Exploring Alternative Strategies for the Synthesis of 15d-PGJ2-EA: Diversification of Synthetic Routes to a Potent Anti-Cancer Agent

Abstract

The compound, 15-deoxy-12, 14-prostaglandin-J2-ethanolamine (15d-PGJ2-EA), is in an active line of research for treating non-melanoma skin cancer and has shown promising potential as a chemotherapeutic drug. 15d-PGJ2-EA may be effective against colon cancer as well. With this drug currently undergoing animal studies, a large quantity (~1 g) is needed to further research efforts. Thus, it is beneficial to have a synthetic strategy using abundantly available precursors. Examination of the metabolic pathway that leads to in vivo production of 15-deoxy-12, 14-prostaglandin-J2 (15d-PGJ2) suggests that the synthesis could be started from an upstream metabolite, prostaglandin-D2 (PGD2), as opposed to 15d-PGJ2. By exploring the possibility of beginning synthesis from a different precursor, the routes for obtaining 15d-PGJ2-EA are diversified. This could potentially lead to more cost effective methods for synthesis of the drug. The research objective is ultimately to perform dehydration reactions on PGD2 in organic solvents using chemical dehydrating reagents, such as POCl3, to make 15d-PGJ2. Using a model system, a strategy to mimic the dehydration reaction has been developed using inexpensive and readily available reagents. One method uses 3-hydroxy-2,3-dihydro-1H-inden-1-one because it contains one of the relevant functional groups in PGD2, a b-hydroxycyclopentanone. Another method uses micro-reactions with very small amounts of PGD2. This research will determine if the dehydration can be carried out efficiently in vitro under non-aqueous conditions and provide a possible economical means of obtaining 15d-PGJ2-EA. If this synthesis proves successful and high yielding, then two different routes to the synthesis of 15d-PGJ2-EA are readily feasible: 1) dehydration followed by amide coupling or 2) amide coupling to form PGD2-EA followed by dehydration.