Luk group has a keen interest in the sciences and applications at the interface of organic chemistry and life sciences. Our research is highly multi-disciplinary. For example, new organic reactions are discovered in aqueous solutions, which are applied for efficient drug synthesis and bioconjugation. Apart from the pursuit in modern medicinal chemistry, the new drug molecules are immediately used in the contexts of surfaces and materials for mechanistic study of adhesion biology for both mammalian cells and community formation (biofilm) of bacteria.
Organic synthesis is also applied to make a new class of drug molecules that also form a unusual class of nonamphiphilic lyotropic liquid crystals, which are used as templates for making a genesis of new structures of hydrogel materials. These nascent sciences form the basis for a new discipline of nonamphiphilic colloidal chemistry. Overall, our research bridges discoveries in fundamental sciences to applications that impact human health. Our approach is largely hypothesis-driven, but we have enjoyed significant amount of discovery-based sciences – they just come to us.
Below describes three intertwined programs in our laboratory with some brief highlights.
I. Bioorganic chemistry: Water-Driven organic reactions, bioconjugation and active agent development
We have made discoveries in organic reactions in water, with unusual organic reaction mechanisms. These reactions lead to the efficient synthesis (2-4 steps) of a new class of highly potent non-peptide integrin antagonists that have the therapeutic potential for a wide range of cell adhesion-based diseases. Other applications include immobilization of peptide on surfaces exclusively via N-terminus cysteines and new warheads for cysteine active proteins, which is useful for array assays for proteomics. We have also made a new class of molecules that inhibitor quorum sensing of bacteria. This new class of molecules can efficiently conjugate with peptides, proteins or labeling agents.
Publication in Program I:
||Modification of Proteins with Cyclodextrins Prevents Aggregation and Surface Adsorption and Increases Thermal Stability Langmuir, 2011, 27, 13091-6.
||Adamantane-Platinum Conjugate Hosted in β-Cyclodextrin: Enhancing Transport and Cytotoxicity by Noncovalent Modification Bioorg. Med. Chem. Lett., 2011, 21, 7421-5.
||Water-Driven Ligations Using Cyclic Amino Squarates: A Class of Useful SN1-Like Reactions Chem. Comm. 2011, 47, 1348-1350.
||Inhibiting microbial biofilm formation by brominated furanones Medical Device Materials V, Proceedings of the Materials & Processes for Medical Devices Conference, 2010, 6-10.
||Inhibition of Candida albicans Growth by Natural and Synthetic Brominated Furanones Appl. Microbiol. Biotechnol., 2010, 85, 1551-1563. (Collaboration with Ren Group)
||Selective Immobilization of Peptides Exclusively via N-Terminus Cysteines by Water-Driven Reactions on Surfaces J. Org. Chem., 2009, 74, 6843-6846.
||Utilizing the high dielectric constant of water: efficient synthesis of amino acid-derivatized cyclobutenones Tet. Lett., 2008, 49, 2128-2131.
||Water-Driven Chemoselective Reaction of Squarate Derivatives with Amino Acids and Peptides Org. Lett., 2007, 9, 4897-4900.
||Identifying the important structural elements of brominated furanones for inhibiting biofilm formation by Escherichia coli Bioorg. Med. Chem. Lett., 2008, 18, 1006-1010. (Collaboration with Ren Group)
II. Self-Assembly: water-in-water emulsion and templated synthesis – a new discipline of nonamphiphilic colloidal science.
For nearly five thousand years, spontaneous self-assemblies of small molecules in water have been known to involve amphiphilic molecules, which are part oily and part water-soluble. This program studies self-assembly of entirely water-soluble molecules, and will use these assemblies as templates to support gel formation of polymers coated on the assemblies. This approach, templated synthesis, will result in a new class of structures, including bicontinuous hydrogels, connected hydroshells, microcapsules and nano-molecular rods. Because the synthesis does not involve amphiphilic or surfactant molecules that can denature proteins, proteins will be copolymerized into the gel materials with preferred spatial location and with retained enzymatic activities. These structures can function as supported biocatalysts, having the potential to simulate living tissues.
Another effort in self-assembly involves designing and making unnatural organic molecules that fold into unique conformations out of many possibilities. With great structures comes great opportunity for functions, including binding recognition, drug candidates, catalysis and assembly of virus-like particles.
Publication in Program II:
||Noncovalent Polymerization of Mesogens Crystallizes Lysozyme: Correlation between Nonamphiphilic Lyotropic Liquid Crystal Phase and Protein Crystal Formation Langmuir, 2011, 27, 10901-6.
||Noncovalent Polymerization and Assembly in Water Promoted by Thermodynamic
Incompatibility J. Phys. Chem. B, 2010, 114, 10357-67.
||Controlling Thread Assemblies of Pharmaceutical Compounds in Liquid Crystal Phase by Using Functionalized Nanotopography Chem. Mater., 2010, 22, 2434–2441.
||Induced Folding by Chiral Non-Planar Aromatics J. Org. Chem., 2009, 74(18), 7023-7033.
||Non-Amphiphilic Assembly in Water: Polymorphic Nature, Thread Structure and Thermodynamic Incompatibility J. Am. Chem. Soc., 2009, 131, 7430-7443.
||Chiral Molecules with Polyhedral T, O or I Symmetry: Theoretical Solution to A Difficult Problem in Stereochemistry Chirality, 2008, 20, 878-884.
||Water-in-Water Emulsions Stabilized by Non-Amphiphilic Interactions: Polymer-Dispersed Lyotropic Liquid Crystals Langmuir, 2007, 23, 1453-8.
||A Biocompatible Surfactant with Folded Hydrophilic Head Group J. Am. Chem. Soc., 2006, 128, 13913-20.
III. Biointerfaces: Anti-biofouling chemistry, protein modification and mechanistic adhesion biology.
Organic chemistry at interfaces is common phenomena for both mammalian cell adhesion that controls normal biology and many diseases as well as for microbial biofilm formation that cause a wide range of infectious diseases and industrial losses. In this program, we have demonstrated prolonged confinements of mammalian cell adhesion and biofilm formation of bacteria. We also use the stereochemistry of the surfaces to study the mechanism for such prolonged resistance to cell adhesion. These progresses in anti-biofouling chemistry have enabled us to form a hypothesis and a systematic approach in another seemingly unrelated area – how to modify protein surfaces to prevent protein aggregation, and increase protein lifetime in the blood stream, which is a key issue in biopharmaceutical sciences that has been entirely empirical.
Publication in Program III:
||Stereochemical Effects of Chiral Monolayers on Enhancing the Resistance to Mammalian Cell Adhesion Chem. Comm. 2011, 47, 6165-7.
||Anti-Fouling Chemistry of Chiral Monolayers: Enhancing Biofilm Resistance on Racemic Surface Langmuir, 2011, 27, 6124-31.
||Prolonged Control of Patterned Biofilm Formation by Bio-inert Surface Chemistry Chem. Commun., 2009, 10, 1207-1209. (Collaboration with Ren Group)
||Molecular Gradients of Bio-inertness Reveal Mechanistic Difference between Mammalian Cell Adhesion and Bacterial Biofilm Formation Langmuir, 2009, 25, 1547-1553. (Collaboration with Ren Group)
||Enhancing Cell Adhesion and Confinement by Gradient Nanotopography J. Am. Chem. Soc., 2007, 129, 4892-4893.
||Inhibiting Escherichia Coli Biofilm Formation by Self-Assembled Monolayers of Functional Alkanethiols on Gold Appl. Environ. Microbiol. 2007, 73, 4300-4307. (Collaboration with Ren Group)
The three programs are well integrated. For example, the chemoselectivity of the water driven reactions (bioorganic chemistry) was tested on the bio-inert surfaces (biointerfaces) for selective peptide immobilization. Organic synthesis of dichromonyl molecule of potential therapeutic value (bioorganic chemistry) also contributed to discovery and study of the nonamphiphilic lyotropic liquid crystals (self-assembly). Heterogeneous biocatalysts (bioorganic chemistry) were built from water-in-water emulsion (self-assembly) based template synthesis.
Non-Amphiphilic Assembly in Water: Polymorphic Nature, Thread Structure and Thermodynamic Incompatibility Lei Wu, Jyotsana Lal, Karen A. Simon, Erik A. Burton and Yan-Yeung Luk* J. Am. Chem. Soc., 2009, 131, 7430-7443.
Water-Driven Chemoselective Reaction of Squarate Derivatives with Amino Acids and Peptides Preeti Sejwal, Yongbin Han, Akshay Shah and Yan-Yeung Luk*, Org. Lett., 2007, 9, 4897-4900. » full
Enhancing Cell Adhesion and Confinement by Gradient Nanotopography Karen A. Simon, Erik A. Burton, Yongbin Han, Jun Li, Anny Huang and Yan-Yeung Luk*, J. Am. Chem. Soc., 2007, 129, 4892-4893.
A Biocompatible Surfactant with Folded Hydrophilic Head Group: Enhancing the Stability of Self-Inclusion Complexes of Ferrocenyl in a β-Cyclodextrin Unit by Bond Rigidity Yongbin Han, Kejun Cheng, Karen A. Simon, Yanmei Lan, Preeti Sejwal, Yan-Yeung Luk*, J. Am. Chem. Soc., 2006, 128, 13913-20. » full
Surface-Driven Switching of Liquid Crystals using Redox-Active Groups on Electrodes Yan-Yeung Luk, Nicholas L. Abbott,* Science, 2003, 301, 623-6.