Broadpharm基礎(chǔ)篇什么是點(diǎn)擊化學(xué)？What is Click Chemistry?

Click Chemistry is a chemical reaction between pairs of reagents (named click chemistry reagents) to exclusively react with each other under mild conditions and is effectively inert to naturally occurring functional groups such as amine groups. The term "Click Chemistry" was first coined by Sharpless in 2001 in an effort to design a method to easily synthesize molecules under mild conditions and the product can be easily isolated.

The first generation of Click Chemistry involved the reaction of azide with alkyne catalyzed by Cu(I). The copper catalyst allows for this reaction to be carried out efficiently under mild conditions in water whereas the reaction would require high temperature and high pressure without the copper catalyst. Copper catalyzed Click Chemistry has been found to have the second fastest rate constant of 10-100 M^-1s^-1.

Due to the toxic nature of copper to living structures and biosystems, copper catalyzed Click Chemistry is not a viable method of carrying out reactions in living systems which has led to the development of the following two generations of Click Chemistry.

(2) Strain-promoted Azide-Alkyne Click Chemistry (SPAAC reactions, Figure 2):

DBCO reagent or BCN reagent can be used to perform Click Chemistry with azide molecules without the need of heavy-metal catalysis.

The bond strain created by the bond angle of the cyclooctyne (DBCO or BCN) requires less energy for the cyclooctyne to form the (3+2) cycloaddition which releases enthalpic energy caused by the ring strain of the cyclooctyne. This generation does not require copper as a catalyst and it can be used in cell surface and in vivo labeling. The rate constant is 10^-2-1 M^-1s^-1.

The third generation of Click Chemistry is the ligation between tetrazine with trans-Cyclooctene (TCO). The mechanism for this ligation utilizes ring strain from the trans-Cyclooctene and an inverse Diels-Alder reaction between the electron rich trans-Cyclooctene and the electron poor tetrazine. This ligation has been found to be the fastest generation of Click Chemistry thus far with a rate constant of 1-10⁶ M^-1s^-1. The reaction can also be carried out in vivo in aqueous solution.

Applications of Click Chemistry

Click Chemistry has been widely used in drug discovery, bioconjugation, labeling, and material sciences in the pharmaceutical and biotech industry due to its mild conditions and high selectivity.

Click Chemistry in Drug Discovery

Click Chemistry is utilized in the formation of ADC linkers in antibody drug conjugates. For example, Trodelvy (Sacituzumab Govitecan), also known as IMMU-132 (Figure 4), is an immune target therapy medicine for triple-negative breast cancer which contains sacituzumab and SN-38 bound with a linker. Click Chemistry is used in the formation of the linker to form a triazole that links SMCC to a PEG8 moiety.

Click Chemistry in Joint Cartilage Therapy

Click Chemistry has also been used in cell-based therapy to treat damage in joint cartilage, relieve pain, and improve function. Autologous chondrocyte transplantation targets apoptotic chondrocytes in cartilage which can be identified by a six amino acid peptide, ApoPep-1, and by binding injected healthy chondrocytes from unaffected cartilage. ApoPep-1 carries a trans-Cyclooctene bound by a PEG Linker to apoptotic chondrocytes which can then bind healthy chondrocytes via Click Chemistry to tetrazine to encourage cartilage regeneration (Figure 5).

Click Chemistry Tools

As a leading click chemisty reagent supplier worldwide, BroadPharm provides over 500 high purity Click Chemistry Reagents (tools) and Kits with an array of functional groups such as: Azide, Alkyne, DBCO, TCO, Tetrazine, BCN to empower our clients' advanced research and drug development.

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