A new strategy increases the photolysis efficiency of the corresponding N-alkylpyridinium salt by about 400 or 700 times, respectively

2020/09/24

In recent years, Photoremovable Protecting Groups and PPGs have been widely used in chemical biology and organic synthesis research fields. Utilizing the covalent bonding of PPG and biologically active small molecules can make the small molecules unable to bind to the target biological macromolecules (such as proteins) and lose their activity. Under light irradiation, the covalent bond between the excited PPGs and the small molecule is broken, thereby releasing the small molecule with biological activity.


At present, most of the chemical groups used to be protected are limited to common leaving groups such as carboxyl radicals. Active molecules without these groups are difficult to use light-controlled release strategies to study, especially pyridine compounds, which act as aromatic heterocycles. Most of the compounds have biological activity, and the pyridine structure is also widely present in drug molecules (such as the anticancer drug Nilotinib). However, light-controlled release of pyridine in aqueous solution is more challenging.


Recently, Fang Xiaohong, a researcher at the Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, has developed a new strategy to release pyridine by inhibiting intramolecular electron transfer in aqueous solution by photolyzing N-alkylpyridine salts.


Taking 7-diethylamino-4-methylcoumarin-protected pyridine as the research object, the research group used solvent effect and TD-DFT theoretical calculations and found that due to the rapid intramolecular photoinduced by coumarin and pyridine salt (Photoinduce Electron Transfer), the photolysis reaction of removing the pyridine protecting group is difficult to proceed. Utilizing the energy difference between the coumarin singlet state S1 and the triplet state T1, the heavy atom bromine or iodine is introduced into the 3 position of the protective group coumarin to increase the probability of crossing the S1 state gap to the T1 state, which can inhibit the electrons Transfer to increase the photolysis efficiency of the corresponding N-alkylpyridine salt by about 400 or 700 times, respectively.


This photolysis reaction strategy has good universality, is suitable for most pyridine derivatives, imidazole and thiazole, and has high chemical yield. It has been successfully used for the light controlled release of more than 20 pyridine compounds, and the photolysis efficiency and pyridine ring The nucleophilic ability of the upper nitrogen atom is related to the electron cloud density of the pyridine ring. In addition, the photolysis reaction can also be realized by two-photon excitation. Taking N-alkylpyridinium salt as an example, its two-photon photolysis absorption cross section under 880 nm light is as high as 0.51 GM. The photolysis reaction was successfully applied to the release of active molecules in living cells. Under the low phototoxicity of 488 nm light, the release of the tubulin polymerization inhibitor Indibulin containing pyridine structure in living cells and the regulation of the inhibitory function of tubulin polymerization are achieved. This is the first reported method to release pyridine by high-efficiency photolysis of N-alkylpyridinium salt protected by organic PPG, which deepens the understanding of the molecular mechanism of the physicochemical process of photodeprotection group, and is useful for the development of pyridine-based structure in living cell systems. Researches on chemical regulation of biologically active molecules, drug delivery, and super-resolution imaging provide new tools.


Source: Xianji.com