Download or read book Platinum IV and Palladium IV Compounds as Anti cancer Agents Tissue Culture Synthesis Characterization and DNA Binding Studies written by Brieanne Vogler and published by . This book was released on 2001 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Platinum IV Complexes as Prospective Anticancer Agents written by Xiao Liu and published by . This book was released on 2023* with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: In recent decades, Pt(II)-based chemotherapy drugs, such as cisplatin, oxaliplatin, and carboplatin, have been among the most effective drugs for cancer treatment. They have been widely used in various malignant solid tumors, including lung cancer, colorectal cancer, testicular cancer, ovarian cancer, bladder cancer, and head and neck cancer. Despite the well-documented success, there are still challenges to be addressed, such as intrinsic and acquired resistance, as well as side effects including nephrotoxicity, neurotoxicity, and cardiotoxicity. To maximize their effectiveness and broaden their therapeutic potential, researchers have devoted a lot of effort to exploring new derivatives and combination therapies. Among these efforts, Pt(IV) complexes, acting as prodrugs that can be activated to release active Pt(II) species, have exhibited great promise. Tremendous efforts have been devoted to exploring new synthesis approaches, elucidating structure-activity relationships, and designing novel Pt(IV) complexes that incorporate biologically active or therapeutically effective ligands. The aim is to enhance drug efficiency through increasing cytotoxicity, achieving more targeted delivery, enabling oral availability, and circumventing drug resistance, among other goals.The specific areas of focus include i) Analysis of the reduction capacity, including the determination of reduction potential (Ep) and the assessment of reduction in the presence of small reducing agents like ascorbic acid; ii) lipophilicity versus cellular accumulation; iii) stability study; iv) binding with 9-methylguanine (a simple DNA model); v) biological activities including cytotoxicity, ROS generation, cellular accumulation, COX inhibition, apoptosis induction, and more.

Download or read book Synthesis Characterization and Biological Evaluation of Platinum IV Complexes Exhibiting Anticancer Properties written by Wayne Ross Edwards and published by . This book was released on 1989 with total page 400 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Synthetic Strategies for the Design of Platinum Anticancer Drug Candidates written by Justin Jeff Wilson and published by . This book was released on 2013 with total page 345 pages. Available in PDF, EPUB and Kindle. Book excerpt: (cont'd) Chapter 6. Synthesis, Characterization, and Cytotoxicity of Platinum(IV) Dicarbamate Complexes The reaction of cis,cis,trans-[Pt(NH3)2Cl2(OH)2] with alkyl and aryl isocyanates (RNCO) in DMF afforded dicarbamate complexes of the general formula cis,cis,trans- [Pt(NH 3)2Cl 2(O 2CNHR)2]. The resulting complexes were fully characterized by X-ray crystallography, multinuclear NMR spectroscopy, and cyclic voltammetry. The anticancer activities of these complexes were assessed in human lung cancer (A549) and human lung fibroblast (MRC-5) cell lines. Although no clear structure-activity relationships could be delineated, the complexes exhibited activity on the same order of magnitude as that of the clinically established drug cisplatin. Therefore, the reaction of cis,cis,trans-[Pt(NH3)2Cl 2(OH)2] with isocyanates provides a powerful new synthetic pathway to functionalize platinum(IV) anticancer agents. Appendix A. Aqueous Electrochemistry of a Platinum(IV) Prodrug Electrochemical studies of cis,cis,trans-[Pt(NH3)2Cl2(OAc) 2] in aqueous media were carried out. Cyclic voltammetry in pH 7.4 phosphate-buffered saline with glassy carbon and Pt disk working electrodes gave substantially different peak potentials for the irreversible reduction feature. Under these conditions, the glassy carbon electrode was plated with platinum metal derived from the platinum(IV) complex, as determined by cyclic voltammetry and chronoamperometry experiments. The bulk electrolysis of cis,cis,trans-[Pt(NH3)2Cl2(OAc)2] in aqueous solution at a carbon felt working electrode was investigated by 1H NMR spectroscopy. These studies indicate ligand loss upon reduction from both axial and equatorial sites of the platinum(IV) complex. Appendix B. Targeting the Mitochondria with Platinum Anticancer Agents using Mitochondria-Penetrating Peptides Early results of a collaborative effort with the lab of Professor Shana 0. Kelley at the University of Toronto to deliver platinum anticancer agents to the mitochondria are presented. Succinylacetone (Hsuccac) was used as a leaving group ligand for a cis-diammineplatinum(II) complex. The complex [Pt(succac)(NH 3)2](NO3), which contains a terminal, uncoordinated carboxylic acid functional group, was prepared and fully characterized. This complex was conjugated to a mitochondria-penetrating peptide (MPP) using standard solid-phase coupling chemistry. The anticancer activity of the Pt-MPP construct was tested in both wild-type and cisplatin-resistant ovarian cancer cell lines, A2780 and A2780CP70. Although less potent than cisplatin, the construct is equally toxic to both cell lines, thereby indicating that targeting the mitochondria provides a viable strategy for circumventing resistance to platinum drugs. Appendix C. Synthesis and Characterization of Several Novel Platinum Complexes Throughout the course of this thesis work, several platinum complexes were synthesized and characterized, but ultimately not fully pursued as potential anticancer agents. These species include platinum compounds with dichloroacetate, 2,2'-bis(1- methylimidazolyl)phenylmethoxymethane (BIPhMe), nitrogen mustard-containing, and nitroimidazole-derivatized ligands. The syntheses and characterization of these compounds are reported. Crystal structures are described for several of them.

Download or read book The Development of Trackable Polynuclear Platinum II Compounds for Targeted Anticancer Applications written by Sinéad O'Carroll and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Recently, there has been major interest in the design and development of therapeutic polynuclear platinum(II) complexes (PPCs). The potential use for these complexes has been epitomised by BBR3464-a trinuclear platinum(II) complex featuring trans geometry with platinum(II) centres separated by 1,6hexanediamine linkers and terminal trans labile chloride ligands-which was the first and only platinum(II) drug to enter clinical trials not based on the conventional mononuclear cis-chemotype. While this drug class has excellent therapeutic potential, issues regarding off-target toxicity cannot be overlooked. This thesis presents the synthesis, characterisation, cytotoxic analyses, and DNA binding studies of a novel azide-appended polynuclear platinum(II) complex series (N3 -PPCs). These agents feature fully trans-symmetric geometry, vary in nuclearity, and contain a terminal azide to enable biological tracking. Furthermore, although each platinum(II) centre is separated by a 1,6hexanediamine linker similar to BBR3464, this series lack a labile chloride ligand and bind with DNA through a non-covalent mechanism called the phosphate clamp. The stand-out complex in this series, N3 -TriplatinNC, has demonstrated excellent anticancer properties in-vitro in MDA-MB-231 triple negative breast cancer cells and displays impressive in-vivo tumour regression in mice bearing MDA-MB-231 xenografts. Click chemistry labelling studies were conducted to investigate the cellular localisation and accumulation properties of the N3 -PPC series in MDA-MB-231 triple negative breast cancer cell lines. This method of post-exposure 'click' modification facilitates accurate detection of the localisation and accumulation properties of the native drug alone. Finally, azide-appended PPCs were functionalised with a thiazole orange (TO) reporter molecule to create the N3 -TO-PPC series. These TO-appended N3 -PPCs were studied for their DNA binding properties and results were compared to the aforementioned N3 -PPCs and earlier reported PPCs. Future work on the TO appended PPCs entails cellular tracking within MDA-MB-231 cell lines and compared to non-TO modified congeners.

Download or read book Metal based Anticancer Agents written by Angela Casini and published by Royal Society of Chemistry. This book was released on 2019-04-05 with total page 370 pages. Available in PDF, EPUB and Kindle. Book excerpt: Metal-based anticancer drugs are among the most successful therapeutic agents, as evidenced by the frequent prescription of selected platinum and arsenic compounds to patients. Metal-based Anticancer Agents covers the interdisciplinary world of inorganic drug discovery and development by introducing the most prominent compound classes based on different transition metals, discussing emerging concepts and enabling methods, as well as presenting key pre-clinical and clinical aspects. Recent progress on the unique features of next-generation targeted metal-based anticancer agents, including supramolecular coordination complexes used for both therapy and drug delivery, promise a bright future beyond the benefits of pure cytotoxic activity. With contributions from global leaders in the field, this book will serve as a useful reference to established researchers as well as a practical guide to those new to metallodrugs, and postgraduate students of medicinal chemistry and metallobiology.

Download or read book Synthesis characterization photochemistry and anticancer activity of novel photoactivatable platinum IV diazidodihydroxido complexes written by Yao Zhao and published by . This book was released on 2012 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book The Synthesis Characterization Spectroscopic and Biological Activity Studies of Pt II and Pd II Cyanoximates written by Daniel Bryant Eddings and published by . This book was released on 2003 with total page 308 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Synthesis Characterization Photochemistry and Anticancer Activity of Novel Photoactivatable Platinum IV Diazidodihydroxido Complexes written by Yao Zhao (Researcher in chemistry) and published by . This book was released on 2012 with total page 590 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Synthesis Characterization and Redox Studies of Platinum and Palladium Complexes with Mer coordinating Ligands written by Seher Kuyuldar Tastan and published by . This book was released on 2009 with total page 206 pages. Available in PDF, EPUB and Kindle. Book excerpt: Synthetic, structural, spectroscopic, and redox studies of platinum(II) and palladium(II) compounds with mer-coordinating ligands have been undertaken in an effort to better understand the role of the metal and the ligands in controlling d^6/d^8 electron-transfer reactions. A series of Pd(pip2NCN)X (pip2NCNH=1,3-bis(piperdylmethyl)benzene) and [Pd(pip2NNN)X]X (X=Cl, Br, I) (pip2NNN=2,6- bis(piperdyl-methyl)pyridine) complexes are reported. Electronic spectra are consistent with stabilization of ligand-to-metal-charge-transfer states as the ancillary ligand is varied along the ClBr

Download or read book The Synthesis and Characterization of Novel Platinum and Palladium Diimene Compounds for Use as Anticancer Drugs and CO2 Reduction Catalyst written by Emma Kate Payne and published by . This book was released on 2003 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Green Synthesis Characterization and Applications of Nanoparticles written by Ashutosh Kumar Shukla and published by Elsevier. This book was released on 2018-11-26 with total page 548 pages. Available in PDF, EPUB and Kindle. Book excerpt: Green Synthesis, Characterization and Applications of Nanoparticles shows how eco-friendly nanoparticles are engineered and used. In particular, metal nanoparticles, metal oxide nanoparticles and other categories of nanoparticles are discussed. The book outlines a range of methodologies and explores the appropriate use of each. Characterization methods include spectroscopic, microscopic and diffraction methods, but magnetic resonance methods are also included as they can be used to understand the mechanism of nanoparticle synthesis using organisms. Applications covered include targeted drug delivery, water purification and hydrogen generation. This is an important research resource for those wishing to learn more about how eco-efficient nanoparticles can best be used. Theoretical details and mathematical derivations are kept to a necessary minimum to suit the need of interdisciplinary audiences and those who may be relatively new to the field. Explores recent trends in growth, characterization, properties and applications of nanoparticles Gives readers an understanding on how they are applied through the use of case studies and examples Assesses the advantages and disadvantages of a variety of synthesis and characterization techniques for green nanoparticles in different situations

Download or read book Synthesis and Testing of Palladium and Platinum Phosphine Complexes with Potential Mitochondrial Targeting Anti cancer Properties written by Patricia Wanjiru Gitari and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The main theme of this thesis focuses on the preparation of palladium and platinum phosphine complexes that possess the potential to act as anti-cancer agents. The design of the complexes was based on the known compound, [Au(dppe)2]Cl which was shown to have an anti-mitochondrial mode of action on cancer cells. Major problems were experienced in the synthesis of these novel palladium and platinum compounds as the five phosphine ligands required diverse reaction conditions. Instability was the major hindrance as decomposition occurred during purification. This led to the substitution of the counter-ion (Cl- ) with PF6-. The complexes prepared in this study were varied in lipophilicity as the gold complex was found to be non-selective due to high lipophilicity. In total, six compounds were prepared, purified and tested for potency against a panel of cancer cell lines as well as normal cells. The most lipophilic compound, [Au(dppe)2]Cl, was non-selective as it exhibited the highest toxicity to both cancerous and normal cells. In general, in vitro studies showed that palladium complexes were more toxic than the platinum analogues. These novel compounds were also non-toxic to both resting and stimulated lymphocytes signifying high selectivity for cancer cells. Three compounds, Pg 3, Pg 4a and Pg 8 exhibited high toxicity and were hence tested as such on murine cancer cell lines. Pg 8, with intermediate lipophilicity, showed toxicity against a larger number of cancer cell lines and this led to further investigations in an attempt to determine its mode of action. Analysis of the effects of Pg 8 on the mitochodria showed that it did not depolarise the mitochondrial membrane potential. A seven day analysis showed that while it did not have any effect on the mitochondrial membrane potential, it depolarised the plasma membrane potential from day 4. In contrast, [Au(dppe)2]Cl depolarised the mitochondrial membrane potential as expected. Pg 8 was shown to induce apoptosis and necrosis on Jurkat cells after exposure for 48 h. It was also shown to induce cell cycle arrest (after 48 h) as it caused blockade in the S-phase. In contrast, [Au(dppe)2]Cl caused a blockade in the G0/G1 phase. Uptake studies with radiolabelled Pg 8, [103Pd(d2pyrpe)2][PF6]2, showed that it accumulated significantly in Jurkat cells. Biodistribution studies in Wistar rats demonstrated that it was mostly taken up in the spleen followed by the liver. However, it was excreted faster than [198Au(dppe)2]Cl as this latter compound accumulated significantly in the lungs followed by the spleen, small intestine and liver. Acute toxicity studies in Balb/c mice showed that Pg 8 was less toxic than [Au(dppe)2]Cl. The latter compound (at 3 and 6? M) caused a significant reduction of total body weight over a 5-day period. Toxicity was evident as it was also shown to cause elevation of liver enzymes (AST and GGT), contrary to the results obtained from the mice treated with Pg 8 (at 3, 6, 12 and 15? M). Preparation of a patent for the synthesis as well as anti-cancer properties of the novel compound, [Pd(d2pyrpe)2][PF6]2 (Pg 8) is currently in progress. Copyright.

Download or read book Structural and Functional Consequences of Platinum Anticancer Drug Binding to Free and Nucleosomal DNA written by Ryan Christopher Todd and published by . This book was released on 2010 with total page 229 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cisplatin, carboplatin, and oxaliplatin are three FDA-approved members of the platinum anticancer drug family. These compounds induce apoptosis in tumor cells by binding to nuclear DNA, forming a variety of adducts, and triggering cellular responses, one of which is the inhibition of transcription. The focus of this thesis is on studying the structure of these adducts, and correlating these effects with inhibition of transcription. Chapter 1 presents (i) a detailed review of the structural investigations of various Pt-DNA adducts and the effects of these lesions on global DNA geometry; (ii) research detailing inhibition of cellular transcription by Pt-DNA adducts; and (iii) a mechanistic analysis of how DNA structural distortions induced by platinum damage may inhibit RNA synthesis in vivo. These hypotheses will be explored in subsequent chapters of the thesis. In Chapter 2, features of the 2.17 A resolution X-ray crystal structure of cisdiammine(pyridine)chloroplatinum(II) (cDPCP) bound in a monofunctional manner to deoxyguanosine in a DNA duplex are discussed and compared to those of a cisplatin-1,2- d(GpG) intrastrand cross-link in double-stranded DNA. The global geometry of cDPCPdamaged DNA is quite different from that of DNA containing a cisplatin 1,2-d(GpG) cross-link. The latter platinated duplex is bent by ~40* toward the major groove at the site of the adduct; however, the monofunctional Pt-dG lesion causes no significant bending of the double helix. Like the cisplatin intrastrand adduct, however, the cDPCP moiety creates a distorted base pair step to the 5' side of the platinum site that may be correlated to its ability to destroy cancer cells. Structural features of monofunctional platinum adducts are analyzed, the results of which suggest that such adducts may provide a new platform for the design and synthesis of Pt anticancer drug candidates. The role of carbonate in the binding of cis-diamminedichloroplatinum(II) to DNA was investigated in Chapter 3 in order to understand the potential involvement of carbonato-cisplatin species in the mechanism of action of platinum anticancer agents. Cisplatin was allowed to react with single-stranded DNA in carbonate, phosphate, and HEPES buffers, and the products were analyzed by enzymatic digestion/mass spectrometry. The data from these experiments demonstrate (1) that carbonate, like other biological nucleophiles, forms relatively inert complexes with platinum that inactivate cisplatin, and (2) that the major cisplatin-DNA adduct formed is a bifunctional cross-link. These results are in accord with previous studies of cisplatin- DNA binding and reveal that the presence of carbonate has no consequence on the nature of the resulting adducts. The 1.77-A resolution X-ray crystal structure of a dodecamer DNA duplex with the sequence 5'-CCTCTGGTCTCC-3' that has been modified to contain a single engineered 1,2-cis- {Pt(NH 3)2}2+-d(GpG) cross-link, the major DNA adduct of cisplatin, is reported in Chapter 4. These data represent a significant improvement in resolution over the previously published 2.6-A structure. The ammine ligands in this structure are clearly resolved, leading to improved visualization of the cross-link geometry with respect to both the platinum center and to the nucleobases, which adopt a higher energy conformation. Also better resolved are the deoxyribose sugar puckers, which allow us to re-examine the global structure of platinum-modified DNA. Another new feature of this model is the location of four octahedral [Mg(H 20)6]2+ ion associated with bases in the DNA major groove and the identification of 124 ordered water molecules that participate in hydrogen bonding interactions with either the nucleic acid or the diammineplatinum(II) moiety. Chapter 5 discusses structural investigations of nucleosomal DNA modified by sitespecific platinum adducts. Nucleosome core particles containing a single 1,3-cis-{Pt(NH 3)2}2+_ d(GpTpG) intrastrand cross-link were synthesized and crystallized, and the X-ray structure was determined at 3.2 A resolution. The cisplatin adduct adopts a conformation facing toward the octamer core, in agreement with previous experiments. DNA in the vicinity of the Pt adduct has a similar helical bend as that observed in the NMR solution structure of free DNA containing the same cross-link, indicating that the rotational positioning power of cisplatin intrastrand crosslinks stems from the propensity to align the bent Pt-DNA structure with the DNA curvature arising from the nucleosome superhelix. Functional consequences of cisplatin binding to nucleosomal DNA are explored in Chapter 6. The effect of a single engineered platinum intrastrand cross-link on ATPindependent nucleosome mobility was investigated in vitro. Both 1,2-d(GpG) and 1,3-d(GpTpG) adducts of cisplatin inhibit translocation of DNA along the histone octamer, with the former Pt lesion providing a larger barrier. In vitro transcription assays with T7 RNA polymerase were conducted to determine whether cisplatin-DNA cross-links inhibit RNA synthesis by preventing access to nucleosomal DNA. Immobilized transcription templates containing a T7 RNAP promoter site, a single engineered cisplatin 1,2-d(GpG) or 1,3-d(GpTpG) intrastrand cross-link, and a phased nucleosome core particle were prepared. Analysis of resulting RNA transcript length revealed that the T7 RNAP elongation complex can overcome the energy barrier to nucleosome sliding caused by platinum intrastrand cross-links, but stalls when it reaches a Pt- DNA adduct placed on the DNA template strand. These results provide further evidence that intrastrand cross-links of cisplatin inhibit transcription by creating a physical barrier that the polymerase cannot pass. Appendices A and B summarize incomplete work that may be of use to future researchers working in this area. Appendix A describes attempts to isolate isomerically pure Pt- DNA probes containing a photoreactive benzophenone moiety, for use in cross-linking experiments that identify proteins that recognize and interact with cisplatin-DNA damage. In Appendix B efforts to obtain an X-ray crystal structure of an 1 Imer duplex DNA containing the 1,3- cis-{Pt(NH 3)2} 2 -d(GpTpG) intrastrand cross-link are reported. Appendix C details HPLC and mass spectrometric methods for purification and analysis of platinated oligonucleotides that were developed in the course of this research.

Download or read book Synthesis Characterization and Reduction of Platinum IV Nitriles and Iminoethers by Biological and Inorganic Reducing Agents written by Russell LaClair and published by . This book was released on 2003 with total page 204 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Platinum and Other Metal Coordination Compounds in Cancer Chemotherapy written by Stephen B. Howell and published by Springer Science & Business Media. This book was released on 1991 with total page 563 pages. Available in PDF, EPUB and Kindle. Book excerpt: Taken together the data presented in this review, and work by many other investigators, support the notion that DNA excision repair is important in a tumor cell's resistance to platinum compounds. Inhibition of this repair system by combination chemotherapy with the excision repair inhibitors HU and Ara-C produces synergistic cell kills and increased levels and persistance of DNA interstrand crosslinks. The studies with cis-DDP and ~-DDP in combination with UV induced thymine dimers suggest that there may be competition for DNA repair enzymes between the dimer and the platinum lesion. Whether the competing lesion is an intrastrand crosslink, interstrand crosslink, or platinum monoadduct (or all of these lesions) cannot be determined. The similarity between an intrastrand crosslink and a cyclobutane dimer suggests that these lesions may compete for repair. However, the increased peak levels of interstrand crosslinks, and increased persistence of these lesions at later time points suggest that this lesion may also be a substrate for the repair system. These observations may be of clinical relevance. Recently Dr. Kathy Albain of our institution has completed a Phase III I study using a 12 hour pretreatment with HU and Ara-C in patients prior to their cis-DDP therapy. She observed a significant number of responders in this trial (54). She is currently completing a second Phase IIII study substituting IV HU for the oral formulation. We anticipate initiating other clinical trials based upon these observations.

Download or read book Cumulated Index Medicus written by and published by . This book was released on 2000 with total page 1836 pages. Available in PDF, EPUB and Kindle. Book excerpt: