Copy, Edit, and Paste: Natural Product Approaches to Biomaterials and Neuroengineering

Abstract

Progress in the chemical sciences has formed the world we live in, both on a macroscopic and on a nanoscopic scale. The last century witnessed the development of high performance materials that interact with humans on many layers, from clothing to construction, from media to medical devices. On a molecular level, natural products and their derivatives influence many biological processes, and these compounds have enormously contributed to the health and quality of living of humans. Although coatings of stone materials with oils or resins (containing natural products) have led to improved tools already millennia ago, in contrast today, natural product approaches to designer materials, that is, combining the best of both worlds, remain scarce. In this Account, we will summarize our recent research efforts directed to the generation of natural product functionalized materials, exploiting the strategy of "copy, edit, and paste with natural products". Natural products embody the wisdom of evolution, and only total synthesis is able to unlock the secrets enshrined in their molecular structure. We employ total synthesis ("copy") as a scientific approach to address problems related to molecular structure, the biosynthesis of natural products, and their bioactivity. Additionally, the fundamental desire to investigate the mechanism of action of natural products constitutes a key driver for scientific inquiry. In an emerging area of relevance to society, we have prepared natural products such as militarinone D that can stimulate neurite outgrowth and facilitate nerve regeneration. This knowledge obtained by synthetic organic chemistry on complex natural products can then be used to design structurally simplified compounds that retain the biological power of the parent natural product ("edit"). This process, sometimes referred to as function-oriented synthesis, allows obtaining derivatives with better properties, improving their chemical tractability and reducing the step count of the synthesis. Along these lines, we have demonstrated that militarinone D can be truncated to yield structurally simplified analogs with improved activity. Finally, with the goal of designing bioactive materials, we have immobilized functionally optimized, neuritogenic natural products ("paste"). These materials could facilitate nerve regeneration, act as nerve guidance conduits, or lead to new approaches in neuroengineering. Based on the surface-adhesive properties of electron-deficient catecholates and the knowledge gathered on neuritogenic natural product derivatives, two mechanistically different design principles have been applied to generate neuritogenic materials. In conclusion, natural products, and their functionally optimized analogs, present a large, mostly untapped reservoir of powerful modulators of biological systems, and their hybridization with materials can lead to new approaches in various fields, from biofilm prevention to neuroengineering.

Inhibitory capacity of Rhus coriaria L. extract and its major component methyl gallate on Streptococcus mutans biofilm formation by optical profilometry: Potential applications for oral health

“…Natural products have been optimized to interact with biological systems through a long natural selection process (9), and because of this, nature is considered the best concocter of medicines and has been a source of medicines for millennia (10)(11)(12)(13). During the last two decades, various plants have been tested for their antimicrobial activity and many of them exhibit significant antibacterial activity against Streptococcus species (14).…”

Interfacing Functional Systems

“…A number of interfacing strategies can be envisioned on a molecular level, and a bio-inspired approach for selection and optimization suggested the use of catechols as building blocks. [7] or trastuzumab yielding primary systems capable of interfacing with cell surfaces or patterning of surfaces. [32] The encapsulation of multiple enzymes working in polymersomes equipped with OmpF allowed the creation of the first artificial peroxisomes 17.…”

“…1). Independent of size and nature, primary components can be small molecules (catalysts, [2,3] transporters, [3,4] chromophores, [5] vitamins, [6] bioadhesives [7] ), macromolecules (enzymes, proteins, [6,8] polymers [5,9] ), supramolecules (protein oligomers, [6,8] polymersomes, [9] liposomes [3] ), cells, [4,8] devices, [5,7] and so on. Interfacing of primary componentsnon-covalent, dynamic-covalent or covalent -produces primary systems.…”

“…[15] Compatible with structural diversity, emergent properties reported for the tertiary system 7 include sensing (polyphenols in green tea), [15,19] spectral tuning (plant flower anthocyanines) or the stabilization of unstable structures (tritylium cations). [16] From there, future perspectives for MSE are as described for covalent systems with the exception that special attention to dynamic-covalent interfacing strategies might become particularly rewarding: Boronic ester exchange is so far not fully orthogonal to hydrazone and disulfide exchange, [7,15] and the fourth orthogonal organic dynamic covalent bond remains to be discovered.…”

Does Size Really Matter? Probing the Efficacy of Structural Reduction in the Optimization of Bioderived Compounds – A Computational “Proof-of-Concept”

“…Surprisingly, a truncated analogue of Ang-D, SB640 was shown to exhibit an unexpectedly stronger inhibition towards CRM1 than its parent compounds and other synthetic analogues [ 31 , 40 ]. As reported, its synthesis involved a significant reduction in the molecular size and weight of Ang-D (nearly 60%) while it still retained its CRM1-inhibitory activities coupled with improved bioavailability, solubility and reduced toxicity [ 24 , 47 ]. Structurally, the presence of the long polyketide chain distinguishes Ang-D from SB640, which has its polyketide chain (tail) completely removed, majorly constituting the conjugate acceptor, α,β-unsaturated δ-lactone ring [ 40 , 42 ] ( Fig.…”