本文選題：氟喹諾酮類抗生素 + 光敏毒性��； 參考：《中國科學(xué)院研究生院(上海應(yīng)用物理研究所)》2017年博士論文

【摘要】：氟喹諾酮(FQs)是具有喹諾酮基本結(jié)構(gòu)的抗菌素類藥物,目前在全球范圍內(nèi)被廣泛使用。該類抗菌素具有抗菌譜寬、藥效好、毒副作用相對較低等優(yōu)點(diǎn),但也存在光敏毒性和光誘導(dǎo)細(xì)胞突變等多種毒副作用。雖然光敏毒性的發(fā)生率較低,但是由于服藥人群的數(shù)量龐大,仍然會(huì)導(dǎo)致大量的患者服藥后遭受額外的痛苦與煩惱。研究其光敏毒性形成機(jī)理匯聚了眾多科研人員的努力,得到了較多有意義的研究結(jié)果。但是迄今為止,造成FQs光敏毒性的結(jié)構(gòu)性因素尚未得到系統(tǒng)、有效地闡明。本論文采用激光光解和脈沖輻解的瞬態(tài)研究手段與凝膠電泳、高效液相色譜、紫外可見吸收光譜、穩(wěn)態(tài)熒光發(fā)射光譜等穩(wěn)態(tài)研究手段相結(jié)合的方式,并輔以理論計(jì)算,對FQs的結(jié)構(gòu)-光敏毒性關(guān)系進(jìn)行了系統(tǒng)地研究。從化學(xué)結(jié)構(gòu)的角度揭示引起光敏毒性的根源。本論文還嘗試引入外源性抗氧化劑,探索減輕或抑制FQs光敏毒性的機(jī)理;并改進(jìn)了光敏毒性的常用檢測方法——四氮唑蘭類比色法,使檢測結(jié)果更為可靠。本論文以培氟沙星(PEF)和二氟沙星(DIF)為研究對象,探究1號位點(diǎn)取代基對FQs光敏毒性的影響。研究發(fā)現(xiàn),如果1號位點(diǎn)為氟代苯基,可使FQs的激發(fā)波長藍(lán)移,由UVA波段藍(lán)移到UVB波段;而太陽光紫外線波段絕大部分UVB波段紫外線被臭氧層吸收,到達(dá)地表的紫外線主要集中在UVA波段,這一藍(lán)移效應(yīng)有效地減輕了光敏毒性。前人文獻(xiàn)認(rèn)為,氟原子較多時(shí),一般因?yàn)槊摲磻?yīng)加劇而使光敏毒性較大。而本研究表明,空間位阻效應(yīng)使激發(fā)波長藍(lán)移的影響可以大于脫氟效應(yīng)的影響。本論文以安托沙星(ANT)和左氧氟沙星(LEV)為研究對象,探究5號位點(diǎn)取代基對FQs光敏毒性的影響。研究發(fā)現(xiàn),5號位點(diǎn)為氨基(ANT)時(shí),通過理論計(jì)算表明該結(jié)構(gòu)下FQs分子由基態(tài)躍遷到激發(fā)態(tài)只需要較低的能量,且具有較高的躍遷幾率。但是卻檢測不到明顯的熒光發(fā)射過程和三重激發(fā)態(tài)。通過系統(tǒng)地分析得知,氨基的加入,改變了激發(fā)態(tài)FQs瞬態(tài)產(chǎn)物的分子內(nèi)電荷轉(zhuǎn)移機(jī)制,使瞬態(tài)產(chǎn)物多以無輻射躍遷的方式返回基態(tài),不產(chǎn)生三重激發(fā)態(tài),從而減輕FQs對生物分子的光敏損傷。減輕光敏毒性途徑通常包括改進(jìn)光敏性物質(zhì)的化學(xué)結(jié)構(gòu)和引入外源性抗氧化劑。所以本論文也嘗試引入外源性抗氧化劑來減輕FQs的光敏毒性。研究發(fā)現(xiàn),氧化石墨烯(GONs)可以通過物理性屏蔽紫外線、電荷轉(zhuǎn)移和能量轉(zhuǎn)移等方式清除FQs在光照下的瞬態(tài)活性物種并可以通過電荷轉(zhuǎn)移的方式修復(fù)受損的蛋白質(zhì)分子,有效降低FQs的光敏毒性。因?yàn)镚ONs已經(jīng)廣泛運(yùn)用于藥物分子的載體,基于本論文的研究結(jié)果,將GONs作為FQs的藥物載體有可能同時(shí)起到藥物緩釋和降低光敏毒性的作用,對于提升FQs療效和降低其毒副作用是一個(gè)可行的方案�？紤]到光敏毒性成因中活性氧自由基(ROS)起到重要作用,本論文對ROS的常用檢測方法進(jìn)行了研究。作為ROS的母體化合物,超氧陰離子自由基的常用檢測方法是四氮唑蘭類比色法。本論文首次發(fā)現(xiàn)原本屬于弱還原劑的該類比色劑在紫外光照射下有很強(qiáng)的光氧化性,不再是超氧陰離子自由基的特異性檢測試劑。通過加入超氧化物歧化酶(SOD)對檢測方法進(jìn)行改進(jìn),得到了較準(zhǔn)確的超氧陰離子自由基產(chǎn)額計(jì)算公式,有助于準(zhǔn)確分析FQs光敏毒性的成因,也有利于納米材料在光照下的納米毒性來源的準(zhǔn)確分析。
[Abstract]:(FQs) is a fluoroquinolone antibiotic drugs has the basic structure of quinolone, currently in the global scope is widely used. This kind of antibiotics has wide antibacterial spectrum, good efficacy, side effects are relatively low, but there are also photosensitive toxicity and light induced cell mutation and other kinds of side effects. Although the photosensitive toxicity occurred the rate is low, but due to the number of large crowds, will still lead to a large number of patients suffer from pain and trouble. Additional study the formation mechanism of phototoxicity brought together many researchers to get the results more meaningful. But so far, the structural factors caused by FQs toxicity has not yet been photosensitive system to clarify, effectively. The thesis adopts the research methods of transient and gel electrophoresis radiolysis and pulsed laser photolysis, HPLC, UV Vis absorption spectra, fluorescence emission. The steady state of the means of spectral combination, supplemented by theoretical calculation, structure of FQs photosensitive toxicity were studied. In order to reveal the root cause photosensitive toxicity from the perspective of their chemical structure. This paper also tries to introduce exogenous antioxidants, explore the mechanism to reduce or inhibit the FQs photosensitive toxicity and improved; the methods of detecting the toxicity of NBT - photosensitive color analogy method, which makes the results more reliable. In this paper, pefloxacin and levofloxacin (PEF) two (DIF) as the research object, explore the impact of 1 sites of substituents on the FQs photosensitive toxicity. The study found that if 1 sites for difluorophenyl that can make the FQs excitation wavelength blue shift from UVA band to UVB band blue shift; and the solar ultraviolet band most ultraviolet UVB absorbed by ozone, ultraviolet radiation reaching the earth's surface is mainly concentrated in the UVA band, the blue shift effect To effectively alleviate the photosensitive toxicity. The previous literature that the fluorine atom is more general, because the defluorination reaction increased the photosensitive toxicity. This study shows that the steric effect effect of the excitation wavelength blue shift can be larger than the effect of defluorination effect. In this paper, Antoine floxacin (ANT) and levofloxacin (LEV) as the research object, explore the impact of 5 sites of substituents on the FQs photosensitive toxicity. The study found that 5 loci of amino (ANT), through theoretical calculations show that the FQs molecule of the structure from the ground state to the excited state transitions only need lower energies, transition probability and high detection. But no obvious fluorescence emission process and three excited states. Through systematic analysis, amino join, change the excited state of FQs products in transient charge transfer mechanism, the transient products return to the ground state of the nonradiative transition, No three excited state, so as to reduce the FQs of photosensitive damage of biological molecules. Reduce toxicity pathways usually include chemical structure of photosensitive photosensitive material improvement and the introduction of exogenous antioxidants. So this paper also phototoxicity to introduce exogenous antioxidants to reduce FQs. The study found that graphene oxide (GONs) by physical of UV shielding, charge transfer and energy transfer way clear transient FQs active species in the light and protein molecules can pass through the charge transfer way to repair damaged, effectively reduce the toxicity of FQs. Because of the photo carrier GONs has been widely used in drug molecules, the research results of this thesis are based on the GONs as a drug vector FQs may delay the release of medicine and reduce the photosensitive toxicity effect, to enhance the FQs effect and reduce the side effect is a feasible scheme. Considering the causes of toxicity in photosensitive active oxygen free radical (ROS) plays an important role, the common detection method of ROS is studied. As the parent compound ROS, commonly used detection methods of superoxide radical anion is blue tetrazolium colorimetric method. The analogy first discovered originally belonged to the weak reducing agent analogy color under ultraviolet radiation light has strong oxidation, is no longer the specificity of detection reagent of superoxide anion radical by adding superoxide dismutase (SOD) on the detection method is improved to get more accurate superoxide anion free radical yield formula, causes contribute to the accurate analysis of FQs photosensitive toxicity, accurate analysis is also conducive to toxicity of nano materials in nano source of light.

【學(xué)位授予單位】：中國科學(xué)院研究生院(上海應(yīng)用物理研究所)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：TQ465

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