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Selective transformations of complex molecules are enabled by aptameric protective groups.
Nat Chem. 2012 Jul 22:Early Online Publication
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07 Aug 2012
Interesting Hypothesis, New Finding, Technical Advance
DOI: 10.3410/f.717952220.793457628
Natural products have long been a source of inspiration for the synthesis of pharmaceutical agents. Complicating these efforts are the multi-step syntheses frequently required to supply sufficient material for clinical development. In contrast, direct modification of natural products themselves offers...Continue reading
Natural products have long been a source of inspiration for the synthesis of pharmaceutical agents. Complicating these efforts are the multi-step syntheses frequently required to supply sufficient material for clinical development. In contrast, direct modification of natural products themselves offers a more succinct route to a pool of candidates for pharmacological optimization. Of course, this strategy of natural product derivatization requires exquisitely selective chemistry. To facilitate this goal, Herrmann and co-workers report the use of RNA aptamers as macromolecular protecting groups for otherwise unmodified natural products. Upon binding to the aptamer, the domains of the natural product that are exposed to the solvent can then be selectively modified. As a proof of concept, the authors demonstrate that the antibiotics neomycin B and paromomycin can be regioselectively modified at one of several amino groups due to the protective binding of an RNA aptamer. Regioselective acylation as well as regioselective reaction with isocyanates was demonstrated on both natural product scaffolds.
The demonstration of this technology on antibiotics is particularly important in that it may facilitate efforts to combat antibiotic resistance by providing rapid access to a diverse panel of antibiotic derivatives. An important consideration for future development of this technology is the development of reagents that are compatible with both the RNA aptamers and the aqueous solutions necessary for their use. Additionally, selection strategies will need to be devised so that multiple aptamers can be evolved to protect different domains of the molecule of interest, thereby providing maximal opportunity for divergence in the chemical modification of the natural product scaffold. Together, these developments are an important milestone in the selective chemical modification of natural products and the use of these modified scaffolds in medicinal chemistry.
The demonstration of this technology on antibiotics is particularly important in that it may facilitate efforts to combat antibiotic resistance by providing rapid access to a diverse panel of antibiotic derivatives. An important consideration for future development of this technology is the development of reagents that are compatible with both the RNA aptamers and the aqueous solutions necessary for their use. Additionally, selection strategies will need to be devised so that multiple aptamers can be evolved to protect different domains of the molecule of interest, thereby providing maximal opportunity for divergence in the chemical modification of the natural product scaffold. Together, these developments are an important milestone in the selective chemical modification of natural products and the use of these modified scaffolds in medicinal chemistry.
Disclosures
None declared
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Chalker J: F1000Prime Recommendation of [Bastian AA et al., Nat Chem 2012:Early Online Publication]. In F1000Prime, 07 Aug 2012; DOI: 10.3410/f.717952220.793457628. F1000Prime.com/717952220#eval793457628
F1000Prime Recommendations, Dissents and Comments for [Bastian AA et al., Nat Chem 2012:Early Online Publication]. In F1000Prime, 25 May 2013; F1000Prime.com/717952220
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Emerging trends in drug discovery are prompting a renewed interest in natural products as a source of chemical diversity and lead structures. However, owing to the structural complexity of many natural compounds, the synthesis of derivatives is not easily realized. Here, we demonstrate a conceptually new approach using oligonucleotides as aptameric protective groups. These block several functionalities by non-covalent interactions in a complex molecule and enable the highly chemo- and regioselective derivatization (>99%) of natural antibiotics in a single synthetic step with excellent conversions of up to 83%. This technique reveals an important structure-activity relationship in neamine-based antibiotics and should help both to accelerate the discovery of new biologically active structures and to avoid potentially costly and cumbersome synthetic routes.
DOI: 10.1038/nchem.1402
PMID: 23000991
