本文選題：氟喹諾酮 + 激光光解��； 參考：《中國科學院研究生院（上海應用物理研究所）》2015年博士論文

【摘要】：氟喹諾酮類藥物(fluoroquinolones,FQs)是臨床上廣泛應用的抗菌藥物,具有高效、廣譜、廉價等優(yōu)點。此類藥物分子有著相似的吡啶酮酸結構,通過抑制DNA旋轉酶,阻斷細菌DNA的復制來發(fā)揮抗菌作用,然而其光敏毒性等副作用在一定程度上阻礙了FQs的發(fā)展。吉米沙星(gemifloxacin,GEFX)、巴洛沙星(balofloxacin,BFX)、帕株沙星(pazufloxacin,PAX)和妥舒沙星(tosufloxacin,TSFX)都屬于FQs類抗菌素,它們對生物分子的光敏損傷機理仍不甚明確。本文利用激光光解、脈沖輻解、穩(wěn)態(tài)光照、紫外-可見吸收光譜等瞬態(tài)和穩(wěn)態(tài)技術手段對其光化學性質以及光敏毒性機理進行了詳細研究,為進一步研究此類藥物分子結構與光敏毒性之間的關系以及新一代FQs藥物的研發(fā)提供了理論依據(jù)。本文研究了吉米沙星三重激發(fā)態(tài)(3GEFX*)和妥舒沙星三重激發(fā)態(tài)(3TSFX*)的光化學性質。利用激光光解技術,確定了中性水溶液中3GEFX*和3TSFX*的最大吸收峰位置。研究了3GEFX*和3TSFX*與萘普生(NAP)之間的能量轉移反應,測定了速率常數(shù)分別為1.2×108和1.3×109 dm3 mol-1 s-1,確定GEFX三重激發(fā)態(tài)的能量為266 k J mol-1。研究了3GEFX*和3TSFX*與2’-脫氧鳥苷酸-5’-單磷酸鹽(d GMP)、色氨酸(Trp H)、酪氨酸(Typ OH)、N,N,N’,N’-四甲基-對-二苯胺(TMPD)、阿魏酸(FCA)之間的反應機理,測定了上述反應的速率常數(shù)。通過設計競爭反應,分別利用TMPD和FCA作為給電子體指示劑,證明了3GEFX*和3TSFX*都是通過電子轉移的方式光敏損傷DNA。本文還利用脈沖輻解技術研究了GEFX與水合電子(eaqˉ)、羥基自由基(?OH)以及疊氮自由基(N3?)之間的反應,得到了GEFX陰離子自由基、中性自由基和陽離子自由基的特征吸收峰,提出了反應機理并測定了瞬態(tài)反應的速率常數(shù)。利用穩(wěn)態(tài)光照和凝膠電泳技術研究了在不同氣氛、不同光照時間、不同濃度條件下GEFX對蛋白質的光敏損傷并提出了損傷機理。在對BFX光化學性質的研究中,本文利用紫外-可見吸收與熒光發(fā)射光譜分析研究了BFX的p H效應及變化規(guī)律,測定了其p Ka值。激光光解實驗表明BFX光致電離效應強烈,通過對其光致電離機理的研究,證明BFX的光致電離為單光子過程。利用脈沖輻解研究了BFX與?OH、eaqˉ和N3?之間的瞬態(tài)反應,測得BFX陰陽離子吸收峰的位置以及反應的速率常數(shù)。通過設計競爭反應研究了巴洛沙星陽離子自由基對生物分子的損傷作用。穩(wěn)態(tài)光照和凝膠電泳實驗證明,有氧條件下BFX造成蛋白質的光敏損傷是I型反應和II型反應協(xié)同作用的結果。本文利用激光光解研究了PAX三重激發(fā)態(tài)與溶菌酶(Lyso)和FCA之間的反應機理,測定了電子轉移反應速率常數(shù)。通過設計競爭反應,利用穩(wěn)態(tài)光照和凝膠電泳分析研究了抗氧化劑FCA對于Lyso光敏損傷的保護作用,結果表明FCA能夠有效抑制FQs光敏氧化造成的蛋白質分子交聯(lián),減弱蛋白質分子的光敏損傷。研究結果為進一步研究抗氧化劑對于蛋白質的保護作用機理提供了理論依據(jù)。通過上述實驗,本文研究了GEFX、BFX和TSFX的光化學性質以及相關瞬態(tài)粒子的動力學性質,確定了GEFX、BFX和TSFX光敏氧化DNA、氨基酸和蛋白質的反應類型和瞬態(tài)反應速率常數(shù),提出了損傷機理,并初步研究了抗氧化劑對生物分子光敏損傷的保護機制。
[Abstract]:Fluoroquinolones (FQs) is a widely used antibacterial drug in clinic. It has the advantages of high efficiency, broad-spectrum and cheap. It has similar structure of pyridoolone acid. It inhibits the replication of DNA by inhibiting the replicating of the bacterial DNA. However, the side effects such as photosensitive toxicity are hindered to some extent. The development of FQs. Jimmy floxacin (gemifloxacin, GEFX), balofloxacin (BFX), pazufloxacin (PAX) and dofloxacin (tosufloxacin, TSFX) are all FQs antibiotics. The mechanism of their photosensitive damage to biomolecules is still not clear. This paper uses laser photolysis, pulse radiolysis, steady state illumination, ultraviolet visible absorption light. The photochemical properties and the mechanism of photosensitive toxicity were studied in detail, such as spectra and other transient and steady-state techniques, which provided a theoretical basis for further study of the relationship between molecular structure and photosensitive toxicity of such drugs, as well as the development of a new generation of FQs drugs. The three heavy excitation state (3GEFX*) and the three weight of dofloxacin were studied in this paper. The photochemical properties of the excited state (3TSFX*). The maximum absorption peak position of 3GEFX* and 3TSFX* in neutral aqueous solution was determined by laser photodissociation. The energy transfer reaction between 3GEFX* and 3TSFX* and naproxen (NAP) was studied. The rate constants were 1.2 * 108 and 1.3 * 109 DM3 mol-1 S-1 respectively, and the energy of GEFX three excited state was 2. 66 K J mol-1. was used to study the reaction mechanism between 3GEFX* and 3TSFX* and 2 'deoxy guanosine monophosphate (D GMP), tryptophan (Trp H), tyrosine (Typ OH), H' - four methyl - to - two aniline and ferulic acid. The progeny indicator proves that both 3GEFX* and 3TSFX* are photosensitive damage DNA. through electron transfer, and the reaction between GEFX and hydrous electrons (EAQ), hydroxyl radical (? OH) and azido radical (N3?) is also studied by pulse radiolysis technology, and the characteristics of GEFX anion radical, neutral radical and cationic radical are obtained. The reaction mechanism was proposed and the rate constant of the transient reaction was measured. The photosensitive damage of GEFX to protein in different atmospheres, different illumination time and different concentration conditions was studied by steady state light and gel electrophoresis. In the study of the photochemical properties of BFX, the UV visible absorption was used in this paper. The P H effect and the change law of BFX were studied with the fluorescence emission spectrum analysis. The P Ka value was measured. The laser photodissociation experiment showed that the photoionization effect of BFX was strong. Through the study of its photoionization mechanism, the photoionization of BFX was a single photon process. The transient reaction between BFX and OH, EAQ and N3? Was studied by the pulse radiolysis, and the B was measured. The location of the absorption peak of FX and the rate constant of the reaction. The damage effect of the free radical of barloxacin cationic radical on the biological molecules was studied by designing a competitive reaction. The steady-state light and gel electrophoresis experiments showed that the photosensitive damage of the protein caused by BFX under the aerobic condition was the result of the synergistic effect of the I type reaction and the II type reaction. The reaction mechanism between PAX three heavy excited state and lysozyme (Lyso) and FCA was studied by laser photolysis. The rate constant of electron transfer reaction was measured. The protective effect of antioxidant FCA on the photosensitivity of Lyso was studied by designing the competitive reaction and using steady-state light and gel electrophoresis. The results showed that FCA could effectively inhibit the photosensitivity of FQs. The results of the study provide a theoretical basis for the further study of the mechanism of the protective action of antioxidants to proteins. The photochemical properties of GEFX, BFX and TSFX and the kinetic properties of the related transient particles are studied by these experiments. GEFX, B is determined. FX and TSFX photosensitive oxidation of DNA, the type of reaction of amino acids and proteins and the rate constant of transient reaction, put forward the mechanism of damage, and preliminarily studied the protective mechanism of antioxidants on the photosensitive damage of biomolecules.

【學位授予單位】：中國科學院研究生院（上海應用物理研究所）
【學位級別】：博士
【學位授予年份】：2015
【分類號】：TQ465

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