Bioorthogonal chemistry facts for kids

Bioorthogonal chemistry is a special type of chemical reaction that can happen inside living things, like cells or even animals, without bothering their natural processes. Imagine trying to fix a tiny part of a complex machine while it's still running – that's kind of what bioorthogonal chemistry does!

The idea was first introduced by Carolyn R. Bertozzi in 2003. Thanks to this concept, scientists can now study important molecules like glycans (sugars), proteins, and lipids (fats) in real-time within living systems. This means they can watch these molecules work without harming the cells.

To do this, scientists usually follow two steps:

• First, they add a tiny, special chemical tag (called a "chemical reporter") to a molecule they want to study. This tag must not change how the molecule normally works.
• Second, they introduce another chemical partner that only reacts with that special tag. This partner often has a "probe" attached, like a glowing dye, so scientists can see where the tagged molecule goes.

Carolyn Bertozzi won the Nobel Prize in Chemistry in 2022 for her amazing work on this field, especially for developing "click chemistry" and bioorthogonal chemistry.

What Does "Bioorthogonal" Mean?

The word "bioorthogonal" comes from two Greek words: bio- meaning "living," and orthogōnios meaning "right-angled" or "perpendicular." So, it literally means a reaction that goes "perpendicular" to a living system, meaning it doesn't get in the way or disturb anything.

What Makes a Reaction Bioorthogonal?

For a chemical reaction to be called "bioorthogonal," it needs to meet some important rules:

• Super Picky: The reaction must only react with the special tag and nothing else in the living system. This stops unwanted side reactions.
• Safe for Life: The chemicals used and the new bonds they form must not harm the living organism or mess with its normal functions.
• Strong Bonds: The new chemical bond created must be strong and not easily broken by other reactions inside the body.
• Super Fast: The reaction needs to happen very quickly, in minutes, so scientists can see what's happening in real-time before the tagged molecules move or get broken down.
• Friendly Conditions: The reaction must work well in the body's natural conditions, like its temperature, water-based environment, and pH levels. It also needs to be non-toxic.
• Easy to Use: It should be easy to add the special chemical tag to the molecules scientists want to study. The tag should also be very small so it doesn't change how the molecule behaves.

Staudinger Ligation

The Staudinger ligation was one of the first bioorthogonal reactions developed by Bertozzi's team in 2000. It helped kick off the whole field of bioorthogonal chemistry. While it's not used as much today, it was a big step forward. It has been used in both living cells and even in live mice.

How it Works (Simply)

This reaction uses a chemical group called an "azide" and another called a "phosphine." Azides are very small and don't exist naturally in living systems, which makes them perfect for tagging. Phosphines are also not found in living things. These two groups react together to form a stable bond.

Why it's Not Used as Much Now

Even though it was a breakthrough, the Staudinger ligation has some downsides:

• The phosphine chemicals can slowly react with air inside living systems.
• The reaction is quite slow. This means scientists need to use a lot of the chemicals, which can sometimes create a lot of background signal, making it harder to see the tagged molecules clearly.

Copper-free Click Chemistry

Copper-free click chemistry is another very important bioorthogonal reaction, also developed by Carolyn Bertozzi. It's a much faster and more popular choice than the Staudinger ligation.

Why "Copper-free"?

The original "click chemistry" reaction was very fast and useful, but it needed a copper catalyst. The problem is, copper ions are toxic to living cells because they can create harmful chemicals that damage cells. Copper-free click chemistry solved this by finding a way for the reaction to happen quickly without any copper, making it safe for living systems.

Why it's So Good

This reaction uses an "azide" group (the same small, safe tag) and a special ring-shaped molecule called a "cyclooctyne."

• Azides are perfect because they are tiny, stable, and don't naturally exist in cells, so they won't react with anything else.
• Cyclooctynes are also stable and don't interfere with living systems. They are "strained" molecules, meaning they have a bit of tension in their rings, which makes them very eager to react quickly with azides.

This reaction has been used successfully in cultured cells, in live zebrafish, and even in mice.

Making Cyclooctynes Better

Scientists have worked hard to create many different types of cyclooctynes to make the reaction even faster and more useful:

• OCT was the first cyclooctyne. It worked but was not very water-soluble and wasn't much faster than the Staudinger ligation.
• ALO was made to be more water-soluble, but it was still slow.
• MOFO and DIFO were created by adding fluorine atoms. Fluorine helps speed up the reaction without causing problems in living systems.
• DIBO was designed to have a lot of "strain," making it react very quickly.
• BARAC added a special bond that increased the reaction speed even more. It's so fast that scientists often don't need to wash away extra chemicals, which is great for real-time imaging.
• Newer versions like DIBAC and ADIBO were made to be even faster.
• DIMAC was developed to be more water-soluble, which is important for studies in animals, as some cyclooctynes can get stuck to proteins in the blood.

How it's Used

The most common use of copper-free click chemistry is in biological imaging. Scientists can tag a molecule with an azide, then add a cyclooctyne that has a glowing dye attached. When they react, the dye lights up, showing where the tagged molecule is in a cell or animal.

It's also being explored for:

• PET imaging: This is a type of medical imaging that uses special radioactive chemicals. Copper-free click chemistry can help make these chemicals quickly and safely.
• Cancer treatment: Companies are even looking into using click chemistry to deliver cancer medicines directly to tumors.

Other Bioorthogonal Reactions

Scientists are always developing new bioorthogonal reactions to have more tools for different studies.

Nitrone Dipole Cycloaddition

This reaction uses "nitrones" instead of azides, reacting with cyclooctynes. It's very fast, but it's harder to add nitrones to molecules using natural cell processes.

Tetrazine Ligation

This reaction is incredibly fast! It uses a "trans-cyclooctene" and a "tetrazine." It's so quick that it can be used to label molecules even when they are present in very small amounts. It works well in water and has been used to label living cells.

Photoclick Chemistry

This cool method uses light to start the reaction. Scientists can shine a light on a specific area to make the reaction happen only there. This allows for very precise control over where and when molecules are labeled.

Quadricyclane Ligation

This reaction uses a molecule called "quadricyclane," which is very strained and reacts with specific chemical partners. It's special because it doesn't react with other common bioorthogonal chemicals, meaning you could potentially use it at the same time as other reactions without them interfering.

Uses of Bioorthogonal Chemistry

Bioorthogonal chemistry is a powerful tool for many areas, especially in medicine:

• Nuclear imaging: This involves using small amounts of radioactive substances to see what's happening inside the body. Bioorthogonal chemistry can help deliver these substances precisely.
• Radiotherapy: This is a type of cancer treatment that uses radiation. Bioorthogonal chemistry could help target radiation more accurately to cancer cells.

See also

In Spanish: Química bioortogonal para niños