Nucleoside conjugates. 13. Synthesis and antitumor activity of 1-beta-D-arabinofuranosylcytosine conjugates of thioether lipids with improved water solubility.
A series of ara-CDP-rac-1-S-alkyl-2-O-acyl-1-thioglycerols (3-12), analogues of highly active Cytoros2 (1), was prepared, and solubility, lipophilicity, and structure-activity relationships of these conjugates were investigated. The conjugates with sn-1 alkyl (< C18) and sn-2 fatty acyl (< C14) substituents of the thioglycerol were water-soluble, while those with the sn-1 alkyl (> C14) and the sn-2 fatty acyl (> C16) were sparingly soluble. The latter formed micelles upon sonication. Conjugate 7 containing the sn-1 tetradecyl and the sn-2 palmitoyl (C16) groups formed micelles by both sonication and shaking. The partition coefficients (1-octanol/PBS) of the water-soluble conjugates were about 20 times greater than that of ara-C. The water-insoluble showed a more than 40 times increase. A single dose of the micelle-forming conjugates 7 and 10 produced a significant increase in life span (ILS > 421%) with 50% long-term survivors (> 45 days) in mice bearing ip-implanted L1210 lymphoid leukemia. These results were comparable to those of previous micelle-forming conjugate 1 (Cytoros). In contrast, the water-soluble conjugates at single doses were less effective (ILS 81-386% with 0-33% long-term survivors). However, three divided doses of the water-soluble conjugates were found to be as effective as a single dose of micellar solution of the water-insoluble. The results indicate that conjugate 7 and most of the water-soluble derivatives warrant further investigation.
Department of Neurosurgery, Roswell Park Cancer Institute, Buffalo, New York 14263.
C I
CI
Hong
A
A
Nechaev
A J
AJ
Kirisits
R
R
Vig
C R
CR
West
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003561:Cytarabine / Q000031:analogs & derivatives*; D005614:Freeze Fracturing; D005990:Glycerol / Q000031:analogs & derivatives* / Q000737:chemistry; D007939:Leukemia L1210 / Q000188:drug therapy; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008823:Micelles; D008854:Microscopy, Electron; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water
D000970:Antineoplastic Agents; D008823:Micelles; D003561:Cytarabine; D014867:Water; C009465:thioglycerol; D005990:Glycerol