Cytotoxic liponucleotide analogs: I. Chemical synthesis of CDP-diacylglycerol analogs containing the cytosine arabinoside moiety

Abstract

Cytidine and deoxycytidine diphosphate diacylglycerol are metabolic liponucleotides which are substrates for the biosynthesis of several classes of cellular phosphoglycerides. In addition to their essential biochemical function, liponucleotides can be considered unique from the point of view of molecular structure (lipid, phosphorus, sugar, heterocyclic moieties) and biophysical properties. Liponucleotides, therefore, have been investigated as possible models for anticancer drug design and development. The chemical synthesis of several liponucleotide analogs of cytidine diphosphate diacylglycerol (CDPdiacylglycerol/dCDPdiacylglycerol) containing the 1-β- d-arabinofuranosyl moiety was undertaken for the purpose of evaluation of the antitumor activity of these compounds. The analogs were synthesized by reaction of 1-β- d-arabinofuranosylcytosine-5'-(hydrogen morpholinophosphonate): N,N'-dicyclohexyl-4-morpholine carboxamidine (1 : 1) in pyridine with either egg lecithin-derived phosphatidic acid, synthetic phosphatidic acid, or synthetic analogs of phosphatidic acid. The yields of liponucleotide analogs after purification were approx. 25–40%. Although reaction yields were not optimized, the condensation of phosphatidic acids and nucleotides represents an expedient laboratory-scale synthetic approach to liponucleotides, especially when phosphatidic acids are obtained from natural sources or by semisynthetic methods, and when 5'-nucleotides can be synthesized directly (i.e., without use of protecting groups) from precursor nucleosides.