Constructive On-DNA Abramov Reaction and Pudovik Reaction for DEL Synthesis

Abstract

Organophosphonic compounds are distinctive among natural products in terms of stability and mimicry. Numerous synthetic organophosphonic compounds, including pamidronic acid, fosmidromycin, and zoledronic acid, are approved drugs. DNA encoded library technology (DELT) is a wellestablished platform for identifying small molecule recognition to target protein of interest (POI). Therefore, it is imperative to create an efficient procedure for the on-DNA synthesis of α-hydroxy phosphonates for DEL builds.

Simple and Practical DNA Quantification Method for DNA-Encoded Library Synthesis

“…Nevertheless, DNA is vulnerable and susceptible to damage under a variety of chemical reaction conditions . Thus, there is an imperative necessity to develop a method that is simple, rapid, practicable, and accurate for monitoring the DNA’s viability during chemical conversion. − Consequently, this should not only facilitate the application of known DNA-compatible reactions to a wide variety of substrates but would also guide the exploration of new on-DNA chemistry. − As part of our efforts to develop novel DNA-compatible reactions and their subsequent implementation in routine DEL synthesis, we recognized DNA damage as a critical and imperative matter to address. Our efforts have resulted in the development of an LC-MS-based method meeting these requirements.…”

Development of On‐DNA Thiophene Synthesis for DEL Construction

“…[13][14][15] In recent years, a great emphasis has thus been put on the development of DNA-compatible reactions, particularly for the creation of new chemical structures which are otherwise difficult to access via conventional approaches. [16][17][18][19][20][21] Thiophene derivatives are a crucial class of heterocycles in medicinal chemistry and well-represented among approved pharmaceuticals (Figure 1). For instance, Canagliflozin, sold under the brand name Invokana, is used to treat type 2 diabetes.…”

“…To expand the DEL‐amenable chemical space, there is a significant need to adapt existing methodologies to DNA‐compatible conditions [13–15] . In recent years, a great emphasis has thus been put on the development of DNA‐compatible reactions, particularly for the creation of new chemical structures which are otherwise difficult to access via conventional approaches [16–21] . Thiophene derivatives are a crucial class of heterocycles in medicinal chemistry and well‐represented among approved pharmaceuticals (Figure 1).…”

On-DNA Morita-Baylis-Hillman Reaction: Accessing Targeted Covalent Inhibitor Motifs in DNA-Encoded Libraries

“…To expand the diversity of the DEL-amenable chemical toolbox, especially in the homologation section, methods were sought to forge C–C bonds through a variety of coupling including Suzuki coupling, olefin metathesis, aldol condensation, cycloaddition, and radical-based cross-coupling . Nonetheless, considering the constant need for C–C bond formation in library builds, the lack of on-DNA access to certain key pharmaceutically relevant motifs, and our thirst for the development of unique and chemical space enriching methodologis, − we naturally took interest in this field and approached it through a new lens.…”