1-β-D-Arabinofuranosylcytosine-Phospholipid Conjugates As Prodrugs of Ara-C

Abstract

The L-, D-, and D,L-isomers of 1-beta-D-arabinofuranosylcytosine 5'-diphosphate-1,2-dipalmitin, new prodrugs of ara-C5, have been evaluated for antitumor activity in L1210 lymphoid leukemic mice. The L-isomer produced significant increase in life span (ILS), and longterm survivors among mice bearing i.p. and i.c. implanted L1210 leukemia and the maximal ILS values found were greater than 543 and greater than 374% with five and four 45-day survivors out of six mice, respectively, at the optimal single doses of 300 mg/kg and 125 mg/kg. The D- and D,L-isomers also displayed significant in vivo antitumor activity against both i.p. and i.c. implanted L1210 leukemia in mice with ILS range of 144-293% at a total dose of 125-250 mg/kg. Significant schedule dependency was not observed when the conjugates were administered i.p. once daily for 5 days, once every 4 days, or as a single dose, but single doses typically produced the best effects. The L-isomer was found to be a more effective prodrug of ara-C than its isomers and other lipophilic prodrugs, 5'-O-palmitoyl-ara-C and N4-acyl-ara-C. Unlike the latter prodrugs, the new conjugates are water soluble by sonication method.

Nucleoside Conjugates V: Synthesis and Biological Activity of 9-(β-D-Arabinofuranosyl)adenine Conjugates of Corticosteroids

“…Chemistry-The conjugates (IV-XI) were prepared by a method similar to that used for the preparation of the l-(P-D-arabinofuranosyl)cytosine conjugates (7)(8)(9). Phosphorylation of I with phosphorus oxychloride in the presence of water and pyridine in acetonitrile (15) afforded I1 in 76% yield.…”

“…The latter compound was then acetylated with acetic anhydride in pyridine. Like the l-(/%D-arabinofuranosyl)cytcsine conjugates (7)(8)(9), hydrolysis of the conjugates (IV-XI) by 0.05 M Ba(OH)Z yielded I and the corresponding steroid 21-monophosphate, which was further hydrolyzed to the steroid. Condensation of Ill with 2 molar equivalents of the various steriods in the presence of N,N'-dicyclohexylcarbodiirnide and pyridine a t room temperature for 2 d and the subsequent removal of the acetyl groups with 2 M methanolic ammonia gave the conjugates (IV-XI) in 10-4@?6 yield after chromatography (Table I).…”

Lipid prodrug nanocarriers in cancer therapy

“…Due to rapid metabolization in the inactive uracil arabinoside and the toxicity on rapid dividing healthy cells, the prodrug approach has also been applied to this molecule in order to improve its pharmacological profile. While the systemic administration of fatty acid- [70], steroid- [71], or phospholipid [72]-modified ara-C would require the use of potentially toxic solvents due to their lipophilic nature, such property makes them suitable for being inserted into a liposomal bilayer. For instance, the chemical…”

Lipid Nucleoside Conjugates for the Treatment of Cancer

“…In further animal studies using these conjugates, Hong et al sought to determine the active range of doses for ara-CDP-L-dipalmitin and found that one dose of 300 mg/kg/day produced greater than 543% ILS in five out of six of the forty-five day DBA/J2 mice survivors [63]. Clearly, these results suggest further that the addition of phospholipids with aliphatic groups of different chain lengths can change the biological efficacy of ara-C to different degrees.…”

“…Previous investigators have had many successes with phospholipid/nucleoside analog conjugates; however, there are still improvements that can be made to these compounds [59,60,[62][63][64]73]. In our laboratory, we focused on the synthesis of a thioether phospholipid (1-S-dodecyl-2-Odecyl-thioglycero-3-phosphatidic acid) conjugated to either gemcitabine or ara-C [75].…”