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Synthesis of Liposomal Phospholipid‐( N 4 ‐palmitoyl‐1‐β‐D‐arabinofuranosylcytosine) Conjugates and Evaluation of Their Cytostatic Activity against l1210 Murine Leukemia
Author(s) -
Schott Herbert,
Schwendener Reto A.
Publication year - 1996
Publication title -
liebigs annalen
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 0947-3440
DOI - 10.1002/jlac.199619960311
Subject(s) - chemistry , prodrug , phospholipid , liposome , phosphate , conjugate , l1210 cells , stereochemistry , biochemistry , cytotoxicity , in vitro , membrane , mathematical analysis , mathematics
N 4 ‐Palmitoyl‐araC, a prodrug of the cytostatic compound 1‐β‐ D ‐arabinofuranosylcytosine (araC), was linked by means of the triester method to the phospholipids (2‐chlorophenyl) (1,2‐di‐ O ‐palmitoylglyceryl) phosphate, (2‐chlorophenyl) (1,2‐di‐ O ‐octadecylglyceryl) phosphate and (2‐chlorophenyl) (1‐ O ‐octadecyl‐2‐ O ‐palmitoylglyceryl) phosphate. In the first step of these gram‐scale syntheses phospholipid‐( N 4 ‐palmitoyl‐araC) conjugates were obtained the linkage of which was accomplished via a triester group. In the second step the final condensates were obtained through transformation of the triester into a diester linkage by removal of the 2‐chlorophenyl group. The cytostatic activity of these compounds which form stable liposomal preparations together with matrix lipids was evaluated according to the L1210 mouse leukemia model. The conjugates containing a triester linkage were shown to be ineffective, whereas those with a diester linkage display a significantly higher antitumor activity as compared to N 4 ‐palmitoyl‐araC and araC. With the diester 6a–8a 80–100% of the treated animals were cured at a total dose of 200 μmol/kg, whereas with araC given at a fourfold higher concentration none of the treated mice survived.