合成與探索發色團之光物理性質與光動力療法應用

Abstract

第一部分 量子產率小於1%的吩噻嗪限制了它做更多的應用而硝基已知的螢光淬滅基，有趣的是當我們將兩者結合在一起時會組成電荷囀移態進而增強螢光放射。首先將在吩噻嗪3號為上分別接上推電子基 (OMe) 和拉電子基 (CN, CHO, NO2) 命名為PTZ-OMe, PTZ-CN, PTZ-CHO and PTZ-NO2, 理論計算顯示PTZ 和PTZ-OMe的過度態是由π軌域的HOMO 到π*軌域與未成對電子混成的LUMO而成，使得其過度態屬於軌域部分禁止的，對比之下拉電子基可以降低硫的未成對電子軌域使其無法影響到π*軌域，讓PTZ-CN, PTZ-CHO and PTZ-NO2 屬於π-π*軌域允許的過度態，而計算結果與光物理性質相符合，相比於PTZ和PTZ-OMe的不放光，吩噻嗪接上拉電子基使得放光增強，值得一提的是PTZ-NO2在非極性溶劑下具有100%的螢光量子產率。最後在電化學分析上，我們發現拉電子基可以降低LUMO的能量讓硫的未成對電子軌域無法參與第一激發態的過渡。這個研究證明一個良好的分子設計去調控吩噻嗪衍生物的過度態進而影響到其放光。

第二部分 烷基或苯基為取代基於苯苝二酰亞胺為主體設計一個具有同步顯影追蹤與針對性光動力療法的分子。經過硫化反應之後得到一取代至四取代硫的產物，在此研究中我們以苯基取代的苯苝二酰亞胺為主體命名為1S-PDI-D, 2S-cis-PDI-D, 2S-trans-PDI-D, 3S-PDI-D 和 4S-PDI-D。在所有的硫化分子中光物理性質跟氮上取代基與硫化數量有相關。在吸收光譜中，主要的吸收峰屬於S0 →S2 (ππ*)的過度態並且會隨著硫化數增加而紅移。最低能階單重態S1 (nπ*)屬於過度態禁止的構型而且其能階與硫化數量與不同取代基有關，在本篇中苯基取代硫化苯苝二酰亞胺的能階低於烷基取代的苯苝二酰亞胺。在室溫下的正常氣體或是除氣條件下，所有的合成的硫化化合物皆不放螢光。經由瞬態吸收光譜與理論計算的支持下，激發態具有超快的系間交叉S1 (nπ*) → T1 (ππ*)將能量轉移到三重態。由理論計算可得最低階三重態的能量排序為1S-PDI-D (1.10 eV) > 2S-cis-PDI-D (0.98 eV) ~ 2S-trans-PDI-D (0.98 eV) > 3S-PDI-D (0.87 eV) > 4S-PDI-D (0.77 eV)，而1S-PDI-D比單氧激發態更高因此具有100%的單氧產率並以此為基底作成兩個目標化合物:第一是將兩端接上具有選擇性的胜肽FC131命名為1S-FC131，第二是一端接FC131一端接Cyanine 5 命名為Cy5-1S-FC131。在細胞實驗，1S-FC131 具有光動力療法且能夠辨認A549細胞而非另外三種正常細胞(WI-38, IMR90 and HEL299)。Cy5-1S-FC131 被證實具有中等選擇性光動力療法與同步螢光顯影在癌細胞中，在A549 xenografted 腫瘤老鼠中，兩種藥物皆具有良好的抗腫瘤能力。

Part I Phenothiazine (PTZ) with weak fluorescent quantum yield (>1% in cyclohexane) limit its derivatives for extensive application. Besides, a strong electron withdrawing group, nitro group (NO2), was a popular fluorescent quencher. Unexpectedly, we combined both moieties together to form strong charge transfer model to enhance their emission. First, PTZ were coupled with electron-donating group (OMe) and electron-withdrawing group (CN, CHO, NO2) at 3 position to form PTZ-OMe, PTZ-CN, PTZ-CHO and PTZ-NO2, respectively. Second, theoretical calculation showed that the transitions of PTZ-OMe and PTZ were mainly from HOMOs of π orbitals to LUMOs dominated by π mixed with nonbonding orbitals of sulfur, meaning its transition were partially forbidden. Conversely, the modification of electron withdrawing groups could reduce their energy levels of the nonbonding orbital from sulfur on PTZ, therefore blocking the incorporation of nonbonding orbital of sulfur with their π* orbital of PTZ to LUMO, and hence their allowed π-π* transition becomes major transition. Third, the series compounds were synthesized and measured their photophysical properties. The phenothiazines with EWGs displayed increased fluorescence rather than PTZ or PTZ-OMe. Worth to talk about that, PTZ-NO2 attained 100% photoluminescent quantum yield in the nonpolar solvent. Last, in electrochemical analysis, we found that the EWGs reduced the LUMO’s energy, which prevent nonbonding of sulfur incorporating in the first excited state. This research developed a series of PTZ analogues with a tunable transition and emission through a wise molecular design.

part II Bearing an aim of simultaneous imaging tracking and targeted photodynamic therapy (PDT), the core chromophore 3,4,9,10-perylenetetracarboxylic diimide (PDI) is anchored by alkyl or phenyl substituents at the imide N-site, followed by delicate thionation, yielding a comprehensive series of thione products. In this study, the phenyl derivatives endowed with n= 1, 2, 3 and 4 thione groups, namely 1S-PDI-D, 2S-cis-PDI-D, 2S-trans-PDI-D, 3S-PDI-D and 4S-PDI-D, respectively, are the main focus. For all studied nS-PDIs, the photophysical properties are dependent of the N-substitution and number of anchored thiones, where the observed prominent lower lying absorption is assigned to be the S0 →S2 (ππ*) transition and is red shifted significantly upon increasing number of thione. The lowest lying singlet state is ascribed to an S1(nπ*) configuration, which is a transition forbidden state and its energy depends on not only the thione group but also the N-substitution, being lower in N-phenyl substitution (cf. N-alkyl substitution) at the same number of thione substitution among all nS-PDIs. All synthesized nS-PDIs are virtually non-emissive in both aerated and degassed solution at room temperature. Supported by femtosecond transient absorption and computation, the excited-state relaxation is dominated by fast S1(nπ*) → T1(ππ*) intersystem crossing (ISC), resulting in ~100% triplet population. The lowest lying T1(ππ*) energy is calculated to be in the order of 1S-PDI-D (1.10 eV) > 2S-cis-PDI-D (0.98 eV) ~ 2S-trans-PDI-D (0.98 eV) > 3S-PDI-D (0.87 eV) > 4S-PDI-D (0.77 eV), where the T1 energy of 1S-PDI-D is close but higher than that (0.97 eV) of the 1O2 1Δg state, rendering 100% yield of 1O2. 1S-PDI-D is further modified by two synthetic strategies: 1. its conjugation with peptide FC131 on the two terminal sides, forming 1S-FC131 and 2. the linkage of peptide FC131 and Cyanine5 dye on each terminal side, yielding Cy5-1S-FC131. In vitro experiments prove that 1S-FC131 is able to recognize A549 cells out of other three lung normal cells (WI-38, IMR90 and HEL299) and perform effective PDT. Cy5-1S-FC131 further demonstrate modest selective PDT and simultaneous fluorescence imaging on the cancer cells. In vivo, both molecular composites also demonstrate outstanding antitumor ability in A549 xenografted tumor mouse.