| 研究課題/領域番号 |
18F18767
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| 研究機関 | 慶應義塾大学 |
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研究代表者 |
チッテリオ ダニエル 慶應義塾大学, 理工学部(矢上), 教授 (00458952)
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| 研究分担者 |
KURUTOS ATANAS 慶應義塾大学, 理工学部, 外国人特別研究員
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| 研究期間 (年度) |
2018-11-09 – 2021-03-31
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| キーワード | cyanine dyes / polymethine dyes / NIR probes / fluorescent probes / pH response / DFT calculations |
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| 研究実績の概要 |
During the period 01/10/2018-28/2/2019, the main achievements of the JSPS Postdoctoral Fellowship of Dr. Atanas Kurutos under the project entitled “Design and synthesis of functional cyanine dyes for imaging and therapeutical applications” cover the design, synthesis, structural elucidation and investigation of photophysical properties of a series of novel symmetric monocationic NIR-heptamethine cyanine dyes. The synthetic part includes the preparation of 14 N-quaternary chromophores, and a total of 24 polymethine dyes, of which 15 target NIR probes featuring pH response and additional 9 functional meso-chloro substituted cyanines - subject to undergo further modifications by introducing various pH sensitive amino moieties. Structural elucidation was achieved by 1H and 13C NMR spectroscopy (400 MHz and 500 MHz), and High-Resolution Mass Spectrometry (ESI+ mode). Analytical purity of the samples was confirmed within 1 ppm. Furthermore, quantum chemical calculations were employed utilizing Density Functional Theory, aiming to predict the desired physical-chemical features of the compounds under study. The DFT calculations were performed using Gaussian 09 software package, where the chemical structures were optimized at ground state configuration using the functional B3LYP and 6-31 (d, p) basis set. Finally, photophysical characteristics of the target cyanine dye were evaluated in buffer solutions (pH range 3-11) by UV-Vis and steady state fluorescence spectroscopy. The finely tuned pKa values cover a range between 5.13 - 7.72 depending on the dye chemical structure.
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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
The implementation of the current project relies on a combination of several and hence essential overlapping steps. The original proposal with a total duration of 24 months covers the following: i) Theoretical studies - Design and quantum chemical calculations via DFT method aiming to optimize the new cyanine fluorophores and select the most appropriate chemical structures containing the various molecular modifications, ii) Synthesis of the target cyanines and intermediate products. Structural characterization of all planned compounds by NMR spectroscopy, mass spectrometry, and IR spectroscopy, and iii) Photophysical studies - Measurements of UV-Vis and emission spectra of all newly synthesized compounds. Up to date, the initial quantum chemical calculations were applied to the majority of the target molecules, such as the physicochemical properties related to its molecular geometry and electronic configuration at ground state using a fairly well-established DFT protocol. In addition to, the synthetic part includes the preparation, isolation and purification of a significant amount of novel organic molecules - NIR heptamethine cyanine dyes and an anchor of N-quaternary intermediates. Beside the synthesis and isolation of the desired heptamethine products, the purity and full structural elucidation of all samples was confirmed by a sequence of contemporary analytical instruments, including NMR spectroscopy and HRMS spectrometry. Last but not least, the finely-tuned pH response of NIR probes classifies them as good potential candidates for further quantitative bioanalysis.
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| 今後の研究の推進方策 |
Future plans leading to the successful accomplishment of the current project, include the implementation of further in-depth photophysical investigation of the newly synthesized NIR cyanine dyes (evaluation of molar extinction coefficients and relative fluorescence quantum yields in buffer solutions and/or organic solvents, allocation of the absorption/emission maxima, studies on photostability of the target probes, as well as the synthesis of further series pointing towards the same direction, and in particular on the design of novel pH responsive sensors. In terms of synthesis, the scope is about to shed more light to the preparation of various organic molecules bearing alternations to both the fluorogenic dye, as well as the introduction an even wider selection of pKa sensitive moieties and systematically extend the overview of the preliminary results obtained to date. Moreover, a completion the DFT studies in both ground and excited state is planned, which is expected to serve as a tool and therefore supporting material to the findings from the experimental part. Finally, applying the same strategy, efforts would be directed to apply these model compounds as a proof of concept via implementation of those chemical structures showing the most promising photophysical properties into bio-imaging, and potentially to be tested as anti-cancer PTT agents, or even be encapsulated into functionalized stimuli-responsive polymeric micelles (prone to undergo disruption at locally acidic pH) for the selective in-target delivery to tumor cells.
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