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首页> 外文期刊>Journal of Systems Chemistry >Design and synthesis of nucleolipids as possible activated precursors for oligomer formation via intramolecular catalysis: stability study and supramolecular organization
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Design and synthesis of nucleolipids as possible activated precursors for oligomer formation via intramolecular catalysis: stability study and supramolecular organization

机译：设计和合成可能通过分子内催化形成低聚物的活化前体的核苷酸：稳定性研究和超分子组织

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Background Fatty acid vesicles are an important part of protocell models currently studied. As protocells can be considered as pre-biological precursors of cells, the models try to contribute to a better understanding of the (cellular) origin of life and emphasize on 2 major aspects: compartmentalization and replication. It has been demonstrated that lipid-based membranes are amenable to growth and division (shell replication). Furthermore compartmentalization creates a unique micro-environment in which biomolecules can accumulate and reactions can occur. Pioneering research by Sugawara, Deamer, Luisi, Szostak and Rasmussen gave more insight in obtaining autocatalytic, self-replicating vesicles capable of containing and reproducing nucleic acid sequences (core replication). Linking both core and shell replication is a challenging feat requiring thorough understanding of membrane dynamics and (auto)catalytic systems. A possible solution may lie in a class of compounds called nucleolipids, who combine a nucleoside, nucleotide or nucleobase with a lipophilic moiety. Early contributions by the group of Yanagawa mentions the prebiotic significance (as a primitive helical template) arising from the supramolecular organization of these compounds. Further contributions, exploring the supramolecular scope regarding phospoliponucleosides (e.g. 5’-dioleylphosphatidyl derivatives of adenosine, uridine and cytidine) can be accounted to Baglioni, Luisi and Berti. This emerging field of amphiphiles is being investigated for surface behavior, supramolecular assembly and even drug ability. Results A series of α/β-hydroxy fatty acids and α-amino fatty acids, covalently bound to nucleoside-5′-monophosphates via a hydroxyl or amino group on the fatty acid was examined for spontaneous self-assembly in spherical aggregates and their stability towards intramolecular cleavage. Staining the resulting hydrophobic aggregates with BODIPY-dyes followed by fluorescent microscopy gave several distinct images of vesicles varying from small, isolated spheres to higher order aggregates and large, multimicrometer sized particles. Other observations include rod-like vesicle precursors. NMR was used to assess the stability of a representative sample of nucleolipids. 1D 31P NMR revealed that β-hydroxy fatty acids containing nucleotides were pH-stable while the α-analogs are acid labile. Degradation products identified by [1H-31P] heteroTOCSY revealed that phosphoesters are cleaved between sugar and phosphate, while phosphoramidates are also cleaved at the lipid-phosphate bond. For the latter compounds, the ratio between both degradation pathways is influenced by the nucleobase moiety. However no oligomerization of nucleotides was observed; nor the formation of 3′-5′-cyclic nucleotides, possible intermediates for oligonucleotide synthesis. Conclusions The nucleolipids with a deoxyribose sugar moiety form small or large vesicles, rod-like structures, vesicle aggregates or large vesicles. Some of these aggregates can be considered as intermediate forms in vesicle formation or division. However, we could not observe nucleotide polymerization or cyclic nucleotide function of these nucleolipids, regardless of the sugar moiety that is investigated (deoxyribose, ribose, xylose). To unravel this observation, the chemical stability of the constructs was studied. While the nucleolipids containing β-hydroxy fatty acids are stable as well in base as in acid circumstances, others degraded in acidic conditions. Phosphoramidate nucleolipids hydrolyzed by P-N as well as P-O bond cleavage where the ratio between both pathways depends on the nucleobase. Diester constructs with an α-hydroxy stearic acid degraded exclusively by hydrolysis of the 5′-O-nucleoside ester bond. As the compounds are too stable and harsh conditions would destruct the material itself, more reactive species such as lipid imidazolates of nucleotides need to be synthesized to further analyze the potential polymerization process.
机译：背景技术脂肪酸囊泡是目前研究的原始细胞模型的重要组成部分。由于原生细胞可以被认为是细胞的生物学前体，因此该模型试图有助于更好地理解生命的（细胞）起源，并强调两个主要方面：区室化和复制。已经证明基于脂质的膜适合于生长和分裂（壳复制）。此外，区室化创建了一个独特的微环境，生物分子可以在其中积累并发生反应。 Sugawara，Deamer，Luisi，Szostak和Rasmussen的开创性研究为获得能够包含和复制核酸序列（核心复制）的自催化，自我复制的囊泡提供了更多见识。将核和壳的复制联系在一起是一项艰巨的任务，需要对膜动力学和（自动）催化系统有透彻的了解。可能的解决方案可能是一类称为核脂质的化合物，它们将核苷，核苷酸或核碱基与亲脂性部分结合在一起。柳川研究小组的早期贡献提到了由这些化合物的超分子组织产生的益生元意义（作为原始的螺旋模板）。探索有关磷脂酰核苷（例如腺苷，尿苷和胞苷的5'-二醇基磷脂酰衍生物）的超分子范围的进一步贡献可归因于Baglioni，Luisi和Berti。正在研究两亲的这个新兴领域的表面行为，超分子组装，甚至药物能力。结果检测了一系列α/β-羟基脂肪酸和α-氨基酸脂肪酸，它们通过羟基上的羟基或氨基共价结合到核苷5'-单磷酸上，在球形聚集体中自发自组装及其稳定性对分子内裂解。用BODIPY染料对所得的疏水性聚集体进行染色，然后进行荧光显微镜检查，可得到囊泡的多个不同图像，囊泡的大小从小，分离的球体到更高阶的聚集体以及大的，微米级的颗粒不等。其他观察结果包括棒状囊泡前体。 NMR被用来评估代表性的核苷酸样品的稳定性。 1D 31 核磁共振显示，含有核苷酸的β-羟基脂肪酸的pH值稳定，而α-类似物的酸不稳定。通过[ 1 H- 31 P] heteroTOCSY鉴定的降解产物表明，磷酸酯在糖和磷酸酯之间裂解，而氨基磷酸酯也在脂质-磷酸酯键裂解。对于后一种化合物，两个降解途径之间的比率受核碱基部分的影响。然而，没有观察到核苷酸的寡聚。 3'-5'-环状核苷酸的形成，也可能是寡核苷酸合成的中间体。结论具有脱氧核糖部分的核糖脂可形成小或大的囊泡，杆状结构，囊泡聚集体或大囊泡。这些聚集体中的一些可以被认为是囊泡形成或分裂的中间形式。但是，无论所研究的糖部分（脱氧核糖，核糖，木糖）如何，我们都无法观察到这些核苷酸的核苷酸聚合或环状核苷酸功能。为了阐明该观察结果，研究了构建体的化学稳定性。尽管含有β-羟基脂肪酸的核苷在碱性条件下和在酸性条件下一样稳定，但其他分子在酸性条件下会降解。 P-N水解的磷酰胺盐核苷以及P-O键裂解，两种途径之间的比例取决于核碱基。具有仅通过5'-O-核苷酯键的水解而降解的α-羟基硬脂酸的二酯结构。由于化合物太稳定且苛刻的条件会破坏材料本身，因此需要合成更多的反应性物种，例如核苷酸的脂质咪唑类脂，以进一步分析潜在的聚合过程。

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