DNA-Compatible Benzotriazinone Formation through Aryl Diazonium Intermediates

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Chemical Biology

Background:

• DNA-encoded chemical libraries (DELs) are crucial for high-throughput screening of drug-like compounds.
• Incorporating N-containing heterocycles with bioactivity into DELs is a key strategy in drug discovery.
• Developing DNA-compatible synthetic methodologies is essential for advancing DEL technology.

Purpose of the Study:

• To report a novel synthetic methodology for constructing benzotriazinone scaffolds.
• To demonstrate the DNA-compatible nature of the developed synthetic route.
• To enable the diversification and late-stage decoration of DNA-encoded combinatorial libraries.

Main Methods:

• Synthesis of benzotriazinone core via aryl diazonium intermediates.
• Coupling of DNA-conjugated amines with anthranilic acid or isatoic anhydride building blocks.
• Tert-butyl nitrite-triggered cyclization to form the 1,2,3-benzotriazin-4(3H)-one structure.

Main Results:

• A versatile methodology for synthesizing drug-like benzotriazinone scaffolds was established.
• The synthetic route is compatible with DNA-encoded library synthesis.
• Late-stage decoration of DNA-conjugated amines with bioactive benzotriazinone caps was achieved.
• Broad substrate scope and high conversion rates were observed.

Conclusions:

• The developed methodology provides a promising approach for diversifying DNA-encoded combinatorial peptide-like libraries.
• This method facilitates the incorporation of medicinally relevant heterocyclic moieties into DELs.
• The strategy enables the efficient synthesis of compound collections for drug discovery and high-throughput screening.