DBCO-C6-acid
[CAS# 1425485-72-8]

Identification

• Classification: Organic raw materials >> Heterocyclic compound
• Name: DBCO-C6-acid
• Synonyms: 6-(2-azatricyclo[10.4.0.04,9]hexadeca-1(16),4,6,8,12,14-hexaen-10-yn-2-yl)-6-oxohexanoic acid
• Molecular Formula: C₂₁H₁₉NO₃
• Molecular Weight: 333.38
• CAS Registry Number: 1425485-72-8
• SMILES: C1C2=CC=CC=C2C#CC3=CC=CC=C3N1C(=O)CCCCC(=O)O

Properties

• Density: 1.3±0.1 g/cm³ Calc.^*
• Melting point: 118 - 125 °C (Expl.)
• Boiling point: 634.4±55.0 °C 760 mmHg (Calc.)^*
• Flash point: 337.5±31.5 °C (Calc.)^*
• Index of refraction: 1.654 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H315-H319-H335
• Safety Statements: P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P305+P351+P338-P330-P332+P313-P337+P313-P362-P403+P233-P405-P501

Discovery and Applications

The chemical substance DBCO-C6-acid, also known as dibenzocyclooctyne-hexanoic acid, is a heterobifunctional linker featuring a dibenzocyclooctyne (DBCO) group and a carboxylic acid connected by a six-carbon spacer. It is widely used in bioconjugation and pharmaceutical chemistry, particularly for bioorthogonal chemistry applications. Its discovery and applications are well-documented in the literature, rooted in the development of strain-promoted azide-alkyne cycloaddition (SPAAC) and linker chemistry.

The origins of DBCO-C6-acid are tied to the development of bioorthogonal chemistry, which gained prominence in the early 2000s with the introduction of SPAAC by Carolyn Bertozzi and coworkers. Unlike copper-catalyzed azide-alkyne cycloaddition, SPAAC uses strained cyclooctynes, such as DBCO, to react selectively with azides without catalysts, making it ideal for biological systems. DBCO, with its dibenzannulated cyclooctyne structure, was developed to enhance reaction kinetics and stability. The addition of a C6 (hexanoic acid) spacer and carboxylic acid group emerged to provide a versatile handle for conjugation, driven by the pharmaceutical industry’s need for biocompatible linkers in applications like antibody-drug conjugates (ADCs) and protein labeling. Advances in cyclooctyne synthesis and functionalization in the 2000s enabled the production of DBCO-C6-acid.

Synthetically, DBCO-C6-acid is prepared through a multi-step process. A typical route starts with the synthesis of the DBCO core, involving cyclization of a diaryl precursor to form the strained cyclooctyne, often via a sequence of Sonogashira coupling, ring-closing reactions, and deprotection. The C6 spacer is introduced by coupling a hexanoic acid derivative, such as 6-bromohexanoic acid, to the DBCO framework through nucleophilic substitution or cross-coupling. The carboxylic acid is either retained from the spacer or installed via hydrolysis of an ester precursor. These steps rely on well-established protocols in alkyne chemistry, cross-coupling, and functional group manipulation, ensuring high purity and functionality.

The primary application of DBCO-C6-acid is as a bioconjugation linker in pharmaceutical and biochemical research. The DBCO group undergoes rapid, selective SPAAC with azides in aqueous environments, forming stable triazole linkages without the need for copper catalysts, which is critical for in vivo applications. The carboxylic acid serves as a handle for conjugation to amines (via amide formation using coupling agents like EDC/NHS) or other nucleophiles, enabling attachment to proteins, peptides, or small molecules. The C6 spacer provides flexibility and reduces steric hindrance, improving conjugation efficiency. This compound is widely used in the synthesis of ADCs, protein-drug conjugates, and diagnostic probes, where it facilitates site-specific labeling or drug attachment to enhance therapeutic efficacy and specificity. It is also employed in biomaterials, such as hydrogels, for creating biocompatible scaffolds.

In academic research, DBCO-C6-acid is used to study bioorthogonal reaction kinetics, linker design, and bioconjugation strategies. Its synthesis has contributed to advancements in cyclooctyne chemistry and heterobifunctional linker development. Commercially, it is available from suppliers like BroadPharm and Sigma-Aldrich as a reagent-grade product for research purposes, typically with high purity (≥95%).

The significance of DBCO-C6-acid lies in its role as a bioorthogonal linker that combines the rapid, selective reactivity of DBCO with the synthetic versatility of a carboxylic acid and a C6 spacer. Its development reflects progress in bioorthogonal chemistry and linker technology. By enabling precise, biocompatible conjugation of biomolecules, it has become a critical tool in advancing pharmaceutical, biochemical, and materials research.

References

none