Structure-activity Relationships of Novel Platinum Complexes as Potential Anticancer Agents PDF Download
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Author: Liliya G. Nikolcheva
Publisher:
ISBN:
Category : Platinum compounds
Languages : en
Pages : 102
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Author: Liliya G. Nikolcheva
Publisher:
ISBN:
Category : Platinum compounds
Languages : en
Pages : 102
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Author: Xiao Liu
Publisher:
ISBN:
Category :
Languages : de
Pages : 0
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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.
Author: Philip K. Wu
Publisher:
ISBN:
Category : Antineoplastic agents
Languages : en
Pages : 392
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Author: Justin Jeff Wilson
Publisher:
ISBN:
Category :
Languages : en
Pages : 345
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(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.
Author: Bernhard Lippert
Publisher: John Wiley & Sons
ISBN: 9783906390208
Category : Medical
Languages : en
Pages : 628
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30 years after its discovery as an antitumor agent, cisplatin represents today one of the most successful drugs in chemotherapy. This book is intended to reminisce this event, to take inventory, and to point out new lines of development in this field. Divided in 6 sections and 22 chapters, the book provides an up-to-date account on topics such as - the chemistry and biochemistry of cisplatin, - the clinical status of Pt anticancer drugs, - the impact of cisplatin on inorganic and coordination chemistry, - new developments in drug design, testing and delivery. It also includes a chapter describing the historical development of the discovery of cisplatin. The ultimate question - How does cisplatin kill a cell? - is yet to be answered, but there are now new links suggesting how Pt binding to DNA may trigger a cascade of cellular reactions that eventually result in apoptosis. p53 and a series of damage recognition proteins of the HMG-domain family appear to be involved. The book addresses the problem of mutagenicity of Pt drugs and raises the question of the possible relevance of the minor DNA adducts, e.g. of interstrand cross-links, and the possible use of trans-(NH3)2Pt(II)-modified oligonucleotides in antisense and antigene strategies. Our present understanding of reactions of cisplatin with DNA is based upon numerous model studies (from isolated model nucleobases to short DNA fragments) and application of a large body of spectroscopic and other physico-chemical techniques. Thanks to these efforts there is presently no other metal ion whose reactions with nucleic acids are better understood than Pt. In a series of chapters, basic studies on the interactions of Pt electrophiles with nucleobases, oligonucleotides, DNA, amino acids, peptides and proteins are reported, which use, among others, sophisticated NMR techniques or X-ray crystallography, to get remarkable understanding of details on such reactions. Reactivity of cisplatin, once bound to DNA and formerly believed to be inert enough to stay, is an emerging phenomenon. It has (not yet) widely been studied but is potentially extremely important. Medicinal bioinorganic chemistry - the role of metal compounds in medicine - has received an enormous boost from cisplatin, and so has bioinorganic chemistry as a whole. There is hardly a better example than cisplatin to demonstrate what bioinorganic chemistry is all about: The marriage between classic inorganic (coordination) chemistry and the other life sciences - medicine, pharmacy, biology, biochemistry. Cisplatin has left its mark also on areas that are generally considered largely inorganic. The subject of mixed-valance Pt compounds is an example: From the sleeping beauty it made its way to the headlines of scientific journals, thanks to a class of novel Pt antitumor agents, the so-called "platinum pyrimidine blues". In the aftermath diplatinum (III) compounds were recognized and studies in large numbers, and now an organometalic chemistry of these diplatinum (III) species is beginning to emerge. The final section of the book is concerned with new developments such as novel di- and trinuclear Pt(II) drugs with DNA binding properties different from those of cisplatin, with orally active Pt(IV) drugs which are presently in clinical studies, and with attempts to modify combinatorial chemistry in such a way that it may become applicable to fast screening of Pt antitumor drugs. The potential of including computational methods in solving questions of Pt-DNA interactions is critically dealt with in the concluding chapter.
Author: Hanni Adel Darwish
Publisher:
ISBN:
Category : Antineoplastic agents
Languages : en
Pages : 96
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Author: Aruna M
Publisher: Self Publisher
ISBN: 9781805250920
Category : Health & Fitness
Languages : en
Pages : 0
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Book Description
This is a comprehensive book that explores the potential of pyrazolo[4,3-c]pyridine and pyrido[4,3-d]pyrimidine scaffolds as anticancer agents. The book presents an experimental and theoretical evaluation of the biological activity of these compounds, highlighting their potential as therapeutic agents for the treatment of cancer. The author provides an in-depth analysis of the synthesis and characterization of these scaffolds, as well as their mechanism of action and structure-activity relationships. The book also explores the theoretical evaluation of the electronic and structural properties of these compounds, using computational chemistry methods. The book is a valuable resource for researchers, academics, and students in the fields of medicinal chemistry and drug discovery. It provides a detailed insight into the design and evaluation of new anticancer agents, with a particular focus on pyrazolo[4,3-c]pyridine and pyrido[4,3-d]pyrimidine scaffolds. With its clear and concise presentation of complex concepts, "Pyrazolo Pyridine Pyrimidine Scaffolds for Anticancer Activity" is an essential addition to any medicinal chemist's bookshelf. Overall, the book offers an interdisciplinary perspective on the potential of pyrazolo[4,3-c]pyridine and pyrido[4,3-d]pyrimidine scaffolds as promising anticancer agents, providing insights for researchers and scientists working towards the discovery of new therapies for cancer treatment.
Author: Shahid Ul-Islam
Publisher: John Wiley & Sons
ISBN: 1119640423
Category : Science
Languages : en
Pages : 432
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Book Description
This book is organized into 12 important chapters that focus on the progress made by metal-based drugs as anticancer, antibacterial, antiviral, anti-inflammatory, and anti-neurodegenerative agents, as well as highlights the application areas of newly discovered metallodrugs. It can prove beneficial for researchers, investigators and scientists whose work involves inorganic and coordination chemistry, medical science, pharmacy, biotechnology and biomedical engineering.
![Structure-activity Screening of Platinum Intercalators and Molecular Mechanisms for the Cytotoxicity of 56MESS - [Pt(5,6-Dimethyl-Phen)(1S,2S-DACH)]2 PDF](https://books.google.com/books/content/images/frontcover/wFFEAQAACAAJ?fife=w80-h100)
Author: Shaoyu Wang
Publisher:
ISBN:
Category : Cancer
Languages : en
Pages :
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Book Description
Efficacy of existing clinical anticancer drugs including cisplatin and its analogues is greatly limited by drug resistance and side effects. Anticancer compounds with novel structures and different mechanisms of action have been sought to expand anticancer activity and to minimise these limitations. First part of this project evaluated the structure-activity relationships for a class of novel platinum metallointercalators using cytotoxicity screening against cancer cell lines, and subsequently identified lead compounds. Second part elucidated the biological mechanisms underlying the cytotoxic action of a lead compound with a genome-wide gene expression profiling technology (or transcriptomics) using a eukaryotic model organism yeast Saccharomyces cerevisiae. These analyses identified the disruption of iron and copper metabolism as the major molecular mechanism of cytotoxic action of the lead compound. The novel platinum(II) metallointercalators studied are of the type of [Pt(IL)(AL)]2+, where IL is the intercalating ligand, such as 1,10-phenanthroline (phen), and AL is the ancillary ligand, either chiral 1,2-diaminocyclohexane (S, S-DACH, R, R-DACH), or achiral 1,2-diaminoethylene (EN). Nineteen (19) platinum metallointercalators, eleven (11) cucurbit[n]ural encapsulated forms of these complexes and three (3) non-platinum metal helicates were screened against cisplatin-sensitive (L1210) and resistant (L1210cisR) murine leukaemia cell lines using a standard methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. These metal complexes are water-soluble. They exhibited a wide range of cytotoxicities. The complex - [Pt(5,6-dimethyl-1,10-phen)(1S,2S-DACH)]2+ (56MESS) was found to be 163-fold more active than cisplatin against the L1210cisR cell line whereas complexes such as [Pt(4-methyl-phen)(EN)]2+ (4MEEN) are inactive. Correlation analysis of the cytotoxicity data with structures revealed three major structure-activity relationships. Chirality of the DACH ligand, the position and electronegativity of functional groups substituted in the intercalating ligand and type of ancillary ligands (i.e DACH or EN) profoundly influenced the cytotoxicity of these complexes. Encapsulation of metal complexes by different sized curcurbit[n]urals led to varied cytotoxicities. Analysis of these data resulted in the identification of three lead complexes including 56MESS, which has excellent activity in L1210 as well as in L1210cisR cell lines. To understand the biological mechanisms underlying the cytotoxicity of the lead complex 56MESS, genes and pathways in response to 56MESS treatment, in parallel to cisplatin treatment, were investigated using transcriptomics in yeast Saccharomyces cerevisiae. Ninety-three (93) genes were revealed to be important for the cytotoxicity of 56MESS as these genes altered their expressions in response to 56MESS challenge. Bioinformatics analysis of these genes showed that defective iron and copper metabolisms are implicated for the cytotoxic action of this compound. The suppression of biosynthesis of sulphur-containing amino acids and arginine and function of mitochondria could also play a role in the cytotoxicity of 56MESS. In comparison, one hundred and sixty-five (165) genes altered their expressions in response to cisplatin treatment. The genes involved in sulphur uptake and its assimilation and response to DNA damage were up-regulated while the genes involved in de novo purine biosynthesis and one carbon metabolism were suppressed by cisplatin. The differences in the major pathways in response to 56MESS and cisplatin suggest that these two platinum agents have different molecular mechanisms for their cytotoxicity. Cellular assays and gene deletion mutant screenings validated these transcriptomic findings. The results from inductively coupled plasma optical emission spectrometry (ICP-OES) revealed that 56MESS treatment reduced concentrations of the intracellular iron and copper, and increased that of manganese. Analysis of viability phenotypes of deletion mutants of the key genes including FTR1 in the iron and copper metabolisms further supported their involvement in the cytotoxicity of 56MESS. The data therefore suggested that iron and copper transporters were the molecular targets of 56MESS. Further biochemical and mutant analyses showed that glutathione, oxidative stress and mitochondria were important in 56MESS' cytotoxicity. 56MESS treatment arrested cells in G1 phase of the cell cycle. The cytotoxicity data, the structure-activity relationships and the elucidated molecular mechanisms of the most active platinum metallointercalator 56MESS suggested that the platinum metallointercalators of the type [Pt(IL)(AL)]2+ have potential as anticancer agents. The findings reported in this thesis can be used for further development of these complexes.
Author: D.N. Reinhoudt
Publisher: Springer Science & Business Media
ISBN: 9400967985
Category : Medical
Languages : en
Pages : 297
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Book Description
The Workshop series of the "Koningin Wilhelmina Fonds" is a feature of the interest of this Foundation to promote research and education in the field of cancer, aiming to improve prognosis of the cancer patient. For almost a century, surgery has now been the main treatment modality for the cancer patient. During the past 50 years radiation therapy has developed as a second important modality of treatment. However, neither of the two modalities are able to cure the majority of cancer patients, as the disease is so often metastasized at presentation. Cancer chemotherapy is a modality which does have the potential to cure patients with this advanced stage of disease. In recent years the three modalities have been combined more and more, and here is one of the reasons why the prospectives for the cancer patient have improved so much. In addition, certain types of cancers, such as testicular car cinoma, childhood tumors, choriocarcinoma, non Hodgkin lymphomas and others, can now indeed often be cured by chemotherapy alone, even if the disease is advanced. The combination of drugs and the use of new drugs have greatly contributed to this development. There are two main groups of new drugs: analogs and new structures. A great number of analogs of conventional structures have been developed during the past ten years. A typical example of this group is adriamycin, which is an analog of dau nomycin.
