| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 1409132 | Journal of Molecular Structure | 2012 | 7 Pages |
To develop alkyl halides for a promising prodrug system, a 5-fluorouracil prodrug containing a bromoethyl group (5-FUBr) was synthesized and its hydrophobicity, cytotoxicity and DNA-bonding ability were investigated in detail. Compare with 5-fluorouracil, 5-FUBr exhibits a great advantage of hydrophobicity and shows significant reduction in toxic side effect. To explore the mechanism of action of 5-FUBr at the molecular level, X-ray crystallography and molecular docking were exploited to make a more detailed analysis of the bromoethyl contribution to the construction of meaningful structure–activity relationship. Details of X-ray crystal structure of 5-FUBr suggest that 5-fluorouracil may be more apt to be released from 5-FUBr. The appearance of the bromoethyl group in 5-FUBr makes a remarkable impact on inhibition of thymidylate synthase (TS), and the impact of subtle structural variation between 5-fluorouracil and 5-FUBr should be taken into account in the process of developing this family of 5-fluorouracil prodrugs.
► Hydrophobicity, cytotoxicity and DNA-bonding ability were evaluated. ► X-ray crystallography and molecular docking were used to make detailed analysis. ► The toxic side-effect was showed significant reduction. ► 5-FU was more apt to be released from 5-FUBr.
