synthesis-information-bearing-peptoids-their-sequence-directed

Synthesis of Information-bearing Peptoids and their Sequence-directed Dynamic Covalent Self-assembly

This protocol presents the use of Lewis acidic multi-role reagents to circumvent kinetic trapping observed during the self-assembly of information-encoded ...

Monash University

The aim of this study is to determine if hexaarylbiimidazoles (HABIs) are efficient, visible light-active photoinitiators for thiol-ene systems. We hypothesize that, owing to the reactivity of lophyl radicals with thiols and the necessarily high concentration of thiol in thiol-ene formulations, HABIs will effectively initiate thiol-ene polymerization upon visible light irradiation.

Hexaarylbiimidazoles as visible light thiol-ene photoinitiators.

Dynamic covalent chemistry, in conjunction with template-directed assembly, enables the fabrication of extended nanostructures that are both precise and tough. Here we demonstrate the dynamic covalent assembly of peptoid-based molecular ladders with up to 12 rungs via scandium(III)-catalyzed imine metathesis by employing the principle of Vernier templating, where small precursor units with mismatched numbers of complementary functional groups are coreacted to yield larger structures with sizes determined by the respective precursor functionalities. Owing to their monomer diversity and synthetic accessibility, sequence-specific oligopeptoids bearing dynamic covalent pendant groups were employed as precursors for molecular ladder fabrication. The generated structures were characterized using matrix-assisted laser desorption/ionization mass spectrometry and gel permeation chromatography, confirming successful molecular ladder fabrication. 

Dynamic Covalent Assembly of Peptoid-Based Ladder Oligomers by Vernier Templating.

Polymerization reactions are commonly effected by exposing monomer formulations to some initiation stimulus such as elevated temperature, light, or a chemical reactant. Increasingly, these polymerization reactions are mediated by enzymes--catalytic proteins--owing to their reaction efficiency under mild conditions as well as their environmental friendliness. The utilization of enzymes, particularly oxidases and peroxidases, for generating radicals via reduction-oxidation mechanisms is especially common for initiating radical-mediated polymerization reactions, including vinyl chain-growth polymerization, atom transfer radical polymerization, thiol-ene step-growth polymerization, and polymerization via oxidative coupling. While enzyme-mediated polymerization is useful for the production of materials intended for subsequent use, it is especially well-suited for in situ polymerizations, where the polymer is formed in the place where it will be utilized. Such polymerizations are especially useful for biomedical adhesives and for sensing applications.

Radical-Mediated Enzymatic Polymerizations.

The ability of vascular-targeted drug carriers (VTCs) to localize and bind to a targeted, diseased endothelium determines their overall clinical utility. Here, we investigate how particle modulus and size determine adhesion of VTCs to the vascular wall under physiological blood flow conditions. In general, deformable microparticles (MPs) outperformed nanoparticles (NPs) in all experimental conditions tested. Our results indicate that MP modulus enhances particle adhesion in a shear-dependent manner. In low shear human blood flow profiles in vitro, low modulus particles showed favorable adhesion, while at high shear, rigid particles showed superior adhesion. This was confirmed in vivo by studying particle adhesion under venous shear profiles in a mouse model of mesenteric inflammation, where MP adhesion was 127% greater (p < 0.0001) for low modulus particles compared to more rigid ones. Mechanistically, we establish that particle collisions with leukocytes drive these trends, rather than differences in particle deformation, localization, or detachment. Overall, this work demonstrates the importance of VTC modulus as a design parameter for enhanced VTC interaction with vascular walls, and thus, contributes important knowledge for development of successful clinical theranostics with applications for many diseases.

Exploring deformable particles in vascular-targeted drug delivery: Softer is only sometimes better.

Utilization of constituent molecular precursors bearing covalently coreactive functional groups for self-assembly risks premature reaction, impeding synthetic and purification efforts. To prevent premature amine-aldehyde condensation for oligomers bearing both groups, we employ a dual-role Lewis acid catalyst for both in situ acetal deprotection and subsequent imine exchange, effecting oligomer assembly.

In situ deprotection and dynamic covalent assembly using a dual role catalyst.

A pyrrolopyrazine-thione derived from oltipraz, a compound that has been investigated as a chemopreventive agent, affords radicals in the presence of thiols and oxygen via a redox cycle, an attribute that suggests its suitability as an initiator for oxygen-mediated polymerization. Here, we explore the utilization of this pyrrolopyrazine-thione, generated in situ from a precursor, as an initiator for the radical-mediated thiol-ene polymerization. While the pyrrolopyrazine-thione was shown to be capable of generating radicals in the presence of atmospheric oxygen and thiol groups, the reaction extents achievable were lower than desired owing to the presence of unwanted side reactions that would quench radical production and, subsequently, suppress polymerization. Moreover, we found that complex interactions between the pyrrolopyrazine-thione, its precursor, oxygen, and thiol groups determine whether or not the quenching reaction dominates over those favorable to polymerization.

Oxygen-mediated Polymerization Initiated by Oltipraz-derived Thiones.

Contemporary, layer-wise additive manufacturing approaches afford sluggish object fabrication rates and often yield parts with ridged surfaces; in contrast, continuous stereolithographic printing overcomes the layer-wise operation of conventional devices, greatly increasing achievable print speeds and generating objects with smooth surfaces. We demonstrate a novel method for rapid and continuous stereolithographic additive manufacturing by using two-color irradiation of (meth)acrylate resin formulations containing complementary photoinitiator and photoinhibitor species. In this approach, photopatterned polymerization inhibition volumes generated by irradiation at one wavelength spatially confine the region photopolymerized by a second concurrent irradiation wavelength. Moreover, the inhibition volumes created using this method enable localized control of the polymerized region thickness to effect single-exposure, topographical patterning.

Article	Year
Hexaarylbiimidazoles as visible light thiol-ene photoinitiators. Dental materials : official publication of the Academy of Dental Materials\| PubMed ID: 26119702	2015
Dynamic Covalent Assembly of Peptoid-Based Ladder Oligomers by Vernier Templating. Journal of the American Chemical Society\| PubMed ID: 26639351	2015
Radical-Mediated Enzymatic Polymerizations. International journal of molecular sciences\| PubMed ID: 26848652	2016
Exploring deformable particles in vascular-targeted drug delivery: Softer is only sometimes better. Biomaterials\| PubMed ID: 28209527	2017
In situ deprotection and dynamic covalent assembly using a dual role catalyst. Chemical communications (Cambridge, England)\| PubMed ID: 28317995	2017
Oxygen-mediated Polymerization Initiated by Oltipraz-derived Thiones. Journal of polymer science. Part A, Polymer chemistry\| PubMed ID: 28947856	2017
Rapid, continuous additive manufacturing by volumetric polymerization inhibition patterning. Science advances\| PubMed ID: 30746465	2019

Timothy F. Scott

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