Synthesis of 5-fluorouracil-lactoside derivatives and experimental study on their anti-oral squamous cell carcinoma
Yuting Zhang1, Jiang Liu1, Hang Zhao1
1State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management & Dept. of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
Objectives:
To reduce the toxicity of 5-fluorouracil (5-FU), design and synthesize 5-FU-lactoside derivatives, and preliminarily study their antitumor activities.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
New 5-fluorouracil (5-FU) lactoside derivatives, Ia and Ib, show reduced toxicity and potent antitumor activity against oral cancer cells. Compound Ib demonstrates superior efficacy compared to Ia and the parent drug 5-FU.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Cancer Research
Background:
- 5-fluorouracil (5-FU) is a widely used chemotherapy drug.
- 5-FU exhibits significant toxicity, limiting its clinical application.
- Developing less toxic and more effective anticancer agents is crucial.
Purpose of the Study:
- To synthesize novel 5-FU-lactoside derivatives (Ia and Ib) to reduce 5-FU toxicity.
- To evaluate the in vitro antitumor activities of these novel compounds.
- To compare the efficacy and toxicity of the derivatives against the parent drug.
Main Methods:
- Synthesis of target compounds using Vorbrüggen glycosylation.
- Structural characterization via HRMS, 1HNMR, 13CNMR, HMQC, and HMBC.
- In vitro assessment of cytotoxicity and antitumor activity using CCK-8 assays.
Main Results:
- Compounds Ia and Ib were successfully synthesized and characterized as 5-FU nucleoside derivatives with lactoside substitutions.
- Both Ia and Ib exhibited lower toxicity to normal oral keratinocytes (NOK) compared to 5-FU.
- Compound Ib demonstrated significant inhibition of oral squamous cell carcinoma cell lines (Cal-27 and UM SCC-47).
Conclusions:
- 5-FU-lactoside derivatives Ia and Ib are less toxic than 5-FU.
- Compound Ib displays more potent antitumor activity against oral squamous cell carcinoma than compound Ia.
- These findings suggest potential for Ia and Ib as improved therapeutic agents for oral cancer.
