engleski

Synthesis of the novel pyrimidine derivatives of L-ascorbic acid for their cytostatic activity evaluations

Nucleoside analogues represent a valuable source that contributes significantly to the arsenal of chemotherapeutic agents against viruses and cancer. In recent years a number of five-membered cytosine nucleoside analogues, such as 1-(2-deoxy-2-methylene--D-erythro-pentofuranosyl) cytosine (DMDC) [1], 2'-deoxy-2', 2'-difluorocytidine (gemcitabine) [2], and 1-(2-C-cyano-2-deoxy--D-arabino-pentofuranosyl) cytosine (CNDAC) [3], have been developed as potent antitumor agents, which are effective not only on leukemias and lymphomas, but also on a wide variety of solid tumor in vitro and in vivo. Cameron and Pauling believed that L-ascorbic acid combats cancer by promoting collagen synthesis and thus preventing tumors from invading other tissues. However, researchers now believe that L-ascorbic acid combats cancer by neutralizing free radicals before they can damage DNA and initiate tumor growth and/or may act as a pro-oxidant helping body's own free radicals to destroy tumors in their early stages [4-6]. For example, a mixture of L-ascorbic acid and cupric sulfate significantly inhibited human mammary tumor growth in mice, while administered orally [7]. L-Ascorbic acid and its derivatives were also shown to be cytotoxic and inhibited growth of a number of malignant and non-malignant cell lines in vitro and in vivo [8-11]. It has also been reported for L-ascorbic acid has to be cytotoxic to some human tumor cells, neuroblastoma [12], osteosarcoma and retinoblastoma [13]. A number of ascorbic acid isomers/derivatives were synthesized and tested on tumor cell lines so far. Substitution at 2- or 6- and both at 2, 6-positions in ascorbic acid have significant cytotoxicity potential on malignant cells [14]. Ascorbate-6-palmitate and ascorbate-6-stearate were found to be more potent inhibitors of growth of murine leukemia cells compared to ascorbate 2-phosphate, ascorbate-6-phosphate and ascorbate-6-sulphate respectively [14]. In addition, ascorbyl palmitate and ascorbyl stearate have attracted considerable interest as anticancer compounds in view of their lipophilic nature alowing them to easily cross cell membranes and blood brain barrier [15]. L-Ascorbic acid and ascorbyl esters have been shown to inhibit the proliferation of mouse glioma and human brain tumor cells, glioma (U-373) and glioblastoma (T98G) cells and renal carcinoma cells [16-18].

Pyrimidine derivatives; L-ascorbic acid

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