Synthesis of 5-fluorouracil-lactoside derivatives and experimental study on their anti-oral squamous cell carcinoma activity.

Abstract

To reduce the toxicity of 5-fluorouracil (5-FU), design and synthesize 5-FU-lactoside derivatives, and preliminarily study their antitumor activities. Target compounds were prepared with Vorbrüggenglycation procedures, the structures were characterized through high resolution mass spectrometry (HRMS), 1H nuclear magnetic resonance (1HNMR), carbon-13 nuclear magnetic resonance (13CNMR), heteronuclear multiple quantum correlation (HMQC), and heteronuclear multiple bond correlation (HMBC). A cell counting kit (CCK)-8 test was performed to examine their in vitro toxicity and antitumor activity. Experimental data were tested by χ2, and statistically significant differences were denoted by P<0.05. The target compounds were synthesized through a simple and efficient method. 1HNMR, 13CNMR, HMQC, HMBC, and HRMS confirmed that Ⅰa and Ⅰb were 5-FU nucleoside derivatives substituted with lactoside groups at N-1 and N-3, respectively. The CCK-8 test verified that high concentrations (0.7 μmol·mL-1) of Ⅰa and Ⅰb inhibited the growth of normal oral keratinocytes (NOK) by 30.28% and 50.68% after 24 h of treatment. Both values were lower than the inhibitory effect of 5-FU (68.22%; P<0.05). Ⅰb had a significant inhibitory effect on the growth of two oral squamous cell carcinoma cell lines. The inhibition rates of Cal-27 cells and UM SCC-47 cells treated with 0.7 μmol·mL-1 for 24 h were 81.20% and 80.19%, respectively. Ⅰa and Ⅰb are less toxic than 5-FU. The antitumor activity of Ⅰb against oral squamous cell carcinoma cells is more obvious than that of Ⅰa.