Using C-F Bonds to Slow Drug Metabolism and Increase Potency
There is a lot of chemistry that can be discussed about established medicine currently on the market. However, one of the most interesting topics to look into is how new drugs are being developed. With the advanced technology we have today and the vast knowledge of both chemistry and biology that we possess, there is a lot that is done to manipulate chemicals to get the best drugs we can for the purposes we need them for. This is the exciting field of drug synthesis.
Of course, there is so much that can be delved into just for this one topic. There are so many factors that make a drug a “medicine.” The characteristics of a particular molecule are important, and even necessary, to how it functions. Now, what the pharmaceutical industry is trying to figure out how to make these drugs in the most efficient way possible, create more of them with new techniques, and to find those which are most effective in the human body.
Redox Chemistry and Hydrogen Bonding
One of the most studied and crucial characteristics of a drug to know about is how it is metabolized in the body. Most basically, drug metabolismdescribes how a drug is processed and excreted from the body. The metabolism of a certain drug effects how long it will stay in the body, which in turn affects how long effective concentrations of the drug will be able to perform their functions. Of course, therefore, drug metabolism is of interest to many people, particularly to pharmaceutical companies creating new medicines. Luckily, drug metabolism is largely affected by the chemical interactions of the the drug molecules, which is something that we can control by manipulating chemical structure. Two things in particular, the oxidation of the drugs as well as hydrogen bonding are often taken into consideration.
Here is a quick overview of redox reactions to go over:
Here is a quick overview of hydrogen bonding.
The Carbon-Fluorine Bond
Let us regress for a second, and establish a basis for what we shall talk about. Naturally there are no carbon-fluorine bonds in the human body. Why? They simply do not occur in nature and hence do not show up in the human body. (Usually in nature there are carbon-hydrogen bonds instead.) Yet, strangely enough, looking at the chemical structures of many drugs, many of them do contain carbon-fluorine bonds. This helps the body more effectively process the drugs, since the body does not know how to digest these molecules and they remain in the body longer. This is because of the particular nature of the bonds, namely that it is polar. The fluorine atom is more electronegative than carbon atoms, and therefore pulls electrons towards itself. The fluorine side of the bond is therefore pseudo-negative whereas the carbon side is pseudo-positive. In a drug molecule, polarity hence also pulls the electrons aways from the rest of the molecule. Recall that redox reactions involve the transfer of electrons. An electron poor molecule therefore will not oxidize easily.
Some examples of the incorporation of C-F bonds can be seen below. Cipro is an antibiotic drug, Paxil is an antidepressant drug, and Sitagliptin is an anti-diabetic drug.
Benefits of Being Harder to Oxidize – Solubility
Drugs are metabolized through a redox reactions with two enzymes in the liver, P450 and Cyp. An enzyme is a natural protein that catalyzes chemical reactions in the body. To briefly go over the kinetics, this means means that it is present as a reactant in the first elementary step of a chemical reaction, but also present as a product in the last elementary step. How an enzyme works is heavily tied to kinetics. The two enzymes mentioned work by oxidizing small molecules, which of course includes all drugs. This oxidation make the molecules more polar as the electron distribution in the molecule changes. In every redox reaction there is an oxidizing agent that gains electrons and a reducing agent that loses electrons. In the case of the chemical reactions taking place in the liver, the liver enzymes take electrons away from all the molecules that pass through the system. Often, these extra electrons are transferred and used in many other reactions throughout the body.
The redox reaction makes the drug molecules more water-soluble which leads to the drug’s secretion from the body. They are more soluble because they are then polar. Recall that water is also a polar molecule. Two polar molecules are often very soluble in one another due to their attraction to each other. Because of this timeless saying, “like dissolves like” the drug is able to dissolve much more easily in the body and spread through the body. Again, the goal going towards the future is to create drugs whose dissolution is more thermodynamically favorable due to a more negative deltaH3, and thus will occur at a faster rate and with more consistent results. Additionally, because it makes the dissolving of the drug spontaneous, with a negative change in Gibb’s free energy. (Overall the change is enthalpy would be negative and change in entropy would be positive, resulting in negative change in free energy.)
A drug that is easily oxidized will be cleared from the body more quickly than one that is difficult to oxidize. Recall that C-F bonds make a molecule electron-poor. Since the drug molecules are the reducing agent in the redox reaction (they are oxidized and hence give electrons,) they are therefore not as reactive with liver enzymes with a C-F bond as they would be if they had a C-H bond instead. Overall, thus, C-F bonds make drug molecules more metabolically stable.
Fluorine as a Hydrogen Bond Acceptor
There are more reasons that medicinal chemists replace C-H bonds in drug molecules with C-F bonds. This is because the fluorine atoms, which, as mentioned before, are very electronegative, can be hydrogen-bond acceptors. In other words, hydrogen atoms can be attracted to them. To understand why this is important, it is important to understand how drugs work. Many drugs work by binding to and inhibiting the activity of a target enzyme. How tightly a drug binds to a specific binding pocket of an enzyme determines how potent, specific, and effective a drug is. The more tightly it can bind, the better drug it is. Fluorine increased the potential hydrogen bonding interactions interactions between the drug and its target. In other words, it increases the intermolecular forces.
It has been proven that C-F bonds increase the potency of a drug. One specific example is the drug Januvia, shown below. This is a drug that is used to treat Type II Diabetes. It is composed of six C-F bonds, three of which are in an aromatic ring. While the drug was being developed, the researchers found that even just one fluorine in the aromatic ring increased the potency of the drug three-fold. Three fluorines increased potency 25-fold.
The Future of Drugs (We Hope!)
The goal for the future is to be able to create drugs more easily and effectively. That would mean being able to make reactions go forward, and find ways to incorporate certain bonds in the structure that would metabolize better in vivo. In addition, creating new reactions, both with the help of redox reactions and with many different synthesis applications such as electrochemistry and the organic chemistry of electron movement is very important for the creating of new drugs. Finding ways to do this that work effectively and efficiently, or in other words are thermodynamically favorable and thus spontaneous, is also a necessary step of the future. Being able to test drugs in a non-animal environment, yet still being able to predict its effects on the body is also a substantial step that needs to be taken, so fewer ineffective drugs will have to go through clinical trials unnecessarily. Overall, the chemists who work in the pharmaceutical industry have a far way to go, and a bright future to go into.