Synthesis and Reactivity of 5-Fluorouracil/Cytarabine Mutual Prodrugs

Abstract

Two mutual prodrugs, in which two different anti-cancer drugs are attached to the same molecule via labile linkages, are synthesized and examined kinetically. One of the mutual prodrugs loses a drug component under physiological conditions within an hour, but the other mutual prodrug (having a longer spacer between the two drugs) is stable to chemical degradation even at higher pH values. Thus, enzymatic hydrolysis alone will release the two anti-cancer drugs. The potential value of anti-cancer mutual prodrugs is discussed.

Synthesis and Bioevaluation of 5-Fluorouracil Derivatives

“…Recently, the concept of mutual prodrugs in which two different antineoplastic agents are coupled directly or by means of a spacer has become well accepted [8][9][10][11][12][13][14][15][16][17]. This technique can be used to overcome many problems including poor solubility or absorption, patient acceptability, drug instability and toxicity, and especially drug resistance [11].…”

“…Their antitumor action results from DNA distortion and altered nuclear protein interaction as a consequence of reversible complex formation. Because the cellular target of 5-Fu is DNA, the combination of 5-Fu and some antineoplastic DNA binders through an ester bond [8,14] helps the resulting dual prodrug reach the target and optimize the efficiency of both 5-Fu and the DNA binders. According to this strategy, we prepared six novel 5-fluorouracil derivatives and evaluated their antitumor activity both in vitro and in vivo.…”

“…Second, imides, which also exhibit efficient DNA-binding properties and antitumor activities on a variety of murine and human tumor cells [20]. The imides were first converted to the corresponding carboxylic acids through the reactions of 1,8-naphthalic or phthalic anhydride with relevant amino acids [21], then the imide moiety was linked to 5-Fu via an (acyloxy)methylene group, known to be easily removable [3,8]. All structures were verified by 1 H-NMR, 13 C-NMR, MS and elemental analysis.…”

“…This could happen if the hydrolysis of compound 2, which contained only two clinically used drugs (5-Fu and naproxen), occurred readily under physiological conditions, liberating toxic formaldehyde. To verify this the hydrolysis of compound 2 was monitored by UV spectroscopy at physiological pH, but no 5-Fu was detected, thus indicating that the (acyloxy)methylene group in target compounds is stable [8], and target compounds might exert their biological functions as a new kind of "drugs". …”

“…The organic layer was collected, dried over sodium sulphate, filtered and finally concentrated under reduced pressure. The target compounds were obtained through flash column chromatography: petroleum ether-acetone = 7:3 and recrystalization from acetone [8,14]. (2 Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl-4-(1,8-naphthalimido) Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) …”