Carbocyclization-based DNA-encoded Glycan Library (DEGL)
Overview of DNA-encoded Glycan Library (DEGL)
DEGLs are emerging as a highly promising instrument in the realm of drug discovery. This technology facilitates the creation and examination of chemical libraries on an unprecedented scale at relatively moderate expenses. DEGLs involve the presentation of individual small organic chemical fragments on DNA sequences, which serve as amplifiable identification barcodes. The DNA tags enhance the synthesis process and permit the simultaneous screening of vast collections of compounds, potentially up to billions of molecules. This is possible because hit compounds can be efficiently identified and quantified through PCR amplification of the DNA barcode followed by high-throughput DNA sequencing. CD BioGlyco utilizes multiple methods to develop DEGLs, varying in both library encoding techniques and the combinatorial assembly of glycan moieties. Various reactions are employed for synthesizing DNA-encoded glycan compounds, such as Coupling Reaction, Multi-component Reaction, Photocatalytic Cycloaddition, Aromatic Heterocyclization, Non-aromatic Heterocyclization, Macrocyclization, and Click Chemistry.
Unlocking Glycan Potential: Carbocyclization-driven DEGL Innovation
The advent of new methodologies for library encoding and compound synthesis in the presence of DNA represents an exciting area of research that is expected to significantly enhance the performance and dissemination of this technology. CD BioGlyco uses on-DNA carbocyclization reactions, an important method in chemical synthesis for constructing cyclic compounds. Performing such reactions on DNA presents unique challenges and potentials.
- We conduct strain-promoted thermally induced carbocyclization reactions involving DNA-linked cyclic allenes and various glycans with activated and non-activated alkene structures. This reaction enables the formation of new carbon-carbon bonds on the DNA template, thereby supporting the construction of a fused four-membered ring structure.
- Besides, our research team uses Robinson cyclization reactions performed on DNA to yield glycans with trisubstituted cyclohexanone structure. In our approach, we use DNA-linked α,β-unsaturated ketones, and 1,3-dicarbonyl building blocks.
We provide new methods and insights for constructing complex glycan structures using DNA templates.
Workflow
The synthesis of DEGLs is a meticulously orchestrated and rigorously controlled process designed to produce libraries brimming with a vast array of drug-like compounds. Below is an elaborate description of our workflow:
Initiation Phase
The process commences with the construction of a DNA scaffold, often termed a DNA headpiece. This headpiece functions as a dual-purpose synthetic starting entity, characterized by a compact, self-complementary hairpin loop endowed with two 3'-overhang nucleotides, known as "sticky ends," facilitating cycle-specific enzymatic ligation. Chemical building blocks are attached to the DNA headpiece through a functional handle, such as a primary amine, which covalently bonds with the initial chemical building block. This handle acts as a pivotal connection point, enabling the systematic addition of chemical entities to the DNA in a controlled sequence.
Split-and-pool Synthesis
Utilizing the split-and-pool synthesis approach, successive chemical building blocks are introduced sequentially into the reaction. Each building block is linked with a distinctive DNA barcode, effectively bridging the chemical structure with the corresponding DNA sequence. This linkage integrates the molecular configuration with the genetic identifier.
Precipitation & Purification
A distinctive feature of DNA is its selective precipitation from an aqueous solution upon ethanol addition. This characteristic is crucial during synthesis, as it permits the efficient removal of excess reagents and non-DNA impurities after each chemical modification step. This process ensures the maintenance of the library's purity and structural integrity.
Finalization & Screening Preparation
Upon the incorporation of all predetermined chemical building blocks, the DEGL is complete and prepared for pooling and screening. The final library can then be subjected to screening against a stationary biological target in a singular experimental setup.
Publication Data
Technology: Robinson annulation
DOI: 10.1021/acs.orglett.3c02798
Journal: Organic Letters
Published: 2023
IF: 4.9
Results: In this paper, authors introduced an innovative aza-Robinson annulation strategy designed to synthesize densely functionalized bicyclic amides, which could be pivotal in alkaloid synthesis. They reviewed the conventional Robinson annulation applications, notably the synthesis of bicyclic diketones such as Wieland-Miescher ketone while highlighting the absence of analogous nitrogenated reactions in the literature. The authors developed a novel two-step aza-Robinson annulation methodology, which combines cyclic imides with vinyl ketones to yield bicyclic amides. The pivotal step in this methodology involves an intramolecular aldol condensation reaction catalyzed by TfOH, which engages the imide carbonyls with transiently formed enol entities derived from ketones. Ultimately, this new protocol was successfully applied to the synthesis of alkaloids (±)-coniceine and quinolizidine, achieved in just four steps with overall yields of 40% and 44%, respectively. Furthermore, the paper reveals an exceptional selectivity in the hydrogenation of enaminone systems present in compounds 4a and 4b, leading to the rapid formation of fully saturated amides.
Applications of DEGL
Advantages
- Our DEGL technology helps clients to swiftly pinpoint compounds with promising biological activity through DEL screening.
- Our DEGL technology notably enhances screening throughput, thereby expediting the drug discovery process.
- Our researchers possess the ability to help clients design targeted DEGLs, clients can effectively screen related glycan structures, pinpointing compounds with enhanced properties.
Frequently Asked Questions
- What are the advantages of DEGL technology over traditional screening?
- High throughput: DEL technology enables the evaluation of millions to billions of compounds in a single assay, a scale that significantly surpasses the traditional HTS capability.
- Operational simplicity: DEL libraries are compact and can be stored within a single, manageable container, streamlining the handling and operational aspects of the screening process.
- Minimal sample requirement: DEL technology demands substantially less target compound compared to traditional HTS.
- Does CD BioGlyco offer subsequent screening services?
- Yes, we do. We offer various screening strategies, including:
CD BioGlyco utilizes the unique attributes of DNA and the principles of combinatorial chemistry to conduct the synthesis of DEGLs. This service facilitates the generation of extensive libraries of diverse drug-like molecules. If you want to utilize its significant potential for drug discovery and other biomedical applications, contact us!
Reference
- Garay-Talero, A.; et al. An aza-Robinson annulation strategy for the synthesis of fused bicyclic amides: synthesis of (±)-coniceine and quinolizidine. Organic Letters. 2023, 25(43): 7940-7945.
For research use only. Not intended for any clinical use.
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