SYNTHESIS AND STRUCTURE-ACTIVITY STUDIES IN-VIVO OF LIPOSOMAL ID-N-4-PALMITOYL-1-BETA-D-ARABINOFURANOSYLCYTOSINE AND N-4-HEXADECYL-1-BETA-D-ARABINOFURANOSYLCYTOSINE CONJUGATES

N-4-Hexadecyl-1-beta-D-arabinofuranosylcytosine (hxd(4)araC), a new cy tostatic derivative of the antileukemic drug 1-beta-D-arabinofuranosyl cytosine (araC), was linked in gram-scale syntheses to phospholipids c ontaining differently substituted glycerol residues. All phospholipid- araC conjugates which were condensed via a phosphotriester linkage wer e shown to be ineffective in the in vivo treatment of L1210 murine leu kemia. The transformation of the triesters into phosphodiester-linked conjugates by cleavage of the 2-chlorophenyl protecting group resulted in conjugates which were highly active against L1210 leukemia. These conjugates form stable liposomes with matrix lipids which exert antile ukemic effects depending on the number and characteristics of the lipo philic residues of the conjugates. By treatment of L1210 leukemic mice with 100 mu mol/kg body wt as total dose given by i.p. injection on d ays 2 and 6 after tumor inoculation with liposomal hxd(4)araC or sphor yl-(3-->5')-1-beta-D-arabinofuranosylcytosine (Ocd(1)GroP-araC) the fr action of 60-day survivors was 100%. Corresponding curative effects we re observed after treatment with 200 mu mol/kg of ')-N-4-palmitoyl-1-b eta-D-arabinofuranosylcytosine (Pam(1)pam(2)GroP-pam(4)araC); ')-N-4-p almitoyl-1-beta-D-arabinofuranosylcytosine (Ocd(1)ocd(2)GroP-pam(4)ara C) or decyl-rac-glycero-3-phosphoryl-(3-->5')-hxd(4)araC (Ocd(1)GroP-h xd(4)araC). Four other conjugates with differently combined palmitoyl- , octadecyl- and hexadecyl residues were significantly less active or inactive. A distinct relationship between the chemical structures and the antileukemic activity of the nine investigated compounds was not f ound.