Chemical hardness (eta), calculated by density functional theory (DFT), was firstly used as one of the chemical reactivity descriptors to set up the one descriptor 2D-QSAR model of platinum drugs. In this simple but promising model, the antitumour activities (log GI50) evaluated by National Cancer Institute (NCI) of structure-based groups containing normal sp 3 nitrogen and R,R-diamminecyclohexane (R,R-DACH) as the ligand showed good correlation. It was also demonstrated that silane and stereoisomers of DACH groups showed special patterns. This study also made use of the COMPARE program from NCI to evaluate the activity profile and the analysis of the data revealed these distinct patterns are influenced by the mechanism of the drugs. / Computer-aided drug design (CADD) techniques have been applied to establish quantitative structure-activity relationships (QSAR) and quantitative structure- property relationships (QSPR) models. Although these techniques are widely used in organic drugs, new metal-based drugs were hindered from development for lack of metal parameters, such as potent new platinum drugs as a major group of drugs used in cancer treatment. The purpose of the present study, therefore, is to generate novel platinum parameters based on previous work and then set up the simple QSAR/QSPR model with predictive abilities. / Finally, two 3D-QSAR and 3D-QSPR models obtained using Sybyl software. One was for demethylcantharidin (DMC) analogues as phosphatase 2A (PP2A) inhibitors. The other was describing the hydrophobicity of platinum drugs. In this research, the platinum atom was introduced to Sybyl and thus made it possible for the first time to use comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods to investigate platinum drugs. All 3D models indicated good predictive ability and thus provided an effective method to design new potent platinum drugs. / To clarify the pattern of stereoisomers of the DACH group, new platinum parameters was introduced to the AMBER software successfully. Moreover, stereoisomers of the DACH group which formed 1,2-GG intrastrand cross-links with DNA were studied by molecular dynamics (MD) simulations using AMBER. The calculated binding energies between R,R-DACH-Pt, S,S-DACH-Pt and cis-DACHPt moieties and DNA revealed a strong correlation with antitumour activities. The result provided more clues to understand the biological interactions of chiral platinum drugs. DNA structure analysis indicated that DNA tolerated the distortion resulted in the different Pt-DNA adducts and various local and global structure distortions were found. Natural bond orbital (NBO) analysis of hydrogen bonding on Pt-DNA adducts at a AGGC site revealed that R,R-DACH-Pt moiety alleviated the repulsion by unwinding the DNA, whereas the S,S-DACH-Pt adduct avoided the interaction by distorting the H bonds of binding site basepairs. Hence, the structural differences of chiral platinum drug led to its distinct activity. / Yang, Lifeng. / "June 2008." / Advisers: Steve C. F. Au Yeung; Yee-Ping Ho. / Source: Dissertation Abstracts International, Volume: 70-03, Section: B, page: 1541. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (p. 159-172). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

No description available.

This thesis mainly deals with some biochemical aspects regarding the efficacy of novel platinum anticancer compounds alone and in combination with mangiferin, as part of a broader study in which both chemistry and biochemistry are involved. Various novel diamine and N-S donor chelate compounds of platinum II and IV have been developed in which factors such as stereochemistry, ligand exchange rate and biocompatibility were considered as additional parameters. In the first order testing, each of these compounds was tested with reference to their “killing” potential by comparing their rate of killing, over a period of 48 hours with those of cisplatin and oxaliplatin. Numerous novel compounds were tested in this way, using the MTT cell viability assay and the three cancer cell lines MCF7, HT29 and HeLa. Although only a few could be regarded as equal to or even better than cisplatin, CPA7 and oxaliplatin, the testing of these compounds on cancer cells provided useful knowledge for the further development of novel compounds. Three of the better compounds, namely Yol 25, Yol 29.1 and Mar 4.1.4 were selected for further studies, together with oxaliplatin and CPA7 as positive controls, to obtain more detailed knowledge of their anticancer action, both alone and when applied in combination with mangiferin. In addition to the above, resistant cells were produced for each of the three different cell lines tested and all the selected compounds, both in the presence and absence of mangiferin. The effects of these treatments on the activation of NFĸB when applied to normal and resistant cell lines were also investigated. All the compounds induced apoptosis in the cell lines tested as well as alter the DNA cycle at one or more phase. Additionally, combination of these compounds with mangiferin enhanced the above-mentioned effects. Mangiferin decreases the IC50 values of the platinum drugs by up to 3.4 times and, although mangiferin alone did not induce cell cycle arrest, the presence of mangiferin in combination with oxaliplatin and Yol 25 shows an earlier and greatly enhanced delay in the S-phase, while cells treated with CPA7, Yol 29.1 and Mar 4.1.4 in combination with mangiferin showed a later, but greatly enhanced delay in the S-phase. It was also found that mangiferin acts as an NFĸB inhibitor when applied in combination with these drugs, which, in turn, reduces the occurrence of resistance in the cell lines. Resistance to oxaliplatin was counteracted by the combination with mangiferin in HeLa and HT29, but not in MCF7 cells, while resistance to CPA7 was only counteracted in the MCF7 cell line. Yol 25 and Mar 4.1.4 did not seem to induce resistance in HeLa and MCF7 cells, but did in HT29 cells, whereas Yol 29.1 caused resistance in HeLa and HT29 cells, but not in MCF7 cells. Finally, an effort was made to evaluate the different compounds by comparing them with respect to their properties relating to anticancer action with and without the addition of mangiferin.

Aim. The aim of this study was to synthesize and characterize novel analogues of [DACH-Pt-DMC] by using different stereoisomers of DACH; and to investigate any differences in in vitro activity of these complexes in human hepatocellular carcinoma (HCC), colorectal carcinoma (CRC) cell lines and acquired cisplatin or oxaliplatin resistant sub-lines, and to compare that of oxaliplatin and other established Pt-based anticancer agents. Mechanistic roles of DACH-Pt- and DMC components of the TCM-Pt complexes on affecting HCT 116 human CRC cell line were investigated by flow cytometry, COMET assay and cDNA microarray analysis. / Background. Demethylcantharidin (DMC), a modified component of the traditional Chinese medicine (TCM), integrated with a platinum (Pt) moiety created a series of TCM-Pt complexes [Pt(C8H8O 5)(NH2R)2] 1-5 which demonstrated superior antitumor activity and circumvention of cisplatin resistance in vitro. Compound 5, derived from the 1,2-diaminocyclohexane (DACH) ligand (where R=trans-C6H10) had the most potent antitumor activity and closest structural resemblance to oxaliplatin (R,R-DACH-Pt complex) which is the first Pt-based anticancer drug to demonstrate convincing clinical activity against colorectal cancer and has a mechanism of action and resistance that is clearly different from that of cisplatin and carboplatin. / Conclusion. This study is the first to examine the mechanism of anticancer activity of new complexes that integrate DMC with different isomers of DACH. It has shown that both DACH-Pt- and DMC components contribute significantly to the compounds' potent anticancer activity, but likely with different mechanisms of action. The DACH-Pt- component appears to dictate the cell cycle distribution, whereas the DMC component appears to enhance cytotoxicity by inducing more DNA damage in HCT 116 colorectal cancer cells. / Methods. DMC was reacted with appropriate DACH-Pt-(NO3) 2 intermediates, which were prepared from treatment of K2PtCl 4 with stereoisomeric DACH (RR-, SS- & cis-), followed by reaction with silver nitrate. Proton NMR, high-resolution MS, polarimetry and circular dichroism (CD) spectroscopy were used to characterize their chemical structures and optical activities. In vitro antitumor activity (IC50 of 72hr drug exposure time) were assessed by a standard MTT assay. Cell cycle analysis by flow cytometry was determined at 0, 6, 12, 18, 24, 48 and 72 h after drug treatment (cisplatin, carboplatin, oxaliplatin, DMC, compound 1 or trans-DACH-Pt-DMC analogues) at IC50 and 5 x IC50 concentrations with three to four replicates. Comet assay was performed with a fluorescent microscope and used to examine DNA damage after drug treatments (50muM of cisplatin, carboplatin, oxaliplatin, DMC, compound 1 or R,R-DACH-Pt-DMC) for 3hr. cDNA microarray was performed on Affymetrix Human Genome U133A Set and used to analyze gene expression profiles in HCT 116 exposed to trans-(+/-)-DACH-Pt-DMC or oxaliplatin at their IC50 for 72hr. / Results. The in vitro results showed that the trans-analogues were consistently the most potent amongst all the compounds tested in both HCC and CRC cell lines: the trans-(+)(1R,2R)-DACH-Pt-DMC complex, in particular, was the most effective stereoisomer. All of the stereoisomeric DACH-Pt-DMC complexes and oxaliplatin were apparently able to circumvent cisplatin resistance in Huh-7 and SK-Hep1 sub-lines, but cross resistant with oxaliplatin in HCT 116 oxaliplatin resistant sub-line. Flow cytometric analysis revealed the novel trans-DACH-Pt-DMC analogues and oxaliplatin behaved similarly: that is, the compounds at 5 x IC50 concentrations all caused a significant decrease in the S-phase population within 18h and at the same time induced G2/M arrest, and without obvious sub-G 1 phase accumulation, but distinct from that of cisplatin, carboplatin or DMC. Comet assay showed that trans-(+)-(1R,2 R)-DACH-Pt-DMC caused the most significant DNA damage at an equivalent molar concentration. Microarray analysis suggested that the mechanistic role of the DMC ligand can induce the cell cycle to accelerate from the G 1 to S-phase and cause M-phase arrest. / Yu Chun Wing. / "July 2006." / Advisers: Yee-ping Ho; Chik Fun Steve Au-Yeung. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1586. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 191-232). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Leung Chung Wai. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (leaves 142-146). / Abstracts in English and Chinese. / ABSTRACT (ENGISH) --- p.iii / ABSTRACT (CHINESS) --- p.v / ACHKNOWLEDGEMENTS --- p.vii / TABLE OF CONTENTS --- p.viii / Chapter CHAPTER 1 --- Introduction and Background / Chapter 1.1 --- Introduction of Platinum Drugs --- p.1 / Chapter 1.2 --- Mechanism of Action of Cisplatin --- p.3 / Chapter 1.3 --- Structure-Activity Relationships of the Platinum Drug 、 --- p.4 / Chapter 1.4 --- QS AR Parameters --- p.9 / Chapter 1.4.1 --- Chemical Hardness: Descriptor of Chemical Reactivity --- p.9 / Chapter 1.4.2 --- Possible Reaction Pathway of Platinum Drugs --- p.12 / Chapter 1.4.2.1 --- Proposed DNA Binding Pathway of Platinum Drugs --- p.13 / Chapter 1.4.2.1.1 --- Hydrolysis Pathway --- p.13 / Chapter 1.4.2.1.2 --- DNA Binding Pathway Involving the S-containing Biomolecules (Methionine Pathways) --- p.16 / Chapter 1.4.2.1.3 --- Conclusion --- p.21 / Chapter 1.5 --- Thesis Scope --- p.22 / Chapter CHAPTER 2 --- Theory and Methodology / Chapter 2.1 --- Introduction --- p.24 / Chapter 2.2 --- Density Functional Theory (DFT) --- p.24 / Chapter 2.2.1 --- Kohn-Sham Theorem --- p.25 / Chapter 2.2.2 --- Exchange-Correlation Energy Functional --- p.27 / Chapter 2.3 --- Basis Set --- p.27 / Chapter 2.3.1 --- Relativistic Effective Core Potential --- p.27 / Chapter 2.3.2 --- Double-Zeta --- p.28 / Chapter 2.3.3 --- Polarized Basis Set --- p.29 / Chapter 2.4 --- Solvation Model --- p.30 / Chapter 2.4.1 --- Continuum Model --- p.30 / Chapter 2.4.1.1 --- Simple Solvation Model --- p.31 / Chapter 2.4.1.1.1 --- Electrostatic Component --- p.31 / Chapter 2.4.1.1.2 --- Dispersion-Repulsion Interaction --- p.33 / Chapter 2.4.1.1.3 --- Cavitatoin Energy --- p.35 / Chapter 2.4.1.2 --- Polarized Continuum Model --- p.36 / Chapter 2.5 --- Methodology --- p.39 / Chapter 2.5.1 --- Calculation of DFT Global Reactivity Index --- p.39 / Chapter 2.5.1.1 --- Calculation for the Reaction Intermediates --- p.41 / Chapter 2.5.2 --- Calculation of the Reaction Pathways --- p.42 / Chapter CHAPTER 3 --- Results and Discussion / Chapter 3.1 --- Introduction --- p.49 / Chapter 3.2 --- Optimized Structure against Experimental Geometry --- p.49 / Chapter 3.3 --- Kohn-Sham Orbitals --- p.54 / Chapter 3.3.1 --- Location of the HOMO and LUMO --- p.55 / Chapter 3.4 --- Results of the DFT Reactivity Parameter --- p.57 / Chapter 3.5 --- Chemical Structure of the Drugs in the QSAR --- p.64 / Chapter 3.6 --- QSAR Analysis --- p.67 / Chapter 3.6.1 --- The Overall QSAR Plot of the Platinum Drugs --- p.68 / Chapter 3.6.1.1 --- Empirical Applicability of the QSAR on the Platinum(IV) Drugs --- p.70 / Chapter 3.6.1.2 --- Detail QASR Study According to the Type of Platinum Drug --- p.71 / Chapter 3.6.1.2.1 --- QSAR Study of the non-“trans-DACH´ح Platinum Drugs --- p.72 / Chapter 3.6.1.2.1.1 --- "QSAR Equation of the non-""trαns-DACH"" Platinum Drugs" --- p.75 / Chapter 3.6.1.2.2 --- QSAR Analysis for the Pt-trαns-DACH Drugs --- p.77 / Chapter 3.6.1.2.2.1 --- "QSAR Study of trans-S,S-DACH Platinum Drugs" --- p.79 / Chapter 3.6.1.2.2.2 --- "QSAR Study of trans-R,R-DACH Platinum Drugs" --- p.80 / Chapter 3.6.1.3 --- Summary --- p.81 / Chapter 3.7 --- QSAR Study of the Important Intermediates Using Chemical Hardness --- p.82 / Chapter 3.7.1 --- Optimized Structure for the Intermediates --- p.84 / Chapter 3.7.2 --- QSAR of the Dichloride Pt-Drugs Using Chemical Hardness of Parent Compounds --- p.90 / Chapter 3.7.3 --- QSAR of the Dichloride Pt-Drugs Using Chemical Hardness of Hydrolysis Intermediates --- p.91 / Chapter 3.7.4 --- QSAR of the Dichloride Pt-Drugs Using Chemical Hardness of Cyclic-Methionine Intermediates --- p.93 / Chapter 3.7.5 --- Conclusion --- p.95 / Chapter CHAPTER 4 --- Results and Discussion / Chapter 4.1 --- Introduction --- p.96 / Chapter 4.2 --- Study Scheme --- p.97 / Chapter 4.3 --- Optimized Structures --- p.98 / Chapter 4.4 --- Comments on the Reliability of the Calculation Model --- p.103 / Chapter 4.4.1 --- Reaction Profile in the Gas Phase --- p.104 / Chapter 4.4.2 --- Reaction Profiles Using Simple Solvation Model --- p.105 / Chapter 4.4.2.1 --- Defects of the Simple Solvation Model --- p.107 / Chapter 4.4.3 --- Reaction Profile Using PCM-UAHF Solvation Model --- p.109 / Chapter 4.4.3.1 --- Selection of the Reaction Parameters for the QSAR Study --- p.112 / Chapter 4.5 --- QSAR Study of Platinum Drugs Using the Reaction Parameters (AG and ΔG+) --- p.121 / Chapter 4.5.1 --- QSAR Analysis Using ΔG+(hydrolysis) --- p.121 / Chapter 4.5.2 --- QSAR Analysis Using ΔG(hydrolysis) --- p.123 / Chapter 4.5.3 --- QSAR Analysis Using ΔG+(guanine) --- p.125 / Chapter 4.5.4 --- QSAR Analysis Using ΔG(guanine) --- p.127 / Chapter 4.5.5 --- Further investigation of the Bidentate Pt-drugs DNA Binding --- p.129 / Chapter 4.5.5.1 --- Calculation Model --- p.129 / Chapter 4.5.5.2 --- Bidentate Pt-Drugs Reactions --- p.130 / Chapter 4.5.5.3 --- Selection of the Calculated Model for the QSAR Study --- p.133 / Chapter 4.5.5.4 --- QSAR Analysis Using ΔG+(guanine) for the Platinum Drugs with Bidentate Caboxylate Ligands --- p.136 / Chapter 4.5.5.5 --- QSAR Analysis Using ΔG(guanine) for the Platinum Drugs with Bidentate Carboxylate Ligands --- p.137 / Chapter 4.5.6 --- Conclusion --- p.138 / Chapter CHAPTER 5 --- Conclusion Remarks and Future Works / Chapter 5.1 --- Conclusion --- p.140 / Chapter 5.2 --- Future Works --- p.141 / REFERENCES --- p.142

Bibliography: leaves 178-195.

Bibliography: leaves 178-195. / xiv, 195 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Chemistry, 2001

"January 2004" / Bibliography: leaves 163-184. / v, 184 leaves : ill. (some col.), photos ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, School of Chemistry and Physics, Discipline of Chemistry, 2004

The experimental cancer therapeutic agent gadolinium texaphyrin (MGd) is a cationic paramagnetic expanded porphyrin currently being tested as an X-Ray sensitizing (XRS) agent, and is a compound with demonstrated tumor localization. Additionally MGd shows promise as a chemotherapeutic agent, both as a stand-alone agent, and showing activity in vitro with ascorbate via a novel ROS generating mechanism.3 This dissertation reports the synthesis, characterization, and cell studies of novel MGdfluorophore, and platinum therapeutic conjugates. Also discussed are cationic Pt agents having cytotoxic activity. In this research we set out to answer three questions: i) can fluorescent conjugates of MGd be synthesized, with observable subcellular localization, different from that of MGd, ii) can MGd-Pt conjugates with observable Pt release be synthesized?, and iii) can Pt compounds containing a cationic moiety be tuned to have efficacy comparable to traditional Pt therapeutic agents? Two MGd-xanthene fluorophore conjugates were synthesized with the goal of using them to probe sub-cellular distribution. The anionic (FITC), and cationic (Rhodamine), fluorophore conjugates demonstrated nuclear and mitochondrial localization, respectively. In an ongoing project designed to reduce non-specific agent toxicity, a platinumreleasing MGd therapeutic conjugate was synthesized. The MGd-amidopropylmalonato-Pt conjugate demonstrated efficacy equivalent to carboplatin, a classical “non-selective” agent as inferred from in-vitro studies with A549 lung cancer cells. Aqueous stability studies of this conjugate gave results in agreement with hydrolytic loss of Pt, reversible with added Pt-diaquo. Finally, Pt complexes of amino-1-benzylpyridinium salts were synthesized and found to demonstrate significant cytotoxicity in screening studies. This latter positive development led to the suggestion that complexes of this type could consititute a new class of lipophilic-quaternary-cation Pt therapeutic agents. It is hoped that this series of putative Pt anti-cancer agents will prove useful as both stand-alone therapeutic agents and as the basis for producing conjugate with biolocalizing properties. / text

[Truncated abstract] The Phase II clinical candidate, [(trans-Pt(NH3)2Cl)2{μ-trans-Pt(NH3)2(H2N(CH2)6NH2)2}]4+ (BBR3464 or 1,0,1/t,t,t) shows a unique binding profile when compared to the anticancer agent cis-[Pt(NH3)2Cl2] (cisplatin) and dinuclear platinum complexes of the general formula [(trans-Pt(NH3)2Cl)2(H2N(CH2)nNH2)]2+. There is evidence that the increased efficacy of 1,0,1/t,t,t results from the presence of the charged central linker, which can alter the mode of binding to DNA. This alternate binding mode may be due to an electrostatic and hydrogen bonding association of the central platinum moiety in the minor groove that occurs prior to covalent binding (termed “pre-association”) . . . This research shows that 0,0,0/t,t,t is an adequate model to study the pre-association process of 1,0,1/t,t,t and that it binds in the minor groove of DNA. Therefore it is likely that 1,0,1/t,t,t pre-associates in the minor groove of DNA prior to covalent binding. This work supports the conclusions reached in NMR studies of the binding of 1,0,1/t,t,t with the 1,4-GG sequence (Qu et al. JBIC. 8, 19-28 (2003)), which showed simultaneous binding in the major and minor groove. The findings of the current work may also explain the observed binding mode of 1,0,1/t,t,t, which can bind to DNA in both the 3',3' and 5',5' directions (Kasparkova et al. JBC. 277, 48076-48086 (2002)). These unique binding characteristics are thought to be responsible for the increased efficacy of 1,0,1/t,t,t, and in light of the current results the observed binding mode most likely stems from the electrostatic pre-association of the central platinum moiety.