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DEL technology and DNA-compatible chemical reaction DEL technology, as a new generation of high-volume screening technology, chemical synthesis and gene coding strategy organic combination, has been widely used in the development of new drugs.
one of the biggest challenges in the synthesis of DNA-coded compound libraries is that the DNA portion of the DEL molecule limits the types of organic chemical reactions available, greatly affecting the chemical spatial diversity of the compound library.
, developing DNA-compatible chemical reactions is key to building a library of diverse compounds.
currently, DNA-compatible chemical reactions have achieved a number of successes in the construction of C-N bonds (alamide/pyrethrea compound synthesis, reductive amineization, Michael Plus, Buchwald joint reactions, SNAr, SN2, etc.); The construction of the -C key is limited to sp2 carbon bonds (Suzuki coupled reaction, Wittig reaction, etc.), while the widespread C(sp3)-C (sp2) and C (sp3)-C (sp3) builds are rarely reported.
note that reports related to visible light-mediated organic chemical reactions have grown exponentially over the past decade.
, compared with traditional synthesis methods, the organic reaction of visible light mediation has the advantages of mild reaction conditions, simple steps and environmental friendliness.
same time, the visible photo catalytic system has demonstrated excellent catalytic synthesis value and application potential in the construction of C(sp3)-C (sp2) and C (sp3)-C (sp3), and is widely used in the synthesis of complex compounds.
, if the photochemical reactions mediated by visible light can be successfully applied to DEL synthesis, the chemical space diversity of the compound library will be greatly enhanced.
Figure 1: DNA-compatible photoreactive research advances the development of DNA-compatible visible light-mediated chemical reactions In recent years, chemists have also developed DNA-compatible visible light-mediated chemical reactions and applied them to the construction of DNA-coding compound libraries (Figure 1).
2019, the Gary A. Molander team at the University of Pennsylvania applied visible light-mediated organic photochemical reactions to the synthesis of DNA-coded compounds, pushing research in the field to a new level.
they used a nickel/photooxidant double catalytic system to achieve a cross-coupled reaction between aromatic halogen substitutes and alkyl free-based pregenitors C(sp3)-C (sp2).
, Pfizer has also developed DNA-compatible visible-light-mediated Giese reactions for C (sp3)-C (sp3) construction.
In view of the fact that 1,2-amino alcohols are important units of various natural products and drug-active molecules, the Pharmaceutical Mingkangde HitS team has developed DNA-compatible visible light-mediated α-amino acids that are de-coupled with niobium compounds for the synthesis of 1,2-amino alcohol compounds.
figure 2: The substrate range of niobium-based compounds Visible light-mediated de-coupled reaction conditions are mild and efficient The reaction uses ir (ppy) 2 (dtbbpy)PF6 as a photocatalyst, and the reaction can be efficiently obtained at room temperature for 10 minutes.
, using α-amino acid 2a as a free-form subject, this paper examines the effects of niobium-based compound 1 on reactions with DNA connections from different hydrometathyl groups (Figure 2).
The method is well suited to aromatic aldehyde derivatives, the vast majority of replacement base (e.g., alkyl, aromatic, halogen, teflone, amide, N/O/S hybrid ring, etc.) position has less effect on the reaction, can be good to excellent yield to get the target product.
addition, the method is also well applied to alkyl-alkylone, dilecone and dylamine and other substrates, but relative to alkaldehyde compounds, the yield will be reduced.
Figure 3:α - The substrate range of amino acids Subsequently, the authors also expanded the α-amino acid 4, as shown in Figure 3, a variety of multi-functional groups (amine, Cl, Br, etc.) of α-amino acids, can and the corresponding on-DNA benzodialyde de-coupled reaction.
4: Reaction devices To meet the production needs of a DNA-coded compound library, the team also designed its own photoreactive devices for high-volume production (Figure 4).
the reaction device can be accurate control of reaction temperature, light intensity and so on, one-time can complete the production of 12 96-well plate.
, the team conducted experiments to assess the damage to DNA caused by light reactions.
dna connection experiment and second-generation sequencing experiment show that the visible light-mediated de-coupled reaction has DNA compatibility and does not cause significant damage to DNA.
, the HitS team is conducting more in-depth research to apply this reaction to the construction and production of high-quality DNA-coded compound libraries.
summary, the visible light-mediated de-coupled reaction expands the de-coupled reaction suitable for del's visible light-mediated de-coupled reaction.
under mild conditions, the use of α-amino acids and carboxyl compounds as substrates to achieve the efficient synthesis of 1,2-amino alcohols, in the construction of del library has a great application prospects.
references: s1, Wen, Huanan; Ge, Rui; Qu, Yi; Sun, Jialin; Shi, Xiaodong; Cui, Weiren; Yan, Hao; Zhang, Qi; An, Yulong; Su, Wenji; Yang, Hongfang; Kuai, Letian; Satz, Alexander. L.; Peng, Xuanjia. Org. Lett. 2020, 22(24), 9484-9489. DOI:10.1021/acs.orglett.0c03461 [2]Romero, N. A.; Nicewicz, D. A. Chem. Rev. 2016, 116, 10075-10166. [3] Phelan, J. P.; Lang, .B.; Sim, J.; Berritt, S.; Peat, A. J.; Billings, K.; Fan, L.; Molander, G. A. J. Am. Chem. Soc. 2019, 141, 3723-3732. [4] Kölmel, D. K.; Loach, R. P.; Knauber, T.; Flanagan, M. E. ChemMedChem 2018, 13, 2159-2165. Source: Medical Mission Hills