Click chemistry has developed organic reaction methodologies that are rapid, effective, and specifically selective, and its reaction system is not sensitive to oxygen or water. This article first reviews the types of click and click-like reactions, and then introduces their applications in medicinal chemistry.
Types of click reactions
1.Cycloaddition reaction
In the earliest click reaction, Cu(I) was used to catalyze azide and terminal alkyne to obtain selective 1,4-disubstituted 1,2,3-triazole compounds, as shown in the first reaction in figure 1. Without Cu catalysis, the reaction is slow and prone to obtain a mixture of 1,4-disubstituted and 1,5-disubstituted triazole.
If the terminal alkyne is replaced with a macrocyclic alkyne, the cycloaddition reaction is more likely to occur, thus releasing the ring tension of the macrocyclic alkyne sp hybridization, which does not require Cu catalysis and is more friendly to biological systems. It is known as strain-promoted azide-alkyne cycloaddition (SPAAC), as the second reaction in figure 1.
If the azide is replaced with tetrazine and the macrocyclic alkyne group is replaced with the macrocyclic trans-alkenyl group, then the DA cycloaddition occurs first, followed by the reverse reaction to remove N2, as shown in the third reaction in figure 1. Since tetrazine is an electron deficient diene unit, which is opposite to the electron rich diene unit in general DA, it is called inverse electron-demand Diels–Alder (IEDDA) reaction.
2.Sulfur (VI) fluoride exchange reaction, SuFEx
This is a method close to click reaction, which uses sulfur tetrafluoride (O=SF4) or sulfuryl fluoride (SO2F2) to prepare sulfonyl derivatives with nucleophile (alcohol or amine), and then reacts with another nucleophile to obtain disubstituted sulfonyl derivatives, as shown in figure 2. Sulfur (VI) fluoride exchange reaction is carried out by using synthetic blocks containing amino heads to efficiently prepare combinatorial chemical libraries. Although they may have competitive reactions in organisms and cannot be used in bioorthogonal reactions, they are suitable for high-throughput reactions in molecular screening and synthesis, and can be directly used in bioassay experiments due to their almost quantitative high yield and biological system compatibility.
3.Addition reaction
Addition reaction often requires free radical initiation conditions (light, reagent catalysis, etc.). The thiol-ene/amine-ene reaction based on Michael addition was developed, as shown in figure 3. The presence of electron withdrawing groups makes the reaction easier to occur, and the reaction conditions are milder compared with free radical reaction.
4.Nucleophilic substitution
Nucleophilic substitution reaction refers to the nucleophilic substitution and ring opening reaction of epoxide or propidium, as shown in figure 4. It can be carried out in ethanol and water systems, with good ring-opening site selectivity, high yield, and convenient post-processing. However, since the amino group of the reaction substrate is also prone to attack other electrophilic functional groups, there may be by-products of competitive reactions, which is not as applicable as cycloaddition, and can only be counted as click-like reactions.
5.Carbonyl condensation reaction
These reactions include the synthesis of hydrazone and oxime, as shown in figure 5, and some heterocycles containing N and O. This kind of reaction also has applications similar to click, but the reaction rate is relatively slow, and is easy to have competitive reactions, so it is rarely used in the field of bioorthogonal chemistry. Since the molecular fragments obtained by the reaction have good drug properties, they are more widely used in drug synthesis. With different substituted substrates, the structure-activity relationships can be further explored.
Applications of click reaction in medicinal chemistry
1.For bioelectronic isoform replacement
The drug properties of 1,2,3-triazole fragments are similar to those of nitrogen aromatic rings such as 1,2-diazole and amide bonds, so fragment substitutions or skeleton transitions can be performed to explore the chemical space for optimizing the lead compound.
2.As a peptide-like fragment
The 1,2,3-triazole fragment is similar to the amide bond (peptide bond), and will not be hydrolyzed by protease. On the one hand, skeleton transitions can be made to explore more possible lead compounds. On the other hand, the more stable chemical property of triazole can be exploited to improve ligand selectivity. Finally, the click reaction of triazole formation can be used to achieve high efficiency of cyclic peptide macrocyclic closure reaction and ensure certain protease tolerance.
3.Linking different molecular fragments
In medicinal chemistry, researchers can use triazole fragments to link different pharmacophores. It can also serve as a linker junction site for PROTAC and conjugate peptides, antibodies, and small molecules (ADCs) for targeted drug delivery.
4.Efficient synthesis and in situ screening of combinatorial chemical libraries
When efficient click chemistry combines with the idea of combinatorial chemistry, researchers can achieve high-throughput molecular library synthesis and in situ screening.
5.In situ synthesis
In situ synthesis of drug molecules in biological systems is closer to the application of bioorthogonal chemistry. For example, the template effect of the target protein and the idea of dynamic combinatorial chemistry can be used to achieve in situ click synthesis and affinity screening of fragments with low activity (IC50 > 1 mM).
Conclusion
More click reactions or click-like reactions are needed to enrich the synthesis methods. At the same time, it is critical to reduce the dependence on metal catalysts and improve the compatibility of biological systems, which can accelerate the discovery of lead compounds and ultimately lift the efficiency of drug development.
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References
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- Jiang, X. et al. Recent applications of click chemistry in drug discovery. Expert Opin. Drug Discov. 14, 779-789 (2019).
- Meng, G. et al. Modular click chemistry libraries for functional screens using a diazotizing reagent. Nature 574, 86-89 (2019).
- Kitamura, S. et al. Sulfur(VI) Fluoride Exchange (SuFEx)-Enabled High-Throughput Medicinal Chemistry. J. Am. Chem. Soc. 142, 10899-10904 (2020).
- Ragnarsson, U. Synthetic methodology for alkyl substituted hydrazines. Chem. Soc. Rev. 30, 205-213 (2001).