Benzo[1,2-b:3,4-b':5,6-b']trithiophene-2,5,8-tricarbaldehyde – a curious, multifunctional organic compound – has become a hit in recent years as a linker in the construction of COFs for drug delivery systems. CoFs are a new type of porous materials that are crystallinity and highly ordered and that could be applied to many different applications such as drugs. As a linker, benzo[1,2-b:3,4-b':5,6-b']trithiophene-2,5,8-tricarbaldehyde is a particular linker with certain advantages owing to its special chemical structure (trithiophene centre and 3 aldehyde functional groups) for the synthesis of stable, durable and polyvalent COFs. The trithiophene base of benzo[1,2-b:3,4-b':5,6-b']trithiophene-2,5,8-tricarbaldehyde imparts astonishing electronic and structural stiffness to the structures that emerge. Three thiophene rings welded together in a tricyclic configuration provides a π-conjugated system that increases the electronic interactions in the COF. This is especially useful in drug delivery applications where the electronic properties of the architecture can impact the loading and release profiles of different therapeutic compounds. The -conjugation, for example, can communicate with some drugs' π-electron systems for higher loading rates and more regulated releases. What's more, the rigidity of the trithiophene core maintains the structure of the COFs, which is essential for them to function in physiology. This durability is important for drug delivery, as it means that the system doesn't break and will continue to secure and transport the drug under controlled conditions.
Figure 1. Synthetic method of BTT-based COFs with torsion angles and stacking.( Qin C, et al. 2023)
Further, the three aldehyde groups in benzo[1,2-b:3,4-b':5,6-b']trithiophene-2,5,8-tricarbaldehyde allows Schiff base linkages to be formed with amine-containing building blocks, producing ultra stable imine COFs. These associations make the COFs more strong and stable, preserving their integrity in the body (which is essential for drug delivery). These imine linkages are stable in different conditions, and can be controlled by altering the reaction conditions used in COF synthesis to yield a flexible framework from which to design customisable drug delivery systems. For example, highly stable imine linkages COFs would be ideally suited for a drug delivery with an extended release time while unstable linkages could be used for a rapid release of drugs in response to stimuli. COFs that contain benzo[1,2-b:3,4-b':5,6-b']trithiophene-2,5,8-tricarbaldehyde have many advantages both in terms of loading capacity and release rate. Since COFs are porous, along with pore sizes and functional groups modulable by the trithiophene core, they can be capsulated in many different drugs from small molecules to large biologics. Getting the pore size right is especially useful for figuring out the optimal loading and release profiles of different drugs. Lesser pores might be best suited for encapsulating small-molecule drugs so they are securely lodged in the structure, while larger pores can store larger biologics like proteins or nucleic acids so they can load and release them efficiently.
The linker's aldehyde groups can also be further functionalised to add more drug-binding sites or targeting ligands, giving the system more specificity and potency. Aldehyde groups, for instance, will react with functional groups to covalently attach with a targeting ligand (antibody or peptide, for instance) and direct the COF-drug complex into cells or tissues. Such targeted delivery can be extremely beneficial in the treatment efficacy of the drug while also eliminating side effects due to a decrease in off-target interactions. Further, drugs can be controlled to release from COFs by controlling how the drug molecules interact with the structure either through non-covalent interactions or via stimuli-responsive links releasing the drug when pH, temperature or enzymatic activity are manipulated. This modularity makes benzo[1,2-b:3,4-b':5,6-b']trithiophene-2,5,8-tricarbaldehyde-based COFs an attractive candidate for the fabrication of novel drug delivery systems with specific properties to cater to a range of therapeutic niches. pH-responsive links, for example, could be constructed to eject the drug in acidic environments (tumour tissues or innercellular regions), so that the drug emitted went exactly where it was intended. Additionally, the biodegradability of COFs can be tailored by choosing the right building blocks and couplings so that the framework decays into non-toxic byproducts when the drug has been delivered. This is especially useful in drug delivery applications as it prevents the COF to build up in the body and cause harm. Selection of biocompatible building blocks and connections also enhances overall safety and performance of the drug delivery system and hence benzo[1,2-b:3,4-b':5,6-b']trithiophene-2,5,8-tricarbaldehyde COFs are attractive candidates for clinical use.
Alternate Names:
Trithiophene tricarbaldehyde
Benzo-trithiophene-2,5,8-tricarbaldehyde
2,5,8-Tricarbaldehyde benzo[1,2-b:3,4-b':5,6-b']trithiophene
Benzo-trithiophene tricarbaldehyde
Trithiophene-2,5,8-tricarbaldehyde
Benzo[1,2-b:3,4-b':5,6-b']trithiophene-3-carbaldehyde
3,4-Benzotrithiophene-2,5,8-tricarbaldehyde
References:
1. Qin C, et al. Twistedly hydrophobic basis with suitable aromatic metrics in covalent organic networks govern micropollutant decontamination. Nat Commun. 2023, 14(1):6740.
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