Friday, September 6, 2019

A Prospective Fluorinated Drugs

[Picture Source: ThoughtCo]


Twenty percents of marketed drugs are fluorinated because fluorine atom can completely change the biological properties, for example, 5-Fluorouracil. Before being introduced by the fluorine atom, the uracil is transformed into DNA by Thymidylate synthase that is not desired in cancer case. By introducing the fluorine atom, the uracil now acts as antimetabolite that inhibits the thymidylate synthase so indirectly inhibit the carcinogenesis also. That's how fluorine atom can completely change the biological properties of natural uracil (Berger, Pittman, & Wyatt, 2009).


Another example is Fludcortisone. Cortisone itself is a steroid that prevents the release of a substance that causes inflammation in the body so it possesses glucocorticoid activity. After being introduced with fluorine atom, the activity exceeded by factor 10 than the parent hormones (cortisone), therefore it possess a remarkable glucocorticoid activity. 

So, how come fluorine atom can completely change biological properties of a compound? What kind of atom is it? 

Fluorine atom as expected in the periodic table of elements possesses ultimate electronegativity and oxidation potential. Talking about the amount, fluorine atom is available abundantly even more significant than other halogens on Earth's crust as it is the 13th most common element on Earth's crust. Compare to other halogens, Fluorine atom also has extraordinary high hydration energy so therefore it behaves as a very poor nucleophile in aqueous solution. Another feature of fluorine atom that makes it different from others is the C-F bond, it is one of the strongest chemical bonds as its biological formation/cleavage will be quiet difficult to generate under normal condition. 

Fluorine atom can give effect to organic compound properties not only due to its electronegativity, but also other properties it possesses such as lipophilicity, size, and electrostatic interaction. Those properties can dramatically influence the chemical reaction. Do you know, even a single fluorine atom is able to change a biological property of a natural product. 

Last but not least, after the fluorination, the fluorine atom can change the acidity or basicity of a parent compound so this can strongly influence binding affinity pharmacokinetic properties and bioavailability of a drug candidate. 

As a powerful functional group, the number fluorinated drugs is expected to increase in the future. How come? Atorvastatin Lipitor became the most profitable drug until 2011. Another example, Fluticasone propionate, the annual sales became more than 5 billion dollars.

You can read all the development of fluorinated drugs from a paper written by Wang et al (2013).

That's all the post I wrote. Thank you for visiting. I apologize if there is a mistake. 

Reference:
Berger, S. H., Pittman, D. L., & Wyatt, M. D. (2009). chemotherapy, 76(6), 697–706. https://doi.org/10.1016/j.bcp.2008.05.019.Uracil
Wang, J., Sánchez-Roselló, M., Aceña, J. L., Del Pozo, C., Sorochinsky, A. E., Fustero, S., … Liu, H. (2014). Fluorine in pharmaceutical industry: Fluorine-containing drugs introduced to the market in the last decade (2001-2011). Chemical Reviews, 114(4), 2432–2506. https://doi.org/10.1021/cr4002879

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