Synthesis of new antitumor phospholipids as inhibitors of the human enzyme cytidine triphosphate (CTP): phosphocholine cytidylyltransferase

Abstract

Antitumor phospholipids are synthetic analogues of endogenous phosphatidylcholines with a remarkable ability: inducing the selective apoptosis of exponentially growing tumor cells. Concerning their mechanism of action, one hypothesis points to the inhibition of the enzyme cytidine triphosphate (CTP):phosphocholine cytidylyltransferase (CCT) as a key event related to the antitumor actions of these phospholipids, which, ultimately, would result from a significant suppression in phosphatidylcholine biosynthesis. The CCT enzyme catalyzes the conversion of choline phosphate to cytidine 5'-diphosphocholine (CDP-choline), which represents a source of phosphocholine for the synthesis of phosphatidylcholines. Phosphatidylcholine is a decisive element for cell cycle progression and its deficiency is recognized as a sign to trigger mechanisms that, eventually, will conduce to cell cycle arrest and apoptosis. Although several synthetic antitumor phospholipids are known inhibitors of the CCT enzyme (e.g. edelfosine, erucylphosphocholine, perifosine and miltefosine), none is extensively used in the clinical practice, highlighting an opportunity for optimization. In this context, herein we propose the syntheses of new antitumor phospholipids with an improved affinity for the human CCT enzyme, focusing on the development of new alternatives for cancer chemotherapy. (AU)