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Anti-cancer and Imaging Properties of Metal Complexes and Detection of Relevant Biomolecules

Title
Anti-cancer and Imaging Properties of Metal Complexes and Detection of Relevant Biomolecules
Authors
TIKUM FLORENCE ANJONG
Issue Date
2018
Department/Major
대학원 화학·나노과학과
Publisher
이화여자대학교 대학원
Degree
Doctor
Advisors
김진흥
Abstract
수년 간 암 진단을 받은 환자들의 증가하는 비율은 과학자들로 하여금 암을 방지하기 위한 더욱 효과적인 방법을 찾게 했다. 시스플라틴은 약 53년 전에 발견된 이후 어떤 형태의 암에 대해서는 최초의 치료제로 작용해 왔지만, 심각한 부작용과 암세포에 대한 내성은 제한적이었다. 이러한 시스플라틴의 한계는 과학자들이 암 치료를 위한 더 강력하고 효과적인 대안을 찾도록 해 주었다. 또한, 수년 간 연구는 생물학적 시스템에서 ATP, NADH, 일산화 탄소 등과 같은 관련 생체 분자의 농도 이상이 암, 심장 마비와 같은 몇 가지 질병으로 이어질 수 있다는 것을 보여 주었다.따라서 생물학적 시스템에서 이러한 생체 분자를 추적하고 관찰하는 방법과 이러한 방법의 개발이 가장 중요하다. 본 연구의 제2장에서, 우리는 시스플라틴에 강한 암 세포(A549)를 포함해 다른 종류의 암 세포에 대한 새로운 루테늄 2분자체의 세포 독성과 항증식성 효과를 종합적으로 다루며 특징을 짓고 평가한다. 이러한 복합체들은 CTDNA와의 브롬화 에티듐 치환 반응으로 나타난 삽입 결합 방식에서 DNA에 결합한다. 게다가, 이러한 복합체들은 실험된 모든 암세포 라인에서 시스플라틴의 효과보다 뛰어난 세포 독성과 항증식성 효과를 보여 주었다. 제3장에서, 우리는 세포의 미토콘드리아 전위 변화를 감시하기 위해 총 유도 방출(AIE)효과를 가지는 두 개의 루테늄 복합체의 이용을 논할 것 이다. 그러나, 미토트래커 deep red를 이용한 공존 연구에서 나타난 것처럼 단지 복합체2만 미토콘드리아에 있었다. 더구나, 복합체2는 그 세포들에 세포독성이지 않았고 미토트랙커 deep red에 더 나은 광안정성과 함께 미토콘드리아 잠재성의 변화를 관찰하는데 이용되어 질 수 있었다. 제3,4장에서 우리는 각기 다른 지방질을 가진 3개의 루테늄 복합체를 사용하여 암 세포에 대한 약물의 세포 독성 본질에 있는 친지방질성의 영향를 평가한다. 우리는 각기 다른 효능을 가진 3개의 루테늄 복합체를 사용하여 약물의 세포 독성에 미치는 지방질의 영향을 평가한다 본 연구의 제5장에서, 우리는 새로운 나프탈이미드와 팔라듐 복합체를 합성했고 유방암 세포에 CO를 감시하는 능력을 평가했다. 형광성과 자외선 가시, 공초점 이미지 기법을 사용하여, 이 화합물을 높은 선택성을 가진 일산화탄소의 선택적 인식에 적용할 수 있었다. 이 화합물에서 팔라듐의 존재는 나프탈이미드 성분의 형광성을 완화한다. 일산화탄소를 추가로 사용하게 되면, 팔라듐은 팔라듐 일산화탄소 복합체를 형성하도록 대체되어 형광 물질과 자외선 가시 분광학으로 발견될 수 있는 형광 물질을 방출한다. 제6장에서, 우리는 도너억셉터 시스템(donor-acceptor system)에 기초한 NADH의 선택적 인식에 대해 보고한다. 형광 물질과 자외선 가시 분광학을 이용해서 높은 선택성과 민감성을 가진 NADH를 발견할 수 있었다. 게다가, 탐침 1은 또한 뛰어난 결과와 탁월한 광안정성을 가진 미토콘드리아에서 내생적 NADH의 영상법에도 적용되었다. 제7장에서, 새로운 두 개의 이리듐 복합체를 합성했고 수소화물 전이와 케톤 퇴화를 통해 포름산염을 발견하는 이 복합체의 능력을 평가했다. 두 개의 복합체는 높은 선택성과 민감성으로 포름산염에 큰 반응을 보였다. 또한 석회수 검사를 이용하여 포르산염의 산화 작용에 의한 이산화탄소 발생이 확인되었다. 제8장에서 우리는 리소좀에 있는 ATP의 인식을 위한 새로운 근적외선이 켜진 탐침을 성공적으로 개발했다. 이 탐침은 다른 뉴클레오사이드 폴리 인산염 음이온에 비해 ATP에 대한 뛰어난 민감성과 선택성을 보여 주었고 리소좀에 축적되는 것으로 보였다. 더욱이, 탐침1은 탁월한 광안정성과 낮은 세포 독성을 가진 리소좀에서 ATP의 실시간 모니터링에 사용될 수 있다.;Chapter 2 Two new dinuclear cyclometalated Ru(II) complexes, [Ru2((phpy)(bpy))2tpphz]PF6 (1)and [Ru2((phpy)(bpy))2tatpp]PF6 (2) where (bpy= 2,2 bipyridyl, phpy =phenyl pyridine,tpphz= tetrapyrido(3 ,2-9: 2; 3-C: 3”-h: 2”’, 3”’-j)phenazine, tatpp=Dipyrido[3',2':5,6;2'',3'':7,8]quinoxalino[2,3-i]dipyrido[3,2-a:2',3'-c]phenazine) were synthesized and analyzedusing 1H NMR and ESI-mass spectrometry and both gave pleasing results. Thesecomplexes showed good stability in aqueous solution within a period of seven days.Interaction with double-stranded DNA (Calf-thymus(CT)) were studied using both UVvisand fluorescent spectroscopy. Both complexes exhibited strong binding to CT-DNAwith binding constants of 3.5 X 105and 3.0 X 105M-1for 2 and 1 respectively. Due to thenon-luminescent nature of both complexes, competitive binding experiments withethidium bromide (EtBr) were carried out, and both complexes were seen to displace CTDNAfrom EtBr. Interestingly, both complexes exhibited high toxicity to all cancer cellline tested with IC50 (10 𝜇M and 7 𝜇M for 1 and 2 respectively) values lower than that forcisplatin (35 𝜇M) after 48hours. Also, both complexes could inhibit cell proliferation inHela tumor cell lines and cause apoptotic cell death. Chapter 3 Two new ruthenium polypyridyl complexes, Ru(bpy)2pp(2) and Ru(phen)2pp(1),where bpy= 2,2 bipyridyl, phen= 1,10 phenanthroline, pp= 3-(1,10 phenanthroline-5-ylamino)propyl)triphenylphosphonium with AIE (aggregate induced Emission) propertieswere synthesized and analyzed using 1H NMR and ESI-MS mass spectrometry and bothgave pleasing result. 2 was more specific for staining the mitochondria as seen by thecolocalisation staining with Mitotracker deep red with a Pearson coefficient of 0.82.Using CCCP, changes in mitochondria potential of the cell could be detected by 2.Furthermore, 2 was found to be more photostable as compared to Mitotracker deep redimplying that 2 could be used for long-term cell tracking. Chapter 4 Three ruthenium complexes containing a bidentate piq ligand, [(piq)Ru(bpy)2]2+(1), [(piq)Ru(phen)2]2+ (2), and [(piq)Ru(DIP)2]2+ (3) (piq = phenylisoquinolinate, bpy =2,2’-bipyridine, phen = 1,10-phenanthroline, DIP = 4,7-diphenyl-1,10-phenanthroline),were prepared. The DNA binding properties of complexes 1 - 3 to double-stranded DNAwere studied. The binding of 1 - 3 to calf-thymus DNA yielded lower emission intensitiesthan those observed with the corresponding Ru complexes alone. To explore potentialinteractions of complexes 1 - 3 with lipid-rich organs in live cells, the emission propertiesof the Ru probes were studied with liposomes. The emission intensities of complexes 1 -3 were enhanced to similar extents upon interaction with liposomes. The cytotoxicactivities of the complexes against MDA-MB-231 and HUVEC cells were evaluated invitro. The effects of complexes 1 - 3 on the survival of MDA-MB-231 cells wereexamined and compared with that of cis-platin. Complexes 2 and 3 were more cytotoxicto cancer cells than cis-platin. Complexes 1 - 3 showed cellular uptakes of 1.1, 10.6, and76.6 %, respectively, indicating that the greatest amount of complex 3 entered the cancercells. Inhibition of cell migration by complexes 1 - 3 was also evaluated by the woundhealing assay Chapter 5 Carbon monoxide (CO), being an extremely toxic gas is also well known as animportant gasotransmitter in the living system. Development of fluorescent probe forrapid sensing of CO is of great significance, considering the lethal effect of CO to thehuman system. However the detection of CO in the living system is still challenging dueto the lack of efficient probes. In this work, a new Pd2+ napthalimide based fluorescentlight-up probe for the recognition of CO in aqueous solution has been developed. Thisprobe displays admirable sensing properties for CO including fast response, highsensitivity and selectivity with low detection limit (0.5 μM) through a carbonylationreaction. Furthermore, this probe showed high efficiency in the sensing of CO in livingcells. The mechanism of sensing of CO is grounded on the fluorescent recovering ofnapthalimide by eliminating Pd2+ from the Pd-napthalimide complex. We anticipated thatthe presence of palladium (II) would quench the fluorescent of napthalimide throughheavy metal atom electronic effect, which when bound to CO, a carbonylation reactionwill occur, which will led to the discharge of Pd (0) and a more fluorescent species. Chapter 6 The Synthesis of fluorescent probes for the recognition of nucleotide such asNADH has recently evolve as a dynamic area of research owing to their biologicalsignificance such as charge carriers in living cells. Due to lack of efficient probes, theinvestigation of changes of NADH in live cell has been restraint. For this purpose, wehave develop a small molecular based probe based on a donor-acceptor system, whichfunction both as a colorimetric and fluorescent indicator of NADH in the biologicalsystem. This probe demonstrate great sensitivity and rapid response toward NADH bothat lower micromolar levels and under physiological conditions. By using alcoholdehydrogenase, we have demonstrated that probe 1 can detect NADH generated fromNAD+and ethanol. Furthermore, our probe demonstrated the ability to detect NADH inliving cell with superior photostability. This study indicates that this probe could serve asa valuable tool for the sensing and visualization of NADH in the cell. Chapter 7 Sensing of formate is very important for numerous applications ranging fromdiagnostic assay to drug delivery. Up to now, detection of formate has been restrained bythe lack of efficient tools. Toward this goal, we have designed and synthesized two newiridium complexes for the sensing of formate.In this study, two new iridium complexes have been synthesized and its ability todetect formate through proton transfer and ketone reduction has been investigated.Interestingly, both complexes were effective in formate detection by transfer of protonfrom formate to the iridium centre bearing a chlorine ligand, which was confirmed bothby 1H NMR, UV-vis and fluorescent spectroscopy. Furthermore, formate was seen toreduce the ketone functional group on 2, which was accompanied by a colour change. Toconfirm the production of carbon dioxide, lime water test experiments where carried andall gave positive results, showing that formate is been converted to water and carbondioxide upon transfer of proton to the iridium centre. Chapter 8 A new far-red infrared fluorescent turn-on probe with lysosomal targeting abilityhas been design, synthesize, characterized and its ability to detect ATP evaluated. Thisprobe display high sensitivity and selectivity toward ATP, which results in great structuralchanges from spirocyclic (Non-fluorescent) form to its ring-opened (fluorescent) form,with an alteration in colour from colourless to purple and a 112 fold increase in thefluorescent intensity. In addition, this probe possesses great advantages such as excellentphotostability, low cytotoxicity and good cell membrane permeability. Furthermore, thisprobe has been applied for selective staining of the lysosomes and for monitoring thechanges in ATP level in the lysosomes.
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