Synthetic Organic Chemistry

(a) Biocompatible ‘click-type’ reactions under physiological conditions

Novel covalent coupling strategies under physiological conditions.

Novel covalent coupling strategies under physiological conditions.

There are several challenges to perform covalent coupling reactions under physiological conditions as the aqueous reaction condition limits the reactivity of nucleophilic and electrophilic reagents. We have discovered a simple and versatile condition to catalyze reactions to yield hydrazone, oxime and thiazolidine bonds. Such reactions are chemoselective and best suited for bioconjugation reactions with sensitive molecules such as DNA, RNA, peptide as well on the cell surface proteoglycans. Such reactions yield stable ‘click-type’ coupling products and could be used to develop drug conjugates.

Recent related publications:

  1. Wang, S.; Nawale, G. N.; Kadekar, S.; Oommen, O. P.; Jena, N. K.; Chakraborty, S.; Hilborn, J.; Varghese, O. P. Saline Accelerates Oxime Reaction with Aldehyde and Keto Substrates at Physiological pH. Sci. Rep. 2018, 8, 2193. https://doi.org/10.1038/s41598-018-20735-0
  2. Bermejo-Velasco, D.; Nawale, G. N.; Oommen, O. P.; Hilborn, J.; Varghese, O. P. Thiazolidine chemistry revisited: a fast, efficient and stable click-type reaction at physiological pH. Chem. Commun. 2018, 54, 12507-12510. http://dx.doi.org/10.1039/C8CC05405C
  3. Wang, S.; Gurav, D.; Oommen, O. P.; Varghese, O. P. Insights into the Mechanism and Catalysis of Oxime Coupling Chemistry at Physiological pH. Chem. Eur. J. 2015, 21, 5980-5985. https://onlinelibrary.wiley.com/doi/abs/10.1002/chem.201406458


(b) Bioorthogonal chemistry for designing 3D scaffolds

Tuning gelling kinetics by using salts as catalysts or by modulating the pKa of the nucleophilic reagents.

Tuning gelling kinetics by using salts as catalysts or by modulating the pKa of the nucleophilic reagents.

Performing organic reactions in the presence of living systems, i.e., cells, tissues, and eventually, human patients is challenging. These reactions should be ‘bioorthogonal’ or should be performed with functional groups that do not exist in nature and have no inherent reactivity with natural components. If such chemical reactions can be performed with biopolymers present in our extracellular matrix (ECM), we get hydrogels that mimic natural ECM. In our body, ECM components self-assemble to provide a highly organized network that provides cues for stem cells to proliferate or differentiate that directly dictate stem cell/tissue function. To recreate artificial ECM, continued efforts at the interface of chemistry, biology and medicine are required to define a sound biological rationale for construct design and to select chemistries that are suitable for specific in vivo use. To be used clinically, these strategies should be gentle and should not involve toxic catalysts or initiators, or byproducts.

The major challenge in performing reactions with large biomolecules is the presence of other functional groups present in the complex biological milieu. Such reactions should also possess reasonably fast reaction kinetics under dilute conditions. Therefore, our ambition is to improve the reactivity of the functional groups by either modulating the pKa of the reactive groups or by identifying catalysts that can drive the forward reaction under aqueous conditions. We also develop novel synthetic strategies to obtain covalent products that are more stable than the conventional reaction products.

Recent related publications:

  1. Bermejo-Velasco, D.; Azémar, A.; Oommen, O. P.; Hilborn, J.; Varghese, O. P. Modulating Thiol pKa Promotes Disulfide Formation at Physiological pH: An Elegant Strategy To Design Disulfide Cross-Linked Hyaluronic Acid Hydrogels. Biomacromolecules 2019. https://doi.org/10.1021/acs.biomac.8b01830
  2. Oommen, O. P.; Wang, S.; Kisiel, M.; Sloff, M.; Hilborn, J.; Varghese, O. P. Smart Design of Stable Extracellular Matrix Mimetic Hydrogel: Synthesis, Characterization, and In Vitro and In Vivo Evaluation for Tissue Engineering. Adv. Funct. Mater 2013, 23, 1273-1280. https://onlinelibrary.wiley.com/doi/abs/10.1002/adfm.201201698
  3. Wang, S.; Oommen, O. P.; Yan, H.; Varghese, O. P. Mild and Efficient Strategy for Site-Selective Aldehyde Modification of Glycosaminoglycans: Tailoring Hydrogels with Tunable Release of Growth Factor. Biomacromolecules 2013, 14, 2427-2432. https://doi.org/10.1021/bm400612h
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