Department of Chemistry and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Nat Chem. 2022 Jan;14(1):85-93. doi: 10.1038/s41557-021-00826-8. Epub 2021 Nov 25.
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.
生物系统依赖离散（大）分子构象之间的立体特异性相互作用，立体化学和刚性对小分子和生物大分子性质的影响已经得到了深入研究。然而，这些特征如何影响合成大分子的性质却受到了相对较少的关注。在这里，我们利用迭代指数增长和开环复分解聚合，从两种对映体的、刚性不同的大分子单体，生成了水溶性的手性瓶刷聚合物（CBP）。值得注意的是，具有构象柔性、镜像侧链的 CBP 在细胞毒性、细胞摄取、血液药代动力学和肝脏清除方面表现出了几倍的差异；而具有相似刚性、镜像侧链的 CBP 则没有差异。这些观察结果可以用一个简单的模型来解释，该模型将更大的构象自由度与增强的手性识别相关联。总的来说，这项工作为手性纳米结构聚合物的合成提供了途径，并表明立体化学和构象刚性在手性生物材料设计中的关键作用。
