Fluorouracil, 1 - -5-, biological activity

Dmgs in which fluorine atoms bring a specific biological activity to molecules that previously had no therapeutic activity. Most of the examples are enzyme inhibitors (difluoroornithine, gemcitabine, 5-fluorouracil). Synthesis of these drugs often comes from a rational approach that is based on the action mechanism. 

Up to 50% of the uracil residues in RNA can be replaced by 5-fluorouracil in various viruses and other biologically active nucleic acids. RNA containing fluorouracil is more sensitive to ultraviolet light than is normal RNA. The photochemical behavior of fluorouracil is therefore important, and has been studied by Shugar et al.67a and by Gordon. 7b... 

Ouchi et al. synthesized l,2-mono-0-isopropylidene-3-[3-(5-fluorouracil-l-yl)propionyl]-6-0-acryloyl-a-D-glucofuranose and copolymerized it with acrylamide [143], Ozaki et al. synthesized l-(meth)acryloyloxymethyl-5-fluorouracils and copolymerized with a number of comonomers, such as acrylic acid, methacrylic acid, methyl acrylate, and methyl methacrylate [144]. All the above mentioned polymer bound drugs possessed biological activity. 

Bevacizumab, a humanized IgG and cetuximab, a chimeric IgGx, are currently marketed in the US for treatment of metastatic colorectal cancer [92, 93]. Bevacizumab neutralizes the biological activity of vascular endothelial growth factor (VEGF), while cetuximab binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). Bevacizumab, in combination with IV 5-fluorouracil (5-FU) -based chemotherapy, is indicated for first-line treatment of metastatic colorectal cancer, whereas cetuximab is used in patients refractory to or intolerant to irinotecan-based chemotherapy. The clinical pharmacokinetics of cetuximab are discussed in detail in Chapter 14. 

Gebelein and coworkers have prepared monomers and polymers based on the antineoplastic agents 5-fluorouracil and 6-mercapto-purine (26). These polymers would be potentially useful in treating various types of cancer or leukemia and some derivatives have shown biological activity. Previous work by this group has Included the synthesis of polyisoprene derivatives containing sulfa drug, carbamate, urea, oxazolldone and oxazole units (27.28). 

The first 5-fluorouracil containing polymer had the 5-FU units in the polymer backbone and this structure is shown below as (XVI). This was claimed to be biologically active (47). More recently, monomer (XVII) was prepared by the reaction of 5-FU with methyl fumaroyl chloride. The polymers and copolymers of (XVII) do show antitumor activity but this may be due to the hydrolysis of this unit to release 5-FU (48). 

The first polymer containing 5-fluorouracil (5-FU) appears to be that of Ballweg, et al (40) which is shown below as (I). This polymer contains the 5-FU as part of the backbone chain and was reported to exhibit biological activity (40). No further work appears to have been reported on this compound since 1969, however. 

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