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Quantum chemical calculations at BP86/TZVPP//BP86/SVP have been carried out for the Nheterocylic carbene and analogues complexes (tetrylene) [(CO)4W-NHE] (W4-NHE) with E = C – Pb. The tetrylene complexes W4-NHE possess end-on-bonded NHE ligands (E = C, Si), while for E = Ge and Sn, they possess slightly side-on-bonded ligands. The strongest side-on-bonded ligand when E = Pb has a bending angle of 102.9°. The trend of the bond dissociations energies (BDEs) for the W-E bond is W4-NHC > W4-NHSi > W4-NHGe > W4-NHSn > W4-NHPb. Analysis of the bonding situation suggests that the NHE ligands in W4-NHE are strong σ-donors and weak π-donors. This is because the tetrylenes have only one lone-pair orbital available for donation. The polarization of the W-E bond and the hybridization at atom E explain the trend in the bond strength of the tetrylene complexes W4-NHE. The W-E bonds of the heavier systems W4-NHE are strongly polarized toward atom E giving rise to rather weak electrostatic attraction with the tungsten atom which is the main source for the decreasing trend of the bond energies. The theoretical calculations suggest that transition-metal complexes tetrylenes [(CO)4W-{NHE}] (E = C – Pb) should be synthetically accessible compounds with tetrylenes NHE act as two-electron-donor ligands in complexes. / Phân tích cấu trúc và bản chất liên kết hóa học của hợp chất với kim loại chuyển tiếp chứa phối tử N-heterocyclic carbene và các đồng đẳng (tetrylene) [(CO)4W–NHE] (W4-NHE) với E = C – Pb sử dụng tính toán hóa lượng tử ở mức BP86/TZVPP//BP86/SVP. Cấu trúc của phức W4-NHE cho thấy các phối tử NHE với E = C, Si tạo với phân tử W(CO)4 một góc thẳng α = 180,0°, trong khi đó các phức W4-NHE thì phối tử NHE với E = Ge – Pb tạo liên kết với nhóm W(CO)4 một góc cong α < 180,0° và góc cong càng trở nên nhọn hơn khi E = Pb (α = 102.9°). Năng lượng phân ly liên kết của liên kết W-E giảm dần: W4-NHC > W4-NHSi > W4-NHGe > W4-NHSn > W4-NHPb. Tính toán hóa lượng tử trong phức [(CO)4W-{NHE}] (E = C – Pb) cho thấy phối tử tetrylene là chất cho electron. Điều này có thể do phối tử tetrylene chỉ giữ lại một cặp electron tại nguyên tử E để đóng vai trò là chất cho điện tử. Độ bền liên kết của phức W4-NHE được giải thích nhờ vào độ phân cực của liên kết W-E và sự lai hóa của nguyên tử trung tâm E. Nguyên nhân chính làm giảm dần năng lượng liên kết là do liên kết W-E của các phức nặng hơn W4-NHE bị phân cực mạnh về phía nguyên tử E dẫn đến lực hút tĩnh điện với nguyên tử W yếu dần. Hệ phức nghiên cứu được coi là hợp chất điển hình cho các nghiên cứu thực nghiệm.

Transition metal bis(thiosemicarbazone) complexes have been of great interest in the last five decades. One of the most striking features of these complexes is that they possess a wide range of biological properties including antimalarial, antibacterial and anticancer activity. Zinc and copper bis(thiosemicarbazone) complexes have recently attracted attention due to their intracellular fluorescence and anticancer activity, respectively. The present work “Targeting Cancer Cells and Live Cell Imaging Using Bis(thiosemicarbazone) Complexes of Copper and Zinc” is an effort to target cancer cells using folic acid or biotin linked anticancer active copper bis(thiosemicarbazone) complexes. Interestingly, bis(thiosemicarbazone) ligands form zinc complexes that could be used to image cancer cells and one of the ligands could be used for imaging zinc in the cells. Chapter 1, provides a brief introduction to metal complexes in medicine. Different classes of metallodrugs and their mechanism of action are listed. A short discussion on different types of diagnostic drugs and transition metal complexes possessing anticancer activity is presented. An overview of the strategies available to target cancer cells is included. Furthermore, the use of thiosemicarbazone compounds for anticancer activity is reviewed in detail. Recent examples of bis(thiosemicarbazone) compounds in medicinal studies is briefly mentioned. This section ends with the scope of the present work which involves bis(thiosemicarbazone) complexes of zinc and copper. Chapter 2, “Zinc bis(thiosemicarbazone) complexes for live cell imaging and anticancer activity” deals with the synthesis and characterization of a series of mononuclear and binuclear zinc bis(thiosemicarbazone) complexes by varying substituents at the diketone moiety or at the thiosemicarbazide fragment of the ligand. The crystal structures of mononuclear ligand benzil-bis(4-pyrrolidine-3-thiosemicarbazone) (BTSCH2), zinc glyoxal-bis(4-methyl-4-phenyl-3-thiosemicarbazone) [Zn(GTSC)]3 and [Zn(BTSC)(DMSO)] complexes were determined using single-crystal X-ray crystallography. Here, the mononuclear zinc complexes were utilized as live cell imaging agents whereas binuclear zinc complexes proved to be anticancer agents. Among the many mononuclear complexes prepared, the trimeric zinc complex derived from glyoxal- bis(4-methyl-4-phenyl-3¬thiosemicarbazone) was found to be the most fluorescent complex owing to its unique structure. This permitted live cell imaging in a number of cancer cell lines. In comparison with the well studied zinc biacetyl-bis(4-methyl-3-thiosemicarbazone) Zn(ATSM) complex, which was used as a reference, [Zn(GTSC)]3 had a 2.5 fold higher fluorescence quantum yield in DMSO. The cellular fluorescence was measured in collaboration with Prof. K.Somasundaram’s laboratory at MCBL using flow cytometry. It was observed that [Zn(GTSC)]3 had 3 to 12 fold higher fluorescence than Zn(ATSM) in various cell lines (n = 9) of different tissue origin. Confocal fluorescence microscopy studies established that [Zn(GTSC)]3 localizes in the nucleus of human breast cancer MCF-7 and MDA-MB-231 cells within 30 minutes of addition. Moreover, [Zn(GTSC)]3 showed relatively less cytotoxicity compared to the Zn(ATSM) complex in all the cancer cell lines tested. DNA interaction studies such as binding and cleavage showed that [Zn(GTSC)]3 was less harmful to DNA as well. All these features make [Zn(GTSC)]3 a good fluorescent imaging agent for live cells. Binuclear zinc bis(thiosemicarbazone) complexes were also synthesized and their cytotoxicity was evaluated in different cancer cells. One of the ligands, 1,3-bis{biacetyl-2′-"-N-pyrrolidinethiosemicarbazide)-3′-(4"-N-thiosemicarbazide)} propane (ProBATpyrH4), and its zinc complex were found to show excellent anticancer activity against human hepatocellular cancer (HepG2) cell line. However, the cellular uptake studies as followed by flow cytometry revealed that these compounds do not fluoresce inside the cells. However, the DNA interaction studies using ethidium bromide displacement assay revealed that these complexes have better binding ability to DNA than mononuclear zinc complexes and the viscometric titrations suggested the binding mode to DNA is through partial intercalation. Apparently, these complexes do not induce DNA cleavage as evident from the cleavage experiments performed on pBR322 DNA. It is likely that their anticancer activity is due to unique DNA binding properties. Imaging zinc is important in the field of metallomics as alteration of zinc concentration in cells is associated with, or attributed to various diseases. In this regard, bis(thiosemicarbazone) ligands are useful. Chapter 3, “Imaging intracellular zinc using glyoxal-bis(4-methyl-4-phenyl-3-thiosemicarbazone) ligand” deals with imaging zinc in live cells using the bis(thiosemicarbazone) ligand, GTSCH2. Since the trimeric zinc complex is fluorescent, the corresponding ligand, GTSCH2, was utilized to visualize the zinc present within cells. The ligand GTSCH2 is found to be a selective fluorescence “turn-on” sensor for zinc. This sensor exhibited excellent sensitivity and selectivity towards zinc over other physiologically relevant cations. The binding affinity of GTSCH2 to zinc was estimated to be 0.59 nM in an aqueous MOPS (50 mM, NaCl; 100 mM; pH 7.3) buffer containing 30% DMSO, from competitive binding experiments carried out with ethylene glycol tetraacetic acid (EGTA). The sensor displayed maximal fluorescence response to zinc ion when present in the ratio of 1:1 and displayed stable fluoresence in the pH range 5.0 to 7.8, which suggests that the probe may be suitable for imaging zinc in both normal and cancer cells. The potential of GTSCH2 to image zinc inside the cell has been demonstrated in two human breast cancer cell lines using confocal fluorescence microscopy. Unlike mononuclear zinc complexes, the mononuclear copper bis(thiosemicarbazone) complexes are cytotoxic. Chapter 4, “Anticancer activity of copper bis(thiosemicarbazone) complexes” deals with the synthesis, characterization and anticancer activity of mononuclear copper bis(thiosemicarbazone) complexes. All of them were characterized by spectroscopic methods and in three cases by single crystal X-ray diffraction. The redox properties, studied by cyclic voltammetry, showed reversible one electron- reduction process that varied from –0.53 V to –0.18 V vsSCE. Anticancer activity for the synthesized complexes and their ligands were tested against many human cancer cell lines where the complexes Cu(GTSC) and Cu(GTSCHCl) derived from glyoxal-bis(4-methyl-4-phenyl-3-thiosemicarbazone) are found to be most cytotoxic (GI50 <0.1 µM to 2.1 µM) in five cancer cell lines tested. Moreover, the cytotoxicity is similar to that of adriamycin, a known anticancer drug, in all cell lines. However, it is less potent than a copper bis(thiosemicarbazone) analog, copper biacetyl-bis(4-methyl-3-thiosemicarbazone) Cu(ATSM), a well studied anticancer agent in many cell lines. Cellular studies were carried out for the selected complexes Cu(GTSC) and Cu(GTSCHCl) along with Cu(ATSM) on HCT116 colon cancer cells. The order of lipophilicity and cellular uptake as studied by ICP-OES are correlated with their cytotoxicity. Based on the interaction of these complexes with DNA using the ethidium bromide displacement assay, DNA -melting, -viscosity and -cleavage studies, it is suggested that these complexes intercalate partially with DNA. DNA cleavage studies using pBR322 DNA revealed that only Cu(GTSCHCl) complex cleaves DNA. Mechanistic discrimination studies suggest that the complex cleaves DNA through the hydrolytic pathway. Since the topoisomerase IIα (Topo IIα), a nuclear enzyme resolving topological problems of DNA, is considered as one of the possible molecular targets for a number of anticancer drugs including some of the copper thiosemicarbazone complexes, Topo IIαinhibition studies were carried out in human Topo IIα. Interestingly, many copper bis(thiosemicarbazone) complexes are able to inhibit Topo IIα activity by acting as Topo IIα poison. Cu(GTSCHCl) complex was found to be the most active in this series of complexes (90 % inhibition at 100 µM) and it inhibits the enzyme in a dose dependant manner. Based on the results, it was concluded that the cell death may be mediated, at least in part, through DNA cleavage and Topo IIαinhibition. Severe side effects, poor distribution profiles and or organ specific toxicity make the conventional chemotherapy of limited value with metal based drugs. Therefore, developing cancer-specific drug delivery systems is an urgent need in cancer therapy. Among the many strategies available to target cancer, targeting the receptors that are overexpressed in the cancer cell membrane is a novel strategy being used in recent studies. Therefore the last part my work, “Copper bis(thiosemicarbazone) complexes linked to poly(ethylene glycol) and multiwalled carbon nanotubes for targeted delivery to cancer cells ” was designed to target cancer cells. Here, copper complexes (therapeutic molecule) were attached with PEG and MWCNT (carrier) along with folic acid or biotin (targeting molecule). First, CuATSM–A was functionalized with a disulfide linker and connected with folic acid via a poly(ethylene glycol) (PEG600) linker. This was synthesized to target KB (human nasopharyngeal carcinoma) cells, a cell line that overexpresses the folate receptor on the cell surface. In order to investigate the targeting efficacy, the corresponding fluorescent labeled analogs and non-targeted PEG conjugates were synthesized. Flow cytometry studies with fluorescent marker (fluorescein isothiocyanate) labeled PEG analogs showed the targeting efficacy on KB cells. The copper complex, CuATSM–A, attached with biotin–PEG2000 also was synthesized to target high-biotin-using HeLa (human cervical carcinoma) cells. Multiwalled carbon nanotubes (MWCNT) were also used as nanocarriers. Here, the MWCNT was decorated with PEG600 diamine and then functionalized with the copper complex (therapeutic molecule), folic acid (targeting molecule), and FITC (fluorescent molecule). The conjugation of all the molecules with MWCNT is characterized by various spectroscopic techniques.

In der vorliegenden Arbeit werden Untersuchungen vorgestellt, die sich mit drei verschiedenen Aspekten der Dynamik offener Quantensysteme beschäftigen. Zwei Themenkreise haben dabei mehr grundsätzliche Probleme der Theorie dissipativer Molekularsysteme zum Gegenstand. Dementsprechend müssen die Betrachtungen dazu auf einem allgemeineren Niveau verbleiben. In dem dritten Themenkreis jedoch, der sich mit Zwei-Teilchen-Effekten in der dissipativen Dynamik befaßt, können die Untersuchungen bis hin zu Berechnung von Meßgrößen geführt werden. Im ersten Teil der Arbeit gelingt eine Verallgemeinerung der vielbenutzten Standardform der Quanten-Master-Gleichung hin zur Nichtlinearen Quanten-Master-Gleichung. Mit der Anwendung der dazugehörigen zeitabhängigen Projektionsoperator-Technik kann ein Formalismus reaktiviert werden, der in der Literatur bisher eine nur sehr eingeschränkte Verbreitung findet. Der zweite Teil der Arbeit widmet sich Untersuchungen zur Monte-Carlo-Wellenfunktions-Methode mit dem Ergebnis, eine konsistente Verallgemeinerung auf ein Reservoir mit endlicher Temperatur anzugeben. Den Ausgangspunkt dazu bildet ein mikroskopisches Modell zur System-Reservoir-Kopplung, welches im Rahmen der Bewegungsgleichung für den reduzierten statistischen Operator in die sogenannte Lindblad-Form der Dissipation überführt wird. Nach der Betrachtung von Ein-Teilchen-Transferprozessen beschäftigt sich der dritte Teil der Arbeit mit der korrelierten Bewegung von zwei Quantenteilchen in einer dissipativen Umgebung mit der Hinwendung zum Zwei-Wasserstoff-System (Dihydrid-System) an Übergangsmetall-Verbindungen. Zunächst werden Modellrechnungen zur dissipationfreien Zwei-Teilchen-Dynamik in einem Potentialmodell durchzuführt. Der Einfluß, den die Teilchen-Teilchen-Korrelationen auf das Durchtunneln eines Potentialwalles besitzt, können durch verschiedene numerische Rechnungen aufgezeigt werden. Wie sich diese Effekte in Neutronenstreuexperimenten an dem Zwei-Teilchen-System der Übergangsmetall-Hydrid-Komplexe äußern, wird basierend auf Simulationsrechnungen untersucht. Kernstück dieser Betrachtungen bildet eine neuartige Formel für die Neutronenstreuung, die auf der dissipativen Dynamik des betrachteten Zwei-Teilchen-Systems aufbaut. / In the report at hand studies are presented dealing with three differentaspects of the dynamics of open quantum systems. Two topics are about the fundamental problems of the theory of dissipative molecular systems. Accordingly these investigations must remain on a more general level. In the third subject, however, which is about the two-particle effects in the dissipative dynamics the analyses can be extended to the computation of measurements. In the first part of the report a generalization of the well known standard quantum master equation to the nonlinear quantum master equation is developed. With the help of the projection operator technique belonging to it a formalism, that has not been popular in literature so far, can be reactivated. The second part of the report concentrates on examinations of the Monte-Carlo wave-function method, and results in the consistent generalization for a reservoir of finite temperature. The starting point for this is a microscopic model of the system-reservoir coupling, which is expanded to the so called Lindblad form of the dissipation in the line of the equation of motion for the reduced statistical operator. After the analysis of one-particle transfer processes the third part of the report is about the correlated motion of two quantum particles in a dissipative environment with main emphasis on the two-hydrogen system (dihydrid system) in transition metal complexes. First of all model computations for the dissipationless two-particle dynamics in a potential model are made. By different numerical computations the influence, which the particle-particle correlations exert on the tunneling through a potential barrier, can be shown.Based on simulations it is examined how these effects can be seen in neutron scattering experiments on two-particle systems of transition metal complexes. Main item of these investigations is a new formula for the neutron scattering which is based on the dissipative dynamics of the examined two-particle system.

Unprecedented Ullmann couplings of murrayafoline-A with either 6-bromo- or 4-bromocarbazole derivatives provide highly efficient synthetic routes to the biscarbazole alkaloids murrastifoline-A (6 steps, 66% overall yield) and bismurrayafoline-A (6 steps, 28% overall yield). / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

We report the first total synthesis of oxydimurrayafoline via nucleophilic substitution at the benzylic position at C-3 of the carbazole framework. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

The present thesis deals with different aspects of the chemistry of oxovanadium(IV) complexes, their interaction with double stranded DNA, photo-induced DNA cleavage, photo-enhanced cytotoxicity in visible light and red light and localisation and cellular uptake to understand the mechanism of cell death. Chapter I presents a general introduction on potential of transition metal complexes as photochemotherapeutic agents. A brief introduction about Photodynamic Therapy (PDT) as a new alternative to chemotherapy for treating cancer has been made. Various modes of interaction of small molecules with duplex DNA are described. Recent reports on metal-based photocytotoxicity, photo-induced DNA cleavage activity and cellular localization are presented in detail. Objective of the present investigation is also dealt in this Chapter. Chapter II of the thesis deals with the synthesis, characterization, DNA binding and photo-induced DNA cleavage activity of ternary oxovanadium(IV) complexes of ONO-donor 2-(2-hydroxybenzylideneamino)phenol (salamp) and phenanthroline bases to explore the photo-induced DNA cleavage activity in UV-A light of 365 nm and photocytotoxicity in visible light. Chapter III deals with the photo-induced DNA cleavage and photocytotoxicity of ternary oxovanadium(IV) complexes containing ONN-donor N-2-pyridylmethylidine-2-hydroxyphenylamine (Hpyamp) Schiff bases and phenanthroline bases. The objective of this work is to investigate the photo-induced DNA cleavage activity in near-IR light. Photocytotoxicity and cell cycle arrest have been studied in HeLa cancer cells. Chapter IV deals serendipitous discovery of planar triazinuim cationic species by vanadyl-assisted novel ring cyclization reaction. The compounds are synthesised, characterized and their DNA binding and anaerobic photoinduced DNA cleavage activity are presented. The importance of the thiazole moiety in the triazinuim species in cellular uptake has been investigated. Photocytotoxicity, localization and cell death mechanism have been studied in HeLa and MCF-7 cells. Chapter V describes the synthesis, characterization, DNA binding, photo-induced DNA cleavage activity and photocytotoxicity of oxovanadium(IV) complexes containing 2-(1H-benzimidazol-2-yl)-N-(pyridin-2-ylmethylene)ethaneamine (Hpy-aebmz) and curcumin as photosensitizer. The effect of conjugating naphthalimide on Hpy-aebmz on photoinduced DNA cleavage and photocytotoxicity has been studied. Cellular uptake, localization and mechanism of cell death induced by complexes have been investigated. Chapter VI presents ternary oxovanadium(IV) complexes having, 2-((1H-benzimidazol-2-yl)methylimino-methyl)phenol (Hsal-ambmz) and phenanthroline bases. The complexes were synthesized, characterized and their DNA binding property studied. Photo-induced DNA cleavage activity and photocytotoxicity in red light has been discussed. Anthracene has been conjugated to a tridentate ligand to investigate cellular uptake, localization and cell death mechanism. Mitochondria targeting property of the complexes having dipeptide has been studied and compared with clinically used drug Photofrin®. The references have been compiled at the end of each chapter and indicated as superscript numbers in the text. The complexes presented in this thesis are represented by bold-faced numbers. Crystallographic data of the complexes, characterized structurally by single crystal X-ray crystallography, are given in CIF format in the enclosed CD (Appendix-I). Due acknowledgements have been made wherever the work described is based on the findings of other investigators. Any unintentional omission that might have happened due to oversight or mistake is regretted.

Unprecedented Ullmann couplings of murrayafoline-A with either 6-bromo- or 4-bromocarbazole derivatives provide highly efficient synthetic routes to the biscarbazole alkaloids murrastifoline-A (6 steps, 66% overall yield) and bismurrayafoline-A (6 steps, 28% overall yield). / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

We report the first total synthesis of oxydimurrayafoline via nucleophilic substitution at the benzylic position at C-3 of the carbazole framework. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

No / A novel series of 1,4-disubstituted aminoanthraquinones were prepared by ipso-displacement of 1,4-difluoro-5,8-dihydroxyanthraquinones by hydroxylated piperidinyl- or pyrrolidinylalkyl-amino side chains. One aminoanthraquinone (13) was further derivatized to a chloropropyl-amino analogue by treatment with triphenylphosphine-carbon tetrachloride. The compounds were evaluated in the A2780 ovarian cancer cell line and its cisplatin-resistant variants (A2780/ cp70 and A2780/MCP1). The novel anthraquinones were shown to possess up to 5-fold increased potency against the cisplatin-resistant cells compared to the wild-type cells. Growth curve analysis of the hydroxyethylaminoanthraquinone 8 in the osteosarcoma cell line U-2 OS showed that the cell cycle is not frozen, rather there is a late cell cycle arrest consistent with the action of a DNA-damaging topoisomerase II inhibitor. Accumulative apoptotic events, using time lapse photography, indicate that 8 is capable of fully engaging cell cycle arrest pathways in G2 in the absence of early apoptotic commitment. 8 and its chloropropyl analogue 13 retained significant activity against human A2780/cp70 xenografted tumors in mice.