The Development of Trackable Polynuclear Platinum(II) Compounds for Targeted Anticancer Applications PDF Download
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Author: Sinéad O'Carroll
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
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.
Author: Sinéad O'Carroll
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
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.
Author: Andrea Bonetti
Publisher: Springer Science & Business Media
ISBN: 1603274596
Category : Medical
Languages : en
Pages : 381
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Book Description
Cisplatin, the first member of the family of platinum-containing chemotherapeutic agents, was discovered by Barnett Rosenberg in 1965 and approved by the FDA for marketing in 1978. After 30 years of use in the clinic, cisplatin remains a central element of many treatment regimens. Cisplatin is still an irreplaceable component of a regimen that produces high cure rates in even advanced nonseminomatous germ-cell cancers, and is widely used in the treatment of ovarian cancers and other gynecologic cancers, head and neck, and numerous other tumor types. The development of carboplatin has reduced some of the adverse events associated with cisplatin treatment, and the introduction of the DACH platinum compound oxaliplatin has broadened the spectrum of activity of the platinums to include gastro-intestinal cancers, especially colorectal cancer. The clinical importance of this family of drugs continues to drive investigation into how these drugs work and how to improve their efficacy and reduce their toxicity. The papers in this volume were presented in Verona, Italy, during the tenth International Symposium on Platinum Coordination Compounds in Cancer Chemotherapy. The symposium was jointly organized by the Department of Oncology of the Mater Salutis Hospital – Azienda Sanitaria Locale 21 of the Veneto Region – and by the Department of Medicine and Public Health, Section of Pharmacology, the University of Verona. They reflect the vitality of this field and the increasing use of new molecular and cell biologic, genetic, and biochemical tools to identify approaches to further improve their use.
Author: Daniel E. Lee
Publisher:
ISBN:
Category : Antineoplastic agents
Languages : en
Pages :
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Book Description
Platinum anticancer compounds with cis geometry, similar to cisplatin, have been explored to circumvent the cisplatin resistance; however, they were not considered broadly active in cisplatin cells due to exhibiting similar or same cell death mechanism as cisplatin. Platinum compounds with trans geometry were less studied due to transplatin being clinically inactive; but with few structural modifications, they resulted in unaffected cytotoxic activities in cisplatin resistant cells with structural modification by exhibiting different modes of DNA binding. This research focused on further exploring and establishing structure-activity relationship of two promising non-classical series of platinum compounds with trans-geometry: trans-platinum planar amine (TPA) compounds and noncovalently binding polynuclear platinum compounds (PPC-NC). During this research, further optimizations of the reactivity of TPA compounds were accomplished by modifying the leaving carboxylate groups. The effects of modified reactivity were probed by a systematic combination of chemical and biophysical assays, followed by evaluating their biological effects in cells. To establish the structural-activity relationship of PPC-NCs, Mono-, Di-, Tri-, and Tetraplatin NC with charge of 4+, 6+, 8+, and 10+ were synthesized and evaluated by utilizing biophysical and biological assays. Lastly, a new class of polynuclear platinum compounds, Hybrid-PPCs, were synthesized and evaluated to overcome the pharmacokinetic problems of BBR3464, phase II clinical trial anticancer drug developed previously in our laboratory.
Author: T.A. Connors
Publisher: Springer Science & Business Media
ISBN: 3642493068
Category : Medical
Languages : en
Pages : 232
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Book Description
It was a great pleasure and honour to have been invited to attend this Seminar and to present a final impression. The association in this field between the Chester Beatty Research Institute and Dr. Rosenberg's School at East Lansing is something which I specially value and many would doubtless like to know how it came about. In the course of its work in carcinogenesis and on chemotherapy over many years, the Chester Beatty Research Institute was frequently drawn to the importance of many metals - as for example lead, iron, metalloid arsenic and the metalloid quali ties of the carcinogenic hydrocarbons. Interest started in platinum many years ago, following the possibility, c1aimed by others, that various complexes between the metal and mercaptopurine might possess significant chemotherapeutic properties. Va rious attempts to confirm such findings ended, however, in complete failure. Interest in platinum was revived by the fresh observations of Dr. Rosenberg and his collea gues, and here the outcome was entirely different. Very soon it was possible to con firm the intense growth-inhibitory properties of cis-platinum (II) diamminedi chloride and related substances. After communicating these results to Dr. Rosenberg, it was a pleasure to welcome hirn in London where he gave a Seminar which greatly engaged the interest of many of the staff. Later, several of these were to enjoy Dr. Rosenberg's hospitality at an international conference on the subject to be held in East Lansing, where many rapidly developing aspects were open for discussion.
Author: Timothy Charles Johnstone
Publisher:
ISBN:
Category :
Languages : en
Pages : 376
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Book Description
Approximately half of all patients receiving cancer chemotherapy are treated with a platinum-containing drug. Despite this intense clinical use, only three platinum complexes, cisplatin, carboplatin, and oxaliplatin, are approved by the United States Food and Drug Administration for the treatment of cancer. A number of side effects accompany platinum-based therapy and novel approaches are under investigation to attenuate these negative effects and circumvent tumor resistance, be it inherent or acquired. One approach is to use non-classical platinum agents such as platinum(IV) prodrugs and monofunctional platinum(II) complexes. The latter, unlike the classical platinum drugs, can only form one bond to the biological target, DNA. Another strategy is to exploit the advantages offered by nanodelivery. The work presented here spans a range of topics aimed at furthering the development of platinum anticancer therapy along these lines. Fundamental platinum chemistry has been explored to provide ready access to platinum(II) starting materials such as oxaliplatin and mixed ammine/amine platinum(II) complexes. Novel platinum(IV) architectures were uncovered while investigating the oxidative halogenation of cisplatin and carboplatin. Nanoparticle constructs based on the biocompatible amphiphilic block copolymer, PLGA-PEG, have been devised that are capable of delivering both hydrophobic and hydrophilic platinum complexes. Nanoparticle encapsulation has a significant effect on the in vivo properties of the platinum(IV) prodrug mitaplatin. Fundamental studies of the chirality of a potent monofunctional complex, phenanthriplatin, revealed aspects of its interaction with derivatives of the nucleobase guanine, that may have a significant effect on the cellular processing of the DNA adducts formed by this compound. Finally, nanoparticle delivery was used to enhance the ability of phenanthriplatin and phenanthriplatin prodrugs to inhibit the growth of tumors in mice.
Author: Shiju C
Publisher: LAP Lambert Academic Publishing
ISBN: 9783846535189
Category :
Languages : en
Pages : 136
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Book Description
Some of the platinum complexes such as Cisplatin, carboplatin, and oxaliplatin are the FDA-approved members of the platinum anticancer drug family. Cisplatin, as one of the leading metal-based drugs, is widely used in the treatment of cancer. Significant side effects and drug resistance, however, have limited its clinical applications. These compounds induce apoptosis in tumor cells by binding to nuclear DNA, forming a variety of structural adducts and triggering cellular responses. Advances in biocoordination chemistry are crucial for improving the design of compounds to reduce toxic side effects and understand their mechanisms of action. In this report we present the development of platinum complexes such as platinum(II)-amine complexes, platinum(IV)-amine complexes, multi nuclear platinum complexes and some other platinum complexes as anti-cancer agents, with the purpose of providing an insight into the benefits of, and reasons for, their success.
Author: Joseph Hennessy
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
Since the serendipitous discovery of cisplatin by Rosenberg platinum agents based on the traditional cis chemotype are still the cornerstone of platinum therapeutic application with cisplatin, carboplatin and oxaliplatin as the only agents approved globally for use. Past research has focused mainly on elucidating the mechanistic action of these traditional Pt(II) agents with great success and streamed into efforts centred on trying to reduce the potent toxic side-effects such as nephrotoxicity, ototoxicity and poor target selectivity. Classes of platinum complexes such as trans-substituted platinum(II) agents, platinum(IV) prodrugs, polynuclear platinum(II) complexes and in particular, platinum(II)-DNA hybrids produced for an antigene strategy, have all observed a significant renewal of interest in recent years. This thesis focuses on the development of a library of platinum(II)-triplex forming oligonucleotide hybrids that possess targeted antigene applications. Firstly, the synthesis of azide-functionalised ligands and their complexation with platinum to form azide-functionalised cis-platinum(II) complexes is reported. Thereafter, the design and synthesis of triplex forming oligonucleotides (TFOs) is reported and followed by the utilisation of the copper-catalysed and strain promoted alkyneazide cycloaddition or 'click chemistry' to generate gene-directed cis-platinum(II)TFO hybrids. The work reported represents the first example of click chemistry strategies being employed to afford cis-platinum(II)-TFO constructs designed this way. DNA interaction studies identified that the azide-functionalised platinum(II) complexes retain activity against dsDNA targets. The cis-platinum(II)-TFO constructs demonstrated sequence specific triplex recognition with no off-target effects observed in the presence of purine rich sequences. However, in general the crosslink formation on target genes of interest by the platinum(II) ion destabilises triplex formation. The introduction of TO - a known intercalating fluorophore - can remediate this destabilisation and this work demonstrates how TO-modified cis-Pt(II)-TFOs retain their targeting abilities with enhanced stabilising characteristics. Finally, TFO constructs containing a novel alkyne-amine nucleobase were developed and investigated for their ability to incorporate TO and Pt(II). This strategy was developed to enhance site-specific metal ion-DNA target interactions whereby the proximity of the complex to the DNA interface was enhanced under the guidance of the neighbouring TO intercalator. The conjugation of Cu(II)-phenanthrene-type scaffolds with alkyne-modifed TFOs to generate novel Cu(II)-AMN-TFOs has afforded unique stabilising properties and represent an innovative class of gene-targeted system.
Author: Peyman Kabolizadeh
Publisher:
ISBN:
Category : Antineoplastic agents
Languages : en
Pages : 444
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Book Description
The novel trinuclear complex, BBR3464 has undergone Phase II clinical trials and been shown to have greater cytotoxicity and cellular uptake than clinical anticancer platinum drugs such as cisplatin, oxaliplatin and carboplatin. The clinical efficacy of cisplatin, oxaliplatin and carboplatin is limited due to acquired resistance and dose limiting side effects. The three major pharmacological factors contributing to the intrinsic cytotoxicity of, and cellular resistance to, platinum drugs are (i) cellular uptake and efflux of platinum; (ii) the frequency and nature of Pt-DNA adducts; and (iii) deactivating metabolic reactions with sulfur-containing nucleophiles. Since decreased cellular uptake of platinum drugs is a common feature of resistant cells, investigating mechanisms of cellular uptake and efflux is of a great importance in the field of cancer biology. The mechanisms of uptake of Platinum drugs are diverse and complex. Similar to cisplatin, BBR3464 v as shown to use copper transporter hCTR1 and ATP7B for influx and efflux respectively. Organic cation transporters (OCT) did not play an important role in BBR3464 cellular uptake, however, desipramine, an OCT inhibitor had synergistic effects on platinun drugs-induced cytotoxicity. This effect is of high clinical relevance since desipramine, an antidepressant, is being used in prostate cancer patients for the treatment of neuropathic pain. The mechanism of this interaction was further addressed. Due to the high charge of BBR3464, studies have shown that its DNA binding has a non-covalent component. To examine the non covalent component, labile chloride leaving groups were replaced by non labile ammonia groups. Besides having higher cellular accumulation than BBR3464, the non covalent analogue, AH78, had a different mechanism of action in cells and showed promising results in vivo. These data confirm the validity of searching for new chemotypes outside the cisplatin structural class to aid in the treatment of recurrent, cisplatin-resistant cancers.
Author: Michael E. Oehlsen
Publisher:
ISBN:
Category :
Languages : en
Pages : 394
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Book Description
Author: Lloyd R. Kelland
Publisher: Springer Science & Business Media
ISBN:
Category : Medical
Languages : en
Pages : 370
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Book Description
Leading international experts comprehensively review all aspects of platinum anticancer drugs and their current use in treatment, as well as examining their future therapeutic prospects. Writing from a variety of disciplines, these authorities discuss the chemistry of cisplatin in aqueous solution, the molecular interaction of platinum drugs with DNA, and such exciting new areas as DNA mismatch repair and replicative bypass, apoptosis, and the transport of platinum drugs into tumor cells. The emergent platinum drugs of the future-orally active agents, the sterically hindered ZD0473, and the polynuclear charged platinum BBR3464-are also fully considered. Timely and interdisciplinary, Platinum-Based Drugs in Cancer Therapy offers cancer therapeutics specialists an illuminating survey of every aspect of platinum drugs from mechanisms of action to toxicology, tumor resistance, and new analogs.
