To fully understand Click Chemistry and its contributions to biotechnologies and life sciences, it is crucial to comprehend the various actors who take part in this complex mix and how they interact.
Biology, the Living and Chemistry
When we deal with biotechnologies or medical sciences, we work on a common basis: Biology, which is all about studying the Living.
Defining the Living is quite complex, it gathers a lot of organisms defined by many different characteristics. Three of these characteristics allow us to determine what a living creature is:
– Ability to feed itself or the ability to use organic material around its own environment to produce energy,
– Ability to reproduce and thus perpetuate the species in an autonomous way,
– Ability to interact with its environment.
All these actions are made possible thanks to the interactions of molecules (the combination of atoms linked by covalent connections) and ions (atoms or groups of charged atoms), whether they are part of the organism, or its surroundings.
In the end, a living organism, no matter how complex it is, is just a mix of numerous coordinated chemical reactions, involving biomolecules. Biology studies these reactions and their consequences on the organism.
To fully understand this article, let’s take an example with muscular contraction, which is the result of a double reaction. On the one hand, we have a reaction between a myosin molecule and an ATP (adenosine triphosphate) molecule and on the other hand, we have a reaction between this same myosin molecule and an actine molecule.
The change in the spatial conformation led by the first one allows the second one to happen, and thus allows the muscle to contract.
What is Click Chemistry?
Click Chemistry refers to a category of chemical reaction. It was first introduced by Barry Sharpless in 2001. This specific class of chemical reaction is defined as a reaction “able to form synthetic intermediates very rapidly and efficiently by making covalent connections”.
Nevertheless, all reactions involving a covalent connection and producing synthetic intermediates are not Click reactions. To be categorised as such, it must be:
– Specific: it must lead to the synthesis of a single product (whether it is led by the original reagent or by the spatial arrangement of atoms),
– Regio-selective: one of the reagents reacts preferentially with the site of the other reagent,
– Active at room temperature,
– In an aqueous, organic (composed of carbon) or hydro-alcoholic reaction environment,
– Without the formation of toxic products or by-products,
– Able to be purified without using chromatography.
To summarize, a Click Chemistry reaction consists in building blocks of molecules by creating a strong connection between two molecule blocks in a selective and reproductive way, at least energetic cost and in mild reaction conditions.
The applications of Click Chemistry
Since its introduction in 2001, Click Chemistry reactions have always been studied in various fields of life sciences, from simple and small molecule synthesis and drug discoveries in the pharmaceutical industry, to polymerisation of materials or Nanoparticles synthesis.
More recently, the studies revealed to be interested by Huisgen’s reactions, also known as 1,3-dipolar cycloaddition. This reaction, published in 1963 by Huisgen, allows to join 2 molecules (for instance azides and alkynes), in a strong and solid way, without affecting the integrity of the radicals. The primary reaction studied by Huisgen was quite costly energy-wise since it needed a high temperature to be made.
Development of new techniques
In 2002, Toner and Medal developed a technique based on Click Chemistry and allowing to achieve Huisgen’s reaction at least energetic cost and without needing to separate reaction products. To do so, they used copper as a catalyst for the synthesis. The reaction is then being made at room temperature (25°C) very rapidly and in a regio-selective way, which brings up an advantage if a certain type of regio-isomer is preferred (to synthetise an intermediate, to work specifically on the regio-isomer, etc.).
Henceforth, numerous studies have concerned the use of the 1,3-dipolar cycloaddition with the method of Click Chemistry, in many different fields like material chemistry, pharmacology, or analytical chemistry. As examples for the use of this reaction, we can mention the synthesis of molecules combining a photosensitiser with targeting peptides, using Click Chemistry in order to fight and eradicate cancer.
The photosensitive molecule is meant to destroy a tumour by forming free radicals, once exposed to a defined wavelength. Targeting peptides act as guides for the molecular block to reach the tumour thanks to the recognition and the fixing to specific receptors which are presents on the surface of the tumour.
Connecting a photosensitive molecule to a targeting peptide can improve the effectiveness of the photodynamic therapy, by making it more specific and by limiting the risks to affect healthy live cells of the body.
There are numerous other studies concerning the use of Click Chemistry to connect two molecules, such as S. Mischler’s thesis in 2012 which shows the use of the 1,3-dipolar cycloaddition with copper to synthetise gold nanoparticles combined with molecules in a liquid crystal state. This study opens a new opportunity in synthetising materials.
The French National Agency of Research has also led a project about the use of Click Chemistry. Researchers have set up a Click – Unclick system which allows to control the release of a drug. This drug is first linked to a carrier peptide (formed by a Click Chemistry reaction), it is then turned inactive. This same link is going to be broken, by the action of a chemical (a change in the pH) or a biochemical (peptidase) trigger.
Click Chemistry reaction, through its specific and regio-selective characteristics ensures a unique synthesis of an inactive and activable prodrug system. The perspectives of the study are raising the question of using a physical trigger: light.
We could keep on enumerating the many other examples showing the use of Click Chemistry reactions in various fields, but all its application presents the same characteristics, simple to set-up and high-yield reactions, allowing the controlled synthesis of a new specific and functional group. This method has already proven to be very useful and offers high innovation perspectives in a lot of different fields.
