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Synthesis and Computational Studies of Photoreactive Caged Molecules.

机译：光反应性笼型分子的合成与计算研究。

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摘要

In photoreactive caged compounds, a molecule of interest is covalently coupled to a protection group, making it functionally inactive. Upon irradiation, the molecule of interest is released and becomes active to perform biological functions. Caged neurotransmitters are of increasing interest in the neuroscience community. Despite the significant progress in biological optical and irradiation (lasers) techniques and equipment, caged neurotransmitters remain challenging to synthesize, and their mechanism of photolysis stays ambiguous.;Our initial approach was to improve the synthesis of 4-carboxymethoxy-5,7-dinitroindolinyl (CDNI) Glu, as previously established by the Ellis-Davies and Corrie groups. By combining several deprotection steps and tweaking the procedure, we shortened the synthesis from 150 hours to just 24 hours, while improving the overall yields. The improved synthetic method for nitrated caged compounds enabled us to make and characterize caged GABA and acyl analogues. Subsequently, we designed and synthesized other novel cages such as di-caged-Glu, di-Glu and di-GABA cages to address phototoxicity and solubility issues commonly reported in nitrated cages.;We also compared the kinetics of several caged neurotransmitters by conventional UV-Vis studies, and developed a quantitative 1H NMR method for relative kinetics. While allowing for a small sample size for analysis, the UV-Vis technique was ambiguous because of overlapping absorbance spectra in certain caged molecules and remnant cages upon photolysis. The 1H NMR method yielded more detailed kinetic data, and was correlated to the UV-Vis method. The ratio of the rate constants for the photolysis of CDNI-Glu vs. MNI-Glu was 1.3 for both UV-Vis and NMR methods; the ratio of reaction rates was 7.0 for the NMR method. HPLC purified samples were successfully tested on brain slices using two-photon microscopy.;To further investigate the mechanism of photolysis, theoretical studies were conducted on CDNI-Glu. Most previous mechanistic reports made assumptions that neglect the effect of the CDNI side chains and nature of the neurotransmitter. We successfully studied the mechanism of photolysis of CDNI-Glu in aqueous and organic media at the B3LYP 6-31G* level of density functional theory (DFT). Key controversial pathways (organic vs. aqueous, long vs. short range rearrangements) were compared and found to be thermodynamically plausible; these were also correlated to our experimental UV-Vis and NMR kinetics results.
机译：在光反应性笼中化合物中，目标分子与保护基团共价偶联，使其功能失活。辐射后，目标分子被释放并变得具有执行生物学功能的活性。笼状神经递质在神经科学界越来越受到关注。尽管在生物光学和辐照（激光）技术和设备方面取得了重大进展，但笼状神经递质的合成仍然具有挑战性，其光解机理仍然不明确。；我们的初步方法是改善4-羧基甲氧基-5,7-二硝基吲哚基的合成（CDNI）Glu，由Ellis-Davies和Corrie小组先前建立。通过组合几个脱保护步骤并调整程序，我们将合成时间从150小时缩短到仅24小时，同时提高了总收率。改进的硝化笼状化合物合成方法使我们能够制备和表征笼状GABA和酰基类似物。随后，我们设计并合成了其他新型笼子，例如di-caged-Glu，di-Glu和di-GABA笼子，以解决硝化笼子中常见的光毒性和溶解性问题。我们还通过常规UV比较了几种笼形神经递质的动力学。 -Vis研究，并开发了用于相对动力学的定量1H NMR方法。虽然允许使用较小的样品进行分析，但由于某些笼形分子和残留笼子在光解后的吸收光谱重叠，因此UV-Vis技术模棱两可。 1H NMR方法产生更详细的动力学数据，并且与UV-Vis方法相关。对于UV-Vis和NMR方法，CDNI-Glu与MNI-Glu的光解速率常数之比为1.3。 NMR法的反应速率之比为7.0。 HPLC纯化的样品已使用双光子显微镜在脑切片上成功测试。;为进一步研究光解的机理，对CDNI-Glu进行了理论研究。以前的大多数机械报告都做出了忽略CDNI侧链和神经递质性质的假设。我们成功地在密度泛函理论（DFT）的B3LYP 6-31G *水平上研究了CDNI-Glu在水和有机介质中的光解机理。比较了主要有争议的途径（有机物与水相，长距离与短程重排），发现它们在热力学上是合理的。这些也与我们的实验UV-Vis和NMR动力学结果相关。

著录项

  • 作者

    Ouedraogo, Yannick Patekede.;

  • 作者单位

    Florida Institute of Technology.;

  • 授予单位 Florida Institute of Technology.;
  • 学科 Chemistry Organic.;Chemistry Physical.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 212 p.
  • 总页数 212
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 农学（农艺学）;
  • 关键词

  • 入库时间 2022-08-17 11:42:33

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