Download or read book Structure activity Relationships in Functionalized Platinum acridine Anticancer Agents written by Leigh Ann Graham and published by . This book was released on 2012 with total page 146 pages. Available in PDF, EPUB and Kindle. Book excerpt: Since Rosenberg's serendipitous discovery of the cytotoxic properties of cisdiamminedichlor(id)oplatinum(II), better known as cisplatin, the development of new platinum-based chemotherapies with improved activity and reduced toxicity has become a pressing goal. Many second- and third-generation derivatives of cisplatin have been successful in decreasing toxicity, enhancing delivery, and showing a broader spectrum of antitumor activity. Recently, a dual platinating/intercalating DNA-targeted agent, [PtCl(en)(N-[acridin-9-ylamino)ethyl]-N-methylpropionamidine] dinitrate (25), has been reported that shows high activity in NCI-H460 non-small-cell-lung cancer (NSCLC) both in vitro and in vivo, but has proven to have high systemic toxicity (nephrotoxicity). In order to reduce the toxicity of this agent, two new methodologies were developed to reduce unwanted platinum interactions with sulfur-containing biomolecules such as glutathione. The first method was aimed at changing the chlor(id)o leaving group of the prototype (25) to a monodentate carboxylate. Although carboxylates in general, and monocarboxylates in particular, are more labile leaving groups than chloride, bulky groups incorporated in this leaving group may be successful in blocking the axial positions in associative substitution reactions. The ultimate goal of generating an analogue of 25 with monodentate carboxylates was not reached due to the tautomerization and N, N-chelation of the acridine chromophore, resulting in the formation of two new complexes that contain seven-membered N, N-chelates that were synthesized and studied for biological activity (28 and 29). These chelates do not undergo ligand substitution reactions with biological nucleophiles, such as nucleobase nitrogen and cysteine sulfur, and do not intercalate into DNA. This was demonstrated in model systems using NMR and UV-visible spectroscopies. Despite their inertness, in colorimetric cell proliferation assays complexes 28 and 29 do maintain micromolar activity in NCI-H460 lung cancer cells. The results are discussed in the context of potential DNA-mediated and DNA-independent cell kill mechanisms and the potential use of the chelates as prodrugs. The second project involved the synthesis of platinum-acridine prodrugs with hydrolysable carboxylic acid ester groups that would lead to the formation of N-O chelate complexes under physiological conditions. The synthesis of these complexes was achieved through the addition of the acridine ligand across the metal-activated triple bond of a nitrile that contained a cleavable ester group. The most active ester-modified derivatives and the unmodified parent compounds showed up to 6-fold higher activity in ovarian cancer (OVCAR-3) and breast cancer (MCF-7, MDA-MB-23) cell lines than cisplatin. An even more pronounced inhibition of cell proliferation at nanomolar concentrations was observed in pancreatic (PANC-1) and non-small cell lung cancer cells (NSCLC, NCI-H460) of 80- and 150-fold, respectively. Most importantly, introduction of the ester groups did not adversely affect the cytotoxic properties of the hybrids, which form the same DNA adducts as the parent compounds. In-line high-performance liquid chromatography-electrospray mass spectrometry (LC-MS) was used to demonstrate that the ester moieties in the newly synthesized compounds undergo platinum-mediated hydrolysis in a chloride concentration-dependent manner to form a chelated carboxylate form of the agent. This new ester-cleavage mechanism under physiological conditions could potentially provide a new opportunity for tumor-targeted therapy of platinumacridines through the self-immolative release of this family of cytotoxic agents.

Download or read book Novel Strategies for Improving the Pharmacological Properties of Platinum acridine Anticancer Agents written by Song Ding and published by . This book was released on 2015 with total page 543 pages. Available in PDF, EPUB and Kindle. Book excerpt: Unlike traditional cisplatin-type platinum-based anticancer drugs, platinum-acridine hybrid agents were designed as dual platinating/intercalating DNA-targeted cytotoxics, which are able to cause cancer cell death at low-nanomolar concentrations. Unfortunately, the preclinical development of these agents has been hampered by their severe systemic toxicity. The goal of this dissertation was to devise strategies that improve the drug-like properties of platinum-acridines and allow their safe delivery. To achieve this, several classical and newly developed synthetic methodologies have been used to generate functionally unique hybrid agents. Several model systems, whole-cell assays, and animal studies have been used in this dissertation to validate their design and demonstrate their utility as anticancer agents. A modular screening platform was developed, based on a platinum-mediated amine-to-nitrile addition reaction, for rapid identification of functionalized platinum-acridine agents. These pre-screening assays produced functionalized "warheads" while providing insight into structure–activity relationships (SAR). Using several library members, we set out to explore synthetic approaches to construct platinum-acridine-based conjugates. A chemically robust azide-modified platinum-acridine was selected to validate the feasibility of copper-mediated and copper-free click chemistry as platinum-compatible conjugation reactions. This chemistry was used to attach fluorescent molecules to detect platinum-acridines in cancer cells by confocal microscopy. Both fluorophore tagging prior to incubation with cells and post-labeling methods were explored. In addition, a hydroxyl-modified warhead was conjugated with endoxifen via a chemically stable carbamate bond to produce a highly active hybrid agent in estrogen receptor positive (ER+) breast cancer. In another study, lipophilic ester-based prodrugs of platinum–acridines were generated showing improved drug-like properties (e. g., partition coefficients, logD). Two distinct pathways by which the target compounds can be activated have been confirmed by LC-ESMS and/or NMR techniques: (i) a platinum-assisted, self-immolative ester cleavage in a low-chloride environment, and (ii) enzymatic cleavage by human carboxylesterase-2 (hCES-2). Highly efficient amide coupling reactions in platinum complexes were also developed. This modular approach can be used to assemble a diverse library of platinum-acridines containing other bioactive components, such as molecularly targeted therapies, targeted ligands, and chemosensitizers. Finally, liposomal encapsulation of platinum-acridine was achieved, and the formulations were evaluated in A549 lung cancer xenograft models in mice. Improved anticancer efficacy of one of the liposomal formulations compared with the free drug was observed in this assay. In conclusion, the research in this dissertation has laid the foundation for the future preclinical development of platinum-acridines as oncology drugs by devising new synthetic methodology and providing proof-of-concept data in clinically relevant models of cancer.

Download or read book Novel Approaches for Controlling Target Selectivity and Pharmacological Properties of Platinum intercalator based Anticancer Agents written by Amanda Jayne Pickard and published by . This book was released on 2014 with total page 235 pages. Available in PDF, EPUB and Kindle. Book excerpt: Traditional DNA-targeted anticancer agents, such as platinum-based therapies, have been a mainstay in the treatment of aggressive solid malignancies in the clinical setting. Unfortunately, due to multifactorial drug resistance and systemic toxicity the clinical efficacy of these drugs is severely limited. Platinum–acridine hybrid agents have proven to overcome multifactorial drug resistance in some of the most aggressive forms of cancer, in particular non-small-cell lung cancer (NSCLC). The remaining challenges with this generation of anticancer agents revolve around overcoming the dose-limiting toxicities caused by indiscriminate chromatin damage (genotoxicity) in malignant and healthy cells and improving the unfavorable pharmacokinetics (PK) caused by the poor drug-like properties of these agents. The goal of this dissertation was to devise a structurally minimalistic approach by which platinum–acridines can be tuned to simultaneously achieve both of these goals. In particular, a design was desired that minimizes platinum adduct formation in the double-stranded portion of genomic DNA but enhances the reactivity with G-quadruplex DNA, a preclinically validated anticancer target. Density functional theory (DFT) calculations were used to study the reactivity of the monofunctional platinum moieties toward nucleobases in relevant target structures. Computational pre-screens were also used to identify DNA-targeted chromophores that show decreased basicity of the endocyclic nitrogen (proton affinities, [triangle]DG[subscript proton].) and an increased planar aromatic surface area to promote G-quadruplex binding. From these pre-screens, quinoline (Q1), acridine (A1), and three benz[c]acridines (B1, B2, B3) were selected and synthesized for a structure–activity relationship (SAR) study. Using microscale reactions, a modular library of 20 hybrid agents was assembled from the 5 chromophores and 4 platinum modules (P1–P4) and evaluated in two aggressive NSCLC cancer cell lines (NCI-H460, NCI-H520) using a cell proliferation assay. From the combinatorial pre-screen, two molecules of interest ("hits") emerged, P1-B1 and P1-B2, which both contained a core benz[c]acridine chromophore. In an extended panel of NSCLC cell lines (NCI-H522, NCI-1435, A549), P1-B1 maintained submicromolar IC50 values. In addition, when compared to the acridine prototype P1-A1, the new benz[c]acridine chromophore showed significantly decreased basicity (pK[subscript a(P1-B1)] = 7.6 vs. pK[subscript a(P1-A1)] = 9.4) (pH-dependent absorbance spectra). The combination of structural and electronic tuning achieved in derivative P1-B1 proved to have a major effect on the subcellular distribution of the hybrid agent and its ability to accumulate in cellular DNA and RNA (confocal fluorescence microscopy, inductively-coupled plasma mass spectrometry, ICP-MS). Although P1-A1 and P1-B1 undergo efficient trafficking from the lysosomes to the nucleus, the latter derivative did not show significant adduct formation in DNA after 6 h of incubation with NCI-H460 cells. All tested hybrids, P1-A1, P1-B1, and P1-B2, as well as their platinum-free carrier ligand modules A1, B1, and B2 were shown to interact favorably with relevant G-quadruplex forming sequences, including the human telomeric repeat and three sequences identified in the genes encoding ribosomal RNA (rRNA) (CD spectroscopy, highresolution mass spectrometry, HRMS). In particular, the benz[c]acridine derivative B1 appears to promote a highly specific interaction with the human telomeric repeat. To validate the approach pursued in this research, a dose escalation study was performed with the new "lead" compound P1-B1 in mice. When administered by intraperitoneal injection for five consecutive days, the new derivative proved to be significantly less toxic to the test animals than the prototype, P1-A1, resulting in an approximately 32-fold higher maximum tolerated dose (MTD). Together with the SAR established in this study, these results attest to the successful design strategy and encourage further preclinical development of P1-B1 and related molecules.

Download or read book Biomedical Applications of Acridines written by Jan Ježek and published by Springer. This book was released on 2017-08-15 with total page 243 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book describes applications of acridines for the treatment of various neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and various prion diseases, and discusses the potential of acridines in neuro-regenerative medicine. Using modern data-mining software, it presents structures of acridines with nucleic acids and proteins and compares them with the native structures. Furthermore, the book presents modern methods of acridine synthesis, comparing them with the most useful conventional methods. Acridines interact with both nucleic acids and proteins, and due to their direct interactions with various enzymes, they can be suitable for the treatment of neurodegenerative diseases, inflammation, immunological disorders, and protozoal diseases. The characteristic spectral properties of acridines can be employed in labeling proteins, nucleic acids, lipids, and even cells and their compartments. Moreover, they can be applied in photodynamic therapy.

Download or read book Advances in Metallodrugs written by Shahid Ul-Islam and published by John Wiley & Sons. This book was released on 2020-07-08 with total page 432 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Download or read book Cisplatin written by Bernhard Lippert and published by John Wiley & Sons. This book was released on 1999 with total page 628 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Download or read book Index Medicus written by and published by . This book was released on 2004 with total page 2164 pages. Available in PDF, EPUB and Kindle. Book excerpt: Vols. for 1963- include as pt. 2 of the Jan. issue: Medical subject headings.

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 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 Bioconjugate Techniques written by Greg T. Hermanson and published by Academic Press. This book was released on 2010-07-26 with total page 1233 pages. Available in PDF, EPUB and Kindle. Book excerpt: Bioconjugate Techniques, 2nd Edition, is the essential guide to the modification and cross linking of biomolecules for use in research, diagnostics, and therapeutics. It provides highly detailed information on the chemistry, reagent systems, and practical applications for creating labeled or conjugate molecules. It also describes dozens of reactions with details on hundreds of commercially available reagents and the use of these reagents for modifying or cross linking peptides and proteins, sugars and polysaccharides, nucleic acids and oligonucleotides, lipids, and synthetic polymers. A one-stop source for proven methods and protocols for synthesizing bioconjugates in the lab Step-by-step presentation makes the book an ideal source for researchers who are less familiar with the synthesis of bioconjugates More than 600 figures that visually describe the complex reactions associated with the synthesis of bioconjugates Includes entirely new chapters on the latest areas in the field of bioconjugation as follows: Microparticles and nanoparticlesSilane coupling agentsDendrimers and dendronsChemoselective ligationQuantum dotsLanthanide chelatesCyanine dyesDiscrete PEG compoundsBuckyballs,fullerenes, and carbon nanotubesMass tags and isotope tagsBioconjugation in the study of protein interactions

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:

Download or read book Drug Monitoring and Clinical Chemistry written by Georg Hempel and published by Elsevier. This book was released on 2004-05-15 with total page 379 pages. Available in PDF, EPUB and Kindle. Book excerpt: Drug Monitoring and Clinical Chemistry, the 5th volume in the Handbook of Analytical Separations series, gives an overview about methods to analyse drugs in biological fluids. The most widely used methods to analyse drugs in biological fluids. i.e. chromatographic methods, CE and immunoassays are described in detail. For important drugs, an overview about the methods available and a comparison of the techniques should be given to enable the reader to choose the right method depending on laboratory equipment, staff, the aim of the investigation etc. Other general aspects important for conducting therapeutic drug monitoring or pharmacokinetics studies are also covered, i.e. sample preparation, validation of the analytical methods and pharmacokinetic methods for interpreting the data. Areas where therapeutic drug monitoring is used frequently such as antibiotics, immunosuppressant drugs, antipsychotic and anticancer drugs will be discussed in detail. In addition, the important field of phenotyping and genotyping for therapy optimisation with special focus on real-life applications is also covered. The book contains important information for analyst working on drug analysis in clinical chemistry, hospital pharmacists involved in therapeutic drug monitoring, other pharmacists, chemists or physicians working on pharmacokinetic studies in industry or academia. In contrast to other books in this field, this book provides up-to-date information regarding both methodology and clinical applications. For the applications, only fields are described where therapeutic drug monitoring is used in clinical routine and provides benefit to the patients. Overview of all important field where therapeutic drug monitoring is applied All relevant analytical and computational methods are discussed Written by experts with a lot of practical experience in the field

Download or read book Human Dna Polymerases Biology Medicine And Biotechnology written by Giovanni Maga and published by World Scientific. This book was released on 2017-11-10 with total page 398 pages. Available in PDF, EPUB and Kindle. Book excerpt: Maintenance of the information embedded in the genomic DNA sequence is essential for life. DNA polymerases play pivotal roles in the complex processes that maintain genetic integrity. Besides their tasks in vivo, DNA polymerases are the workhorses in numerous biotechnology applications such as the polymerase chain reaction (PCR), cDNA cloning, next generation sequencing, nucleic acids based diagnostics and in techniques to analyze ancient and otherwise damaged DNA (e.g. for forensic applications). Moreover, some diseases are related to DNA polymerase defects and chemotherapy through inhibition of DNA polymerases is used to fight HIV, Herpes and Hepatitis B and C infections. This book focuses on (i) biology of DNA polymerases, (ii) medical aspects of DNA polymerases and (iii) biotechnological applications of DNA polymerases. It is intended for a wide audience from basic scientists, to diagnostic laboratories, to companies and to clinicians, who seek a better understanding and the practical use of these fascinating enzymes.

Download or read book Cisplatin Current Status and New Developments written by Archie W. Prestayko and published by . This book was released on 1980 with total page 552 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Methods of Therapeutic Drug Monitoring Including Pharmacogenetics written by Georg Hempel and published by Elsevier. This book was released on 2019-10-17 with total page 380 pages. Available in PDF, EPUB and Kindle. Book excerpt: Methods of Therapeutic Drug Monitoring Including Pharmacogenetics, Second Edition, Volume Seven in the Handbook of Analytical Separations series, covers all aspects of drug monitoring, including laboratory work, pharmacokinetic analysis and clinical aspects, thus enabling readers from different fields to understand the whole process of therapeutic drug monitoring and how to avoid common pitfalls. The book contains analytical techniques for the quantification of drugs, along with pharmacogenetic and pharmacogenomic methods. Also included are updates on sample preparation, including dried blood spot technology and microextraction methods. In addition, the book includes new drugs, such as tyrosine kinase inhibitors and the monitoring of immunosuppressant drugs. Presents a unique, interdisciplinary approach that appeals to a wide range of users Written by authors from international labs, providing a global perspective that can be applied in various regulatory environments Features additional therapeutic drugs to reflect the rising number of immunocompromised patients Includes a new mass spectroscopic methods chapter to capture the frequent use in TDM and the improved availability of LC-MS across laboratories

Download or read book Bioinorganic Medicinal Chemistry written by Enzo Alessio and published by John Wiley & Sons. This book was released on 2011-02-25 with total page 625 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book gives a comprehensive overview about medicinal inorganic chemistry. Topics like targeting strategies, mechanism of action, Pt-based antitumor drugs, radiopharmaceuticals are covered in detail and offer the reader an in-depth overview about this important topic.

Download or read book Therapeutic Applications of Quadruplex Nucleic Acids written by Stephen Neidle and published by Academic Press. This book was released on 2012 with total page 210 pages. Available in PDF, EPUB and Kindle. Book excerpt: "Therapeutic applications of quadruplex nucleic acids provides a single comprehensive survey that describes and assesses recent advances in quadruplex therapeutics and targeting strategies. It also covers the underlying fundamentals of such topics as quadruplex structure, small-molecule recognition, biological roles of genomic quadruplexes, and quadruplex informatics"--P. [4] of cover.