Improved Diazo-Transfer Reaction for DNA-Encoded Chemistry and Its Potential Application for Macrocyclic DEL-Libraries.

Selahattin Ede,Keith Graham,Donald Bierer,Mandy Schenk,Hilmar Weinmann

doi:10.3390/molecules26061790

Selahattin Ede, Keith Graham + Show 3 more

Open Access

https://doi.org/10.3390/molecules26061790

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Abstract

DNA-encoded libraries (DEL) are increasingly being used to identify new starting points for medicinal chemistry in drug discovery. Herein, we discuss the development of methods that allow the conversion of both primary amines and anilines, attached to DNA, to their corresponding azides in excellent yields. The scope of these diazo-transfer reactions was investigated, and a proof-of-concept has been devised to allow for the synthesis of macrocycles on DNA.

Highlights

The power of DNA-encoded libraries (DEL) has become an important and powerful platform to identify new ligands for diseases of pharmacologically interest
More recent discoveries show that radical chemistry [9], photochemistry [10,11,12], palladium and copper cross coupling reaction [13,14,15,16,17], and reactions carried out in non-aqueous conditions using a solid phase approach are possible [18,19]
We were interested in developing methods to introduce an azide selectively at a late stage of the library synthesis and use this azide to explore different conjugations, in an intramolecular Huisgen [3 + 2]-cycloaddition to generate medicinal chemistry-like macrocycles

Summary

Introduction

The power of DNA-encoded libraries (DEL) has become an important and powerful platform to identify new ligands for diseases of pharmacologically interest. DEL libraries can vary significantly in size; they typically contain millions of compounds each individually linked covalently to a unique DNA strand This DNA strand has a unique set of different base pairs that act as a barcode to identify the compound structure that is covalently attached. The work of Gironda-Martínez et al [24] showed that it was possible to generate azides selectively from the corresponding a-amino group within amino acids conjugated to DNA, via a diazo-transfer reaction, using the relatively safe imidazole1-sulfonyl azide tetrafluoroborate salt. This method was developed to proceed without copper as a catalyst as the copper could potentially cause DNA-damage.

Optimization of the Diazo-Transfer Reaction on Two Model Systems

Determining the Scope for the Optimized Diazo Reaction Conditions

Off-DNA and on-DNA Macrocycle Formation

Conclusions