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Potential applications of Diel's Alder reaction.pptx

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Potential applications of Diel's Alder reaction.pptx

  1. 1. Potential uses of Diel's Alder reaction in biomedical applications: A detailed evaluation By- Riyansha Verma (38) Sanya Gulati (41) Submitted to - Dr. Ram Singh
  2. 2. INTRODUCTION What is a diel's alder reaction? A diel's alder reaction(DA) is a [4+2] cycloaddition reaction in which two bound molecules combine to generate a new cyclic molecule with two new bonds. There is a reaction between a diene which has 2 pi bonds (4 pi electrons) and a dienophile which has 1 pi bond (2 pi electrons). In DA reactions, there is a loss of 2 pi bonds and gain of 2 sigma bonds. For faster DA reactions, an electron withdrawing group is attached to dienophile and an electron donating group is attached to diene. Potential applications The DA reactions has various applications in biomedical field, for instance, in the synthesis of hydrogels used for drug delivery. It is used for organic synthesis as well and used in nanotechnology. It is a type of click reaction which is used in bioconjugation, which is a process of attaching a biomolecule with a substrate. It is also used for the synthesis of polymers and dendrimers which are spherical macromolecules made of a synthetic polymer with a structure of repeatedly branching chains. Generally, in click reactions certain metal catalysts are used such as copper catalyst which is toxic so DA reaction is used instead as it requires no metal catalyst. The DA reaction is one of the most potent ways for synthesising unsaturated six-membered rings because it is stereoselective, atom-efficient, and very efficient.
  3. 3. Potential applications of diel's alder reaction in synthesis of copolymers Copolymers are polymers that are made of atleast 2 species of monomers, for instance, -A-B-A-B- . Drug formulation, biomaterial design, and nanotechnology are all areas where copolymers might be useful. In water, copolymers with hydrophobic and hydrophilic segments may self-assemble to produce micellar structures, which have a variety of uses in drug administration. • The DA reactions are used in the synthesis of recyclable shape memory copolymers (polymers which have the ability to return to their original shape by an external stimuli). • For instance, DA reaction is used for the synthesis of biodegradable shape-memory elastomers, Ninh and Bettinger coupled hyperbranched furan-modified poly(glycerol- co-sebacate) precursors with bifunctional maleimide cross- linking agents. • In given figure, cross-linking of hyperbranched furan- modified poly(glycerol-co-sebacate) precursors with 1,10- (methylenedi-4,1-phenylene) bismaleimide is taking place (A). Fabrication of elastomers via DA reaction (B).
  4. 4.  The creation of organic–inorganic hybrid compounds is another fascinating use of the DA reaction. In the presence of tetraethoxysilane, a styrene copolymer having pendant furan moieties was interacting with a maleimide-containing silane coupling agent to produce these polymer hybrids.  These hybrid materials, which include the benefits of both organic and inorganic materials, might be employed as biomaterials in applications that need great mechanical strength.  The DA reaction between anthracene and maleimide has been utilised to make block copolymers(a polymer made up of molecules in which the blocks are arranged in a linear pattern), graft copolymers(a form of copolymer in which one or more homopolymer blocks are grafted onto a main chain as branches), and star-shaped copolymers, in addition to the furan– maleimide pair.
  5. 5. BIOCONJUGATION: AN APPLICATION OF DA REACTION  Biomolecules can be immobilised on solid surfaces via the DA reaction.  The functionalization of nanoparticles with DNA or antibodies can be done in a similar way. Anti-HER2 antibodies (trastuzumab) were covalently linked to the nanoparticles by DA coupling after being treated with maleimide functional groups.  The figure given here represents Antibodies are used to make nanoparticles functional. Amphiphilic block copolymers that have been furan-functionalized self- assemble into nanoparticles with a hydrophobic core and a hydrophilic outer shell containing furyl groups. Anti- HER2 antibodies that have been labelled with maleimide are covalently linked to the nanoparticles through DA coupling.  These anti-HER2 immuno-nanoparticles are used for targeted drug delivery.
  6. 6. A thermoreversible DA linker anchors a fluorescein dye on the surface of silica– gold core–shell nanoparticles. The retro DA reaction was triggered by surface plasmon resonance (SPR) heat, and the dye was liberated from the nanoparticles. The release is controlled which is useful for drug delivery and other biomedical applications.
  7. 7. Application of DA reaction in nanotechnology  Nanotechnology is the study of nanomaterials having size of less than 100nm.  Dendrimers, polymeric micelles, polyplexes, nanoparticles, nanocapsules, and liposomes are examples of nanomaterials that provide new possibilities in medication development and delivery.  Many nanomaterials, for example, increase the solubility of hydrophobic medicines, extend their circulation half-life, and reduce immunogenicity.  Furthermore, nanoparticles can deliver continuous or triggered drug release, reducing the frequency of medication administration. Because of the increased permeability and retention impact, nanoscale drug delivery devices frequently accumulate in certain tissues (e.g. cancers). Furthermore, the presence of targeted ligands, such as antibodies or aptamers, can improve nanomaterial retention and cellular uptake (active drug targeting).  DA reactions are used in the synthesis of block polymers which are used in coating of nanoparticles. For example, Costanzo et al. used thiol-terminated PS-b-PEG copolymers to coat gold nanoparticles, with the PS and PEG blocks connected by thermoreversible DA links.  Drug release from nanoparticulate carriers can also be controlled via the retro DA reaction. For instance, gold nanorods were modified with PEG chains through DA cycloadducts.
  8. 8. Hydrogels for drug delivery The Hydrogels protect incorporated proteins against degradation, and provide sustained or triggered drug release. This requires efficient cross-linking reactions that do not adversely affect the stability of incorporated proteins. The DA reaction meets these criteria. The reaction proceeds in water at room temperature and no purification step is required to remove potentially toxic catalysts or initiators. Therefore, the DA reaction is a suitable crosslinking method for preparation of hydrogels. In the field of tissue engineering, hydrogels can be used as space filling agents, as vehicles for the delivery of bioactive molecules, or as scaffolds for cell delivery. Hydrogels designed to encapsulate cells must meet specific requirements. For example, the gelation process and the cross-linked material must be compatible with cells and the surrounding tissue, the hydrogel must allow the diffusion of nutrients and metabolites, and the scaffold must have sufficient mechanical integrity to withstand the occurring mechanical loads. Furthermore, the hydrogel must present chemical and physical stimuli to direct the formation of a desired tissue [159]. Since the DA cycloaddition proceeds under physiological conditions without any catalyst or initiator, the reaction is suitable for the preparation of cell-laden hydrogels.
  9. 9. Possible applications of the DA reaction in pharmaceutics and biomedical engineering
  10. 10. (A) The above two slides illustrates possible applications of the DA reaction in pharmaceutics and biomedical engineering. The furan–maleimide pair is exemplarily used in the illustration. In practice, other diene– dienophile pairs, such as anthracene and maleimide, can be employed as well. The DA cycloaddition is an efficient and selective coupling reaction that can be employed for the synthesis of copolymers and dendrimers. (B) In this context, the cycloaddition of furan and maleimide can protect the maleimide functionality during incompatible reaction steps, e.g. during radical polymerizations. (C) In the biomedical field, the DA reaction (and in particular the IEDDA reaction) can be applied to bioconjugation. For example, the DA cycloaddition can be employed for the functionalization of drug delivery systems with targeting ligands such as peptides, antibodies or aptamers. (D) In the context of drug delivery systems, the DA/rDA equilibrium can also be exploited to control and sustain the release of active ingredients from nanoparticulate carriers or hydrogels. (E) Similar strategies can be applied to the functionalization of surfaces with biomolecules, such as cell adhesion peptides or ECM proteins. (F) And last but not least, the DA reaction can be used as a cross-linking method for hydrogel preparation. These kinds of hydrogels may serve as controlled release systems for biopharmaceuticals or as three-dimensional scaffolds for cell transplantation.
  11. 11. Agrochemicals The agrochemical and pharmaceutical industries share common goals in terms of optimizing chemical processes for the set-up of commercially viable manufacturing routes to active substances. When implemented early on in the synthetic sequence, the DA reaction has also proven to be industrially viable in this area. MGK-264 and captan are two prominent examples of agrochemicals prepared through a DA reaction. MGK-264 is an ingredient of pyrethroid pesticides which enhances their activity. This N- octylbicycloheptene dicarboximide was prepared by treating the maleic anhydride/cyclopentadiene adduct with 2-ethylhexylamine in toluene with removal of water by azeotropic distillation. Captan, which is a plant- growth regulator, was prepared from butadiene in the presence of maleic anhydride followed by treatment with ammonia and perchlorylmercaptan. MGK-264 Captan
  12. 12. Pitfalls and challenges of the Diels–Alder reaction As outlined in the previous section, the DA reaction has been successfully applied to various problems in drug delivery and biomaterial design. However, it is necessary to talk about possible pitfalls as well. Although the DA reaction is extremely efficient, the comparatively slow reaction rate at room temperature may be a potential drawback. While the reaction rate may be less of an issue in applications such as the synthesis of polymers or dendrimers, it is certainly critical in the preparation of in situ forming hydrogels. Such hydrogels must completely encapsulate the drug after injection and rapidly form a drug depot at the application site, e.g. under the skin or inside the eye. Cross-linking via DA reaction can result in dose dumping. This may cause adverse effects or drug-induced toxicity.
  13. 13. Furthermore, it has been reported that with the addition of b-cyclodextrin, it catalyzes the DA reaction of some dienes and dienophiles. Therefore, b-cyclodextrin might serve as innocuous alternative to Lewis acids and accelerate the formation of hydrogels. Besides the reaction rate, the reversibility of the normal electron-demand DA reaction represents another potential pitfall that needs to be considered. Although the reversibility of the reaction opens up many possibilities, such as the fabrication of degradable materials or the development of controlled release systems, the formation of stable adducts may be required in applications such as the synthesis of non-degradable polymers. However, the most serious drawback is that the normal electron-demand DA reaction is not inert to nucleophiles of proteins or cells.
  14. 14. Although the DA reaction has certain limitations, it is without doubt one of the most useful reactions for the development of drug delivery systems and biomaterials. We have illustrated possible applications of the DA reaction in pharmaceutics and biomedical engineering. The DA reaction is undoubtedly one of the most favored transformations available to the synthetic organic chemist for the rapid construction of complex molecular frameworks. We have mainly focused on industrial applications, the beautiful developments in the field of catalytic asymmetric DA reactions that appeared in recent years are discussed. The DA reaction as a key step is a tribute to the perseverance of drug, agrochemical, and fragrance hunters, be they discovery or process-development chemists. This reaction can be very effective for synthesis of more productive derivatives considering the pitfalls and challenges of the reaction.

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