomedical Applications.

The project examines the synthesis of antimicrobial 13C-labelled 3/5-alkyl-6-styryl-2-pyrone based on the known pharmacological activities exhibited by this class of compounds. The compounds were designed to be employed as hydrogenative ‘hyperpolarizable’ imaging agents in cell-based assay to characterise their interaction with their cellular receptor in bacterial cells. The targeted compounds would therefore be potential drug candidates and also imaging agents and were therefore screened for in-silico druglikeness. They exhibited good to excellent physicochemical, solubilities and toxicological properties. Their binding affinity profile was evaluated employing the same protein (human tyrosyl-DNA phosphodiesterase) and it was found that 5-decyl-6-styryl-2-pyrone 133e had a higher binding affinity than 5-benzyl-6-styryl-2-pyrone 133d. 5-Pentyl-6-styryl-2-pyrone 133c was less effective than both 133e and 133d. Hence 5-decyl- and 5-benzyl-6-styryl-2-pyrone were selected as potential imaging agents.
The selected potential imaging agents were synthesized in five steps employing [13C-1,3]-diethyl malonate, haloalkane (benzyl chloride and 1-bromodecane) and methyl propiolate leading to an overall yield of 17%. Beside the labelled compounds, the optimization procedure led to the synthesis of several new compounds in moderate to good yields. The key step in the synthetic route is the Sonogashira cross-coupling between 3-alkyl-6-chloro-2-pyrone-13C-2 and phenyl acetylene to afford the targeted imaging agents 168/169a-b in yields ranging from 52-69%. The project led to the discovery of a novel room temperature Pd/Cu-catalysed (1,5)-sigmatropic shift of the phenylacetylene moiety. Furthermore, the targeted compounds were evaluated for their proton signal enhancements on hydrogenation using parahydrogen in the presence of a cationic Rh catalyst. An enhancement of 92-100% was observed with a relaxation time of 140 seconds. Polarization transfer from parahydrogen to the 13C-isotopically labelled carbon at low fields of (50 and 100 gauss) were observed. Therefore, the designed and synthesized 13C-isotopically labelled imaging agents can be employed both as 1H and 13C imaging agents.