Hydrazone Dynamic Combinatorial Chemistry (DCC) is based on hydrazone exchange. Under acidic conditions, hydrazone exchange takes place reversibly.
The building blocks we are using are based on peptide scaffolds. The aldehyde terminus can be protected by an acetal group while the hydrazide group is generally obtained by hydrazinolysis of an amino acid methyl ester. Under acidic conditions, the acetal group will be deprotected and hydrazone formation and exchange will occur.
The hydrazone library was created by mixing 5 mM building blocks with 5 equivalent trifluoroacetic acid (TFA). The major product for mPro library is cyclic dimer in the absence of template. And cyclic trimer can be significantly amplified by ammonium cations, especially acetylcholine.
In the pPFm library, several products are present in equilibrium, mainly cyclic dimer, trimer, tetramer and pentamer. pPFm is more soluble and flexible than mPro, and gives a more diverse library which is susceptible to several kinds of templates.
Metal salts, such as LiI and NaI, can amplify the trimer at the expense of other oligomers to give up to 99% yield, allowing its ready isolation as a pure product.
We are currently exploring a range of different building blocks and templates.
We have recently selected an extraordinary acetylcholine receptor by adding the neurotransmitter to solutions of the same pPFm building block described above. At thermodynamic equilibrium, the dominant receptor structure was an elaborate -catenane, consisting of two interlocked macrocyclic trimers. This complex receptor with a remarkable affinity and selectivity for acetylcholine could be isolated on a preparative scale in 65% yield.