Tubulin-Binding Agents

Synthetic, Structural and Mechanistic Insights

Author: Teresa Carlomagno

Publisher: Springer

ISBN:

Category: Science

Page: 331

View: 224

reviews. The SAR data are discussed in light of the structural information available for each agent. The second chapter focuses on the total synthesis of the marine sponge-derived polyketide discodermolide. A comprehensive survey of the synthetic chemistry efforts of several groups over a 14-year period is provided together with a compa- son of the different approaches. The third chapter describes a comprehensive study of the mechanisms of activity of microtubules stabilizing drugs. Thermodynamic, kinetic, structural and fu- tional data on microtubules stabilizing drugs are discussed in an interdisciplinary manner to generate a “time-resolved” picture of the interaction of the drugs with different tubulin forms. The fourth and fifth chapters review the efforts and achievements made in the characterization of the structure of the complexes of tubulin with microtubules stabilizing agents by NMR (Chapter 4) and EM (Chapter 5). Especially evident is the discrepancy of the results obtained for epothilones, where the two techniques deliver radically different structures of the bound drug. Both NMR and EM models are, however, able to explain a consistent set of SAR data. The authors of the two chapters discuss critically the advantages and limitations of each methodology.

Tubulin-Binding Agents

Synthetic, Structural and Mechanistic Insights

Author: Teresa Carlomagno

Publisher: Springer Science & Business Media

ISBN:

Category: Medical

Page: 331

View: 685

This series presents critical reviews of the present position and future trends in modern chemical research. It contains short and concise reports on chemistry, each written by the world renowned experts.

The Pursuit of Tubulin-binding Agents

Author: Vicki Chang

Publisher:

ISBN:

Category: Chemistry, Organic

Page: 284

View: 677

Presented here are two bodies of work regarding the synthesis of molecules related to tubulin-binding agents. Described in Chapter 1 is the synthesis of a library of biosynthetically-inspired colchicine-related compounds and the data regarding their biological activity. This chapter discusses using a pair of oxidative coupling reagents to generate molecular diversity in hopes of creating highly bioactive molecules. Described in Chapter 2 is the progress towards the synthesis of fluorinated epothilone B sulfonamide analogs. This chapter delineates approaches taken during the pursuit of a pair of analogs desired for biological testing. As the title alludes, the original compounds of colchicine and the epothilones are tubulin-binding agents, and it is this quality that affords them their highly desired biological activity as anticancer agents.

Microtubule Growth, Nucleation, and Novel Tubulin-binding Drugs

Author: Michal Wieczorek

Publisher:

ISBN:

Category:

Page:

View: 170

"Cellular morphology depends on a complex network of microtubules, which are long, hollow polymers made up of a/b-tubulin subunits. Microtubules are not fixed structures; rather, they are highly dynamic, constantly being built, taken apart, and changing in shape and location to suit the needs of the cell. This thesis aims to answer some of these questions. Microtubule growth is accelerated by enzymes such as XMAP215, but in vivo microtubule growth rates remain much higher than in vitro reconstitution assays using purified components. Recently, XMAP215 and EB1 have been shown to synergistically enhance microtubule growth to near physiological rates. The growth rates reported remain lower, however, than those observed in C. elegans embryos and the theoretical upper limit derived from mass-transfer models. We sought to determine the effects of macromolecular crowding agents on microtubule growth rates. We found that the apparent rate constant for tubulin addition increased up to 10-fold inviscous environments with large macromolecules. In contrast, increasing the viscosity with small solutes decreased growth rates in a manner consistent with tubulin binding to microtubule ends in a diffusion-limited reaction. Adding crowding agents with XMAP215 and EB1 resulted in growth rates that saturated at 45 um min−1 at 10 uM tubulin. To our knowledge, this represents the fastest in vitro microtubule growth rates measured to date and approaches the theoretical limit. Microtubules are born and reborn continuously, even during quiescence, but nucleation is arguably the least understood aspect of microtubule dynamics. Using single-molecule biophysics, we show that nucleation from g-TuRCs, axonemes, and seed microtubules requires tubulin concentrations that lie well above the critical concentration yet do not support spontaneous nucleation. We measured considerable time lags between the arrival of tubulin and the onset of steady-state elongation. Microtubule associated proteins (MAPs) alter these time-lags. Catastrophe factors (MCAK and EB1) inhibited nucleation, while a polymerase (XMAP215) and an anti-catastrophe factor, which we have characterized for the first time (TPX2), both promoted nucleation. We observed similar phenomena in cells: depleting soluble tubulin levels in cells with tubulin-sequestering drugs reduced centrosomal nucleation rates. We conclude that GTP hydrolysis inhibits microtubule nucleation by destabilizing the nascent plus ends required for persistent elongation. Given its importance for the survival of cells, it is not surprising that tubulin is an important pharmacological target. Several drugs used to treat cancer patients directly target microtubules. Some drugs stabilize microtubules, preventing disassembly, while others destabilize microtubules, but the resulting mechanism of action is generally the same: a block in M phase progression and subsequent cell death. The use of effective dosages of these drugs is often limited, however, by severely toxic side effects on non-cancerous cells. Diazonamide A (DZA) is a potent anti-tumor agent that disrupts mitotic spindle assembly but displays significantly reduced off-target toxicities. The literature is conflicted as to whether or not DZA directly targets microtubules, and therefore its mechanism of action is not known. We have discovered that DZA inhibits the growth of individual microtubules by directly binding to the vinca binding site of tubulin. This study describes how DZA acts on microtubules using a combination of in vitro reconstitutions, measurements of microtubule growth in cells, X-ray crystallography, and clinically relevant tumor models. The crystal structure of the DZA-tubulin complex revealed that DZA straightens the tubulin interdimer angle relative to the vinblastine-tubulin structure. Though they share a common binding site, vinca alkaloids are simultaneously less potent and more toxic than DZA." --

Mechanism Studies of Antitubulin Agents-mediated MMP Down-regulation and Nitroxoline Repurposing in Human Prostate Cancer Cells

Author: Wei-Ling Chang

Publisher:

ISBN:

Category:

Page:

View: 790

Tubulin-binding drugs demonstrated palliative responses of decreasing prostate-specific antigen (PSA), improvement of life quality, and extension of survival in advanced hormone-refractory prostate cancer patients. In the first study, three tubulin-binding agents, paclitaxel, vincristine, and evodiamine, were used to explore the mechanism of the down-regulation of MMP-2 and MMP-9 protein expression. In the second study, nitroxoline induced cell cycle arrest in G1 phase and resulted in apoptosis in both hormone-sensitive and hormone-refractory prostate cancers.

Encyclopedia of Cancer

Author: Manfred Schwab

Publisher: Springer Science & Business Media

ISBN:

Category: Medical

Page: 3984

View: 879

The merging of different basic and clinical science disciplines towards the common goal of fighting against cancer has long ago called for the establishment of a comprehensive reference source both as a tool to close the language gap between clinical and basic science investigators and as a platform of information for students and informed laymen alike. The Encyclopedia of Cancer provides rapid access to focused information on all topics of cancer research for clinicians, research scientists and advanced students. Given the overwhelming success of the Second Edition, which appeared in 2009, and fast recent development in the different fields of cancer research, it has been decided to publish a third fully revised and expanded edition, following the principal concept of the first edition that has proven so successful. Recent developments are seeing a dynamic progress in basic and clinical cancer science, with translational research increasingly becoming a new paradigm in cancer research. In particular, new approaches to both Personalized Cancer Medicine and Targeted Therapies have made promising progress. While the Second Edition featured scholarly contributions from approximately 1.000 scientists/clinicians in four Volumes, the Third Edition includes 1.300 contributors in 7 Volumes with an A-Z format of approx. 7000 entries. It provides definitions of common acronyms and short definitions of related terms and processes in the form of keyword entries. In addition, there are detailed essays, which provide comprehensive information on syndromes, genes and molecules, and processes and methods. Each essay is well-structured, with extensive cross-referencing between all entries. In the Third Edition, topical Essays present a comprehensive picture of major cancers, such as Breast Cancer, Colorectal Cancer, Prostate Cancer, Ovarian Cancer, Renal Cancer, Lung Cancer, and Hematological Maligancies, Leukemias and Lymphomas. For each of these cancers, different authoritative Essays are included that cover topics ranging from Pathology, to Clinical Oncology and Targeted Therapies. This new feature should meet the expectance that a wide community has towards a major cancer reference works. The Encyclopedia of Cancer will be accessible both in print and online, and this information source should be of value to both the clinical and basic scientific community as well as to the public.

Anticancer Agents from Natural Products, Second Edition

Author: Gordon M. Cragg

Publisher: CRC Press

ISBN:

Category: Science

Page: 767

View: 635

The approach to drug discovery from natural sources has yielded many important new pharmaceuticals inaccessible by other routes. In many cases the isolated natural product may not be an effective drug for any of several reasons, but it nevertheless may become a drug through chemical modification or have a novel pharmacophore for future drug design. In summarizing the status of natural products as cancer chemotherapeutics, Anticancer Agents from Natural Products, Second Edition covers the: History of each covered drug—a discussion of its mechanism on action, medicinal chemistry, synthesis, and clinical applications Potential for novel drug discovery through the use of genome mining as well as future developments in anticancer drug discovery Important biosynthetic approaches to "unnatural" natural products Anticancer Agents from Natural Products, Second Edition discusses how complex target-oriented synthesis—enabled by historic advances in methodology—has enormously expanded the scope of the possible. This book covers the current clinically used anticancer agents that are either natural products or are clearly derived from natural product leads. It also reviews drug candidates currently in clinical development since many of these will be clinically used drugs in the future. Examples include the drugs etoposide and teniposide derived from the lead compound podophyllotoxin; numerous analogs derived from taxol; topotecan, derived from camptothecin; and the synthetic clinical candidates, E7389 and HTI-286, developed from the marine leads, halichondrin B and hemiasterlin.

Annual Reports in Medicinal Chemistry

Author: Annette M. Doherty

Publisher: Elsevier

ISBN:

Category: Medical

Page: 364

View: 564

Annual Reports in Medicinal Chemistry provides timely and critical reviews of important topics in medicinal chemistry together with an emphasis on emerging topics in the biological sciences, which are expected to provide the basis for entirely new future therapies.

Cancer: New Insights for the Healthcare Professional: 2011 Edition

Author:

Publisher: ScholarlyEditions

ISBN:

Category: Medical

Page: 3937

View: 623

Cancer: New Insights for the Healthcare Professional: 2011 Edition is a ScholarlyEditions™ eBook that delivers timely, authoritative, and comprehensive information about Cancer. The editors have built Cancer: New Insights for the Healthcare Professional: 2011 Edition on the vast information databases of ScholarlyNews.™ You can expect the information about Cancer in this eBook to be deeper than what you can access anywhere else, as well as consistently reliable, authoritative, informed, and relevant. The content of Cancer: New Insights for the Healthcare Professional: 2011 Edition has been produced by the world’s leading scientists, engineers, analysts, research institutions, and companies. All of the content is from peer-reviewed sources, and all of it is written, assembled, and edited by the editors at ScholarlyEditions™ and available exclusively from us. You now have a source you can cite with authority, confidence, and credibility. More information is available at http://www.ScholarlyEditions.com/.

Cytotoxic Payloads for AntibodyDrug Conjugates

Author: David E Thurston

Publisher: Royal Society of Chemistry

ISBN:

Category: Medical

Page: 480

View: 167

Antibody–drug conjugates (ADCs) represent one of the most promising and exciting areas of anticancer drug discovery. Five ADCs are now approved in the US and EU [i.e., ado-trastuzumab emtansine (KadcylaTM), brentuximab vedotin (AdcetrisTM), inotuzumab ozogamicin (BesponsaTM), gemtuzumab ozogamicin (MylotargTM) and moxetumomab pasudotox-tdfk (Lumoxiti®)] and over 70 others are in various stages of clinical development, with impressive interim results being reported for many. The technology is based on the concept of delivering a cytotoxic payload selectively to cancer cells by attaching it to an antibody targeted to antigens on the cell surfaces. This approach has several advantages including the ability to select patients as likely responders based on the presence of antigen on the surface of their cancer cells and a wider therapeutic index, given that ADC targeting enables a more efficient delivery of cytotoxic agents to cancer cells than can be achieved by conventional chemotherapy, thus minimising systemic toxicity. Although there are many examples of antibodies that have been developed for this purpose, along with numerous linker technologies used to attach the cytotoxic agent to the antibody, there is presently a relatively small number of payload molecules in clinical use. The purpose of this book is to describe the variety of payloads used to date, along with a discussion of their advantages and disadvantages and to provide information on novel payloads at the research stage that may be used clinically in the future.

Tumor Angiogenesis

Basic Mechanisms and Cancer Therapy

Author: Dieter Marmé

Publisher: Springer Science & Business Media

ISBN:

Category: Medical

Page: 845

View: 175

Tumor angiogenesis is one of the most prominent mechanisms driving tumor development and progression. This book is written by internationally renowned experts. Part 1 describes the basic mechanisms. Tumor-angiogenic signaling pathways are presented as new potential targets for anti-angiogenic therapy. Part 2 reviews the efforts made to validate new targets and to show efficacy in animals. Part 3 is devoted to the clinical development of the novel anti-angiogenic drugs and their use in clinical practice.