Chirality and molecular conformation are central components of life: biological systems rely on stereospecific interactions between discrete (macro)molecular conformers, and the impacts of stereochemistry and rigidity on the properties of small molecules and biomacromolecules have been intensively studied. Nevertheless, how these features affect the properties of synthetic macromolecules has received comparably little attention. Here we leverage iterative exponential growth and ring-opening metathesis polymerization to produce water-soluble, chiral bottlebrush polymers (CBPs) from two enantiomeric pairs of macromonomers of differing rigidity. Remarkably, CBPs with conformationally flexible, mirror image side chains show several-fold differences in cytotoxicity, cell uptake, blood pharmacokinetics and liver clearance; CBPs with comparably rigid, mirror image side chains show no differences. These observations are rationalized with a simple model that correlates greater conformational freedom with enhanced chiral recognition. Altogether, this work provides routes to the synthesis of chiral nanostructured polymers and suggests key roles for stereochemistry and conformational rigidity in the design of future biomaterials.
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Achiral organoiodine-functionalized helical polyisocyanides for multiple asymmetric dearomative oxidations
Nature Communications Open Access 02 February 2023
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We thank the Army Research Office (W911NF-17-1-0521) and the National Institutes of Health (R01-CA220468-01 and postdoctoral fellowships for M.R.G. and N.J.O.) for supporting this work. We thank the National Science Foundation (graduate research fellowship for H.V.-T.N.). This work was supported in part by the Koch Institute Support (core) Grant P30-CA14051 from the National Cancer Institute. We acknowledge the support of the National Institute of Standards and Technology, US Department of Commerce, in providing the neutron research facilities used in this work. We also thank J. Zhao for assistance with Fig. 1. We thank S.E. Denmark and A.F. Zahrt for helpful discussions.
The authors declare no competing interests.
Peer review information Nature Chemistry thanks Arthi Jayaraman and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Nguyen, H.VT., Jiang, Y., Mohapatra, S. et al. Bottlebrush polymers with flexible enantiomeric side chains display differential biological properties. Nat. Chem. 14, 85–93 (2022). https://doi.org/10.1038/s41557-021-00826-8
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