Advances in Anticancer Agents in Medicinal Chemistry: Volume 1 E-Book

• Herausgeber: Bentham Science Publishers
• Kategorie: Fachliteratur
• Serie: Advances in Anticancer Agents in Medicinal Chemistry
• Sprache: Englisch

Seitenzahl: 703

Veröffentlichungsjahr: 2013

Beschreibung

Advances in Anticancer Agents in Medicinal Chemistry is an exciting eBook series copmrising a selection of updated articles previously published in the peer-reviewed journal Anti-Cancer Agents in Medicinal Chemistry. The first volume presents reviews of many classes of drugs of contemporary interest for cancer therapy and is devoted to small inhibitors of various proteins involved in cancer development such as casein kinase 2 (CK2), protein kinase B (PKB), mTOR, Hsp90, P-glycoprotein (P-gp), kinesin spindle protein (KSP), cyclooxygenase 2 (COX-2), histone deacetylase enzymes (HDACs) and topoisomerase I.
Advances in Anticancer Agents in Medicinal Chemistry will be of particular interest to readers interested in anticancer drug therapy as the series provides relevant reviews written by experts in this important field.

Leseprobe

Table of Contents

Welcome

Table of Contents

Title

BENTHAM SCIENCE PUBLISHERS LTD.

End User License Agreement (for non-institutional, personal use)

Usage Rules:

Disclaimer:

Limitation of Liability:

General:

FOREWORD

PREFACE

Casein Kinase 2 (CK2) Inhibitors: Emerging Anticancer Therapeutic Agents?

Abstract

Introduction

Structural insight of protein kinase CK2

Biological role of CK2

Cell Cycle

Protection Role Against Cellular Stress

CK2 and Transcriptional Control

Neural Function

CK2 and Membrane Substrates

CK2 and human diseases

CK2 and Inflammatory Diseases

CK2 and Neurodegenerative Diseases

CK2 and Cardiovascular Diseases

CK2 and Cardiovascular Diseases

CK2 and Parasites Infection

CK2 and Tumors

CK2 and Other Diseases

The inhibition of protein kinase CK2

ATP- Competitive Inhibitors (Type I)

Polyalogenated Benzimidazole Derivatives

Benzofuran Derivatives

Anthraquinone, Xanthenone and Fluorenone

Pyrazolo-Triazine Derivatives

Carboxyl Acid Derivatives

ATP Non Competitive Inhibitors (Type II-V)

Conclusion

CONFLICT OF INTEREST

ACKNOWLEDGEMENTs

Disclosure

REFERENCES

An Update 2009 – 2012 to “Targeted Small-Molecule Inhibitors of Protein Kinase B as Anticancer Agents”

Abstract

Introduction

Pharmacology of PKB Inhibitors

ATP-Competitive Inhibitors

PH-Domain Dependent Inhibitors

Substrate Peptide Mimetic Inhibitors

Conclusions

ABBREVIATIONS

CONFLICT OF INTEREST

ACKNOWLEDGEMENTS

DISCLOSURE

REFERENCES

Advances in mTOR Inhibitors

Abstract

Introduction

MTOR complexes

MTOR inhibitors

Rapalogs

mTOR and PI3K Dual-Specificity Inhibitors

Selective mTORC1/2 Inhibitors

Natural Products

Summary and perspectives

CONFLICT OF INTEREST

ACKNOWLEDGMENTS

DISCLOSURE

REFERENCE

Recent Advances in Hsp90 Inhibitors as Antitumor Agents

Abstract

Introduction

HSP90 Health and diseases

HSP90 structure and ATPASE cycle

HSP90 and treatment of cancers

HSP90 inhibitors [55-61]

N-terminal domain binders

1) Ansamycin Macrolactames

Quinone Derivatives

Hydroquinone Derivatives

2) Resorcylic Lactones (Radicicol)

3) Purine Scaffold Inhibitors

6-Amino-8-Arylpurines

2-Amino-7-Arylpurines

6-Substituted Purines

Others Scaffolds

4) Pyrazole Scaffold Inhibitors

Pyrazole Analogues [150]

Triazole and Imidazole Analogues

Isoxazole Analogues

C-Terminal domain binders

Coumarin inhibitors

Others inhibitors

Aminoimidazole Derivative AICAR

Benzisoxazole Resorcinol Derivatives

Polyphenols

Isoquinoline, Quinazoline and Phtalazine Derivatives

Inhibitors of HSP90 and Interaction with Co-Chaperones

General conclusion

Abbreviations

CONFLICT OF INTEREST

Acknowledgments

Disclosure

References

Recent Developments of P-gp Inhibitors

Abstract

1.. Introduction

2.. P-GP Inhibitors

2.1.. Arylalkylamines

2.1.1.. Verapamil Analogues

2.1.2.. Miscellaneous Arylalkylamines

2.2.. Heteroaryloxypropanolamines

2.3.. Propafenone-Related Compounds and Anthranylamide Derivatives

2.4.. Nitrogen Heterocycles

2.4.1.. Pyrroles, Pyrimidines, Pyrazoles and Pyrimidin Derivatives

2.4.2.. Isoquinolines and Quinoline Derivatives

2.4.3.. Quinazoline and Indole Derivatives

2.4.4.. Pyridine and Dihydropyridine Derivatives

2.4.5.. Miscellaneous Nitrogen Heterocycles

2.5.. Oxygen Heterocycles

2.5.1.. Dioxol and Dioxolane Derivatives

2.5.2.. Coumarin Derivatives

2.5.3.. Flavonoids

2.5.4.. Cannabinoids

2.5.5.. Anthracycline Glycosides

2.6.. Peptides

2.7.. Terpenes and Related Compounds

2.7.1.. Diterpenes

2.7.2.. Sesquiterpenes

2.7.3.. Triterpenes

2.7.4.. Steroid Related Compounds

2.8.. Miscellaneous Lipophilic Compounds

2.8.1.. Polyenes

2.8.2.. Lignans

2.8.3.. Pharmaceutical Excipients

2.9.. Miscellaneous P-gp Modulators

2.9.1.. Organometallic and Organosilicon Compounds

2.9.2.. Hyaluronan Oligomeres

3.. Conclusions

Conflict of interest

Acknowledgements

Disclosure

References

Progress Review on Kinesin Spindle Protein Inhibitors as Anti-Cancer Agents

Abstract

1.. INTRODUCTION

2.. STRUCTURE AND FUNCTION OF KSP

3.. SEVERAL CATEGORIES OF KSP INHIBITORS

3.1.. ATP-Uncompetitive Allosteric Inhibitors

3.1.1.. Monastrol Analogs

3.1.2.. Tetrahydroisoquinolines

3.1.3.. Ispinesib and Related Compounds

3.1.4.. Tetrahydro-β-Carbolines

3.1.5.. Dihydropyrroles and Dihydropyrazoles

3.1.6.. Thiophenes

3.1.7.. Benzimidazoles

3.1.8.. Thiadiazolines

3.1.9.. Trityls

3.1.10.. Hexahydro-2H-Pyrano[3,2-c]Quinolines

3.2.. ATP-Competitive Inhibitors

3.2.1.. Bis(hetero)aryl

3.2.2.. Thiazole

3.2.3.. Carbazoles and Carbolines

4.. CONCLUSION AND PROSPECT

CONFLICT OF INTEREST

ACKNOWLEDGEMENTS

DISCLOSURE

REFERENCES

Discovery of Allosteric Inhibitors of Kinesin Spindle Protein (KSP) for the Treatment of Taxane-Refractory Cancer: MK-0731 and Analogs

Abstract

Introduction

Hit to Lead Identification

Optimization of PGP efflux profile and HERG binding: Discovery of MK-0731

Preclinical Characterization of MK-0731

Advanced Backup Compounds

Clinical Study of MK-0731

CONCLUSIONS

CONFLICT OF INTEREST

ACKNOWLEDGEMENTS

DISCLOSURE

REFERENCES

Selective Cyclooxygenase-2 Inhibitors for Malignant Glioma Therapy: Molecular Targets Beyond COX-2

Abstract

1.. Introduction

2.. NSAIDS in Malignant Glioma Therapy

3.. COX-2 Independent Mechanisms of COX-2 Inhibitors

3.1.. 2,5-Dimethyl-Celecoxib

3.2.. COX-2 Independent Targets

3.2.1.. 3-Phosphoinositide-Dependent Protein Kinase-1

3.2.2.. Carbonic Anhydrases

3.2.3.. Endoplasmic Reticulum Stress

3.3.. Drug Concentrations In Vitro vs In Vivo

4.. clinical trials

5.. SUMMARY

CONFLICT OF INTEREST

ACKNOWLEDGEMENTS

DISCLOSURE

References

Histone Deacetylase Inhibitors: Their Structure, Function and Potential to Treat Cancer

Abstract

BIOLOGY

Modification of Histone Protein and Regulation of Transcription

Histone Deacetylases (HDACs)

Molecular Modeling of HDACs Relevant to Design of Inhibitors

Associated Complexes of HDAC

Relevance of HDAC Enzymes to Cancer

Effects of HDAC Inhibitors on Cell Function

PRECLINICAL AND CLINICAL STUDIES

Combination Therapies

Valproic acid

SAHA (ZolinzaTM, Vorinostat)

PXD-101 (Belinostat)

NVP-LAQ824 (Dacinostat)

NVP-LBH589 (Panobinostat)

CRA-026440

SNDX-275 or MS-275 (Entinostat)

MGCD0103 (Mocetinostat)

FK228 (Romidepsin)

CHEMISTRY

Saturated-Chain Hydroxamate Inhibitors

Alkylene-Linked Hydroxamates

Ether-Linked Hydroxamates

Sulfur-Linked Hydroxamates

Amino-Linked Hydroxamates

Amido-Linked Hydroxamates

Unsaturated Chain Hydroxamate Inhibitors

Dienic and Trienic Hydroxamates

Hydroxamic Acids of Acrylate Derivatives

Hydroxamic Acids of Cinnamates

Hydroxamic Acids of 3-Substituted Heterocyclic Acrylates

N-Hydroxybenzamide Inhibitors

Heteroaromatic Hydroxamate Inhibitors

Pyrimidine-Containing Hydroxamic Acids

Thiophene Hydroxamic Acids

Benzothiophene Hydroxamic Acids

HDAC Inhibitors Containing Non-Hydroxamate Zinc-Binding Groups

Ketones and Derivatives

Carboxylic Acids and Derivatives

Amides Including Benzamides

Thiols, Sulfides and Derivatives

Selenium Compounds

Silicon-Containing Compounds

Miscellaneous Non-Hydroxamate Inhibitors

HDAC Inhibitors with Extended Contacts in the HDAC Cap Region

Branched Chain Inhibitors

Cyclic Peptide-Based Inhibitors

Cyclic Depsipeptides

Non-Peptidic Macrocycles

HDAC Inhibitors and Isoform Selectivity

CONCLUSIONS

Conflict of interest

Acknowledgements

Disclosure

REFERENCES

Inhibiting Topoisomerase I, an Emerging Treatment for Primary CNS Malignancies

Abstract

Introduction

Methods

Topoisomerase Inhibitors

Irinotecan and Topotecan

Topoisomerase I Inhibitors Alone or with Radiation Therapy

Topoisomerase I Inhibitor Combination Therapy

Combination Therapy with Bevacizumab

Future Directions

CONFLICT OF INTEREST

ACKNOWLEDGEMENTS

DISCLOSURE

REFERENCES

Advances in Anticancer Agents in

Medicinal Chemistry

Volume 1

Edited By:

Michelle Prudhomme

Institut de Chimie de Clermont-Ferrand ICCF

CNRS UMR 6296 24 Avenue des Landais 63177 Aubiere Cedex

France

BENTHAM SCIENCE PUBLISHERS LTD.

End User License Agreement (for non-institutional, personal use)

This is an agreement between you and Bentham Science Publishers Ltd. Please read this License Agreement carefully before using the ebook/echapter/ejournal (“Work”). Your use of the Work constitutes your agreement to the terms and conditions set forth in this License Agreement. If you do not agree to these terms and conditions then you should not use the Work.

Bentham Science Publishers agrees to grant you a non-exclusive, non-transferable limited license to use the Work subject to and in accordance with the following terms and conditions. This License Agreement is for non-library, personal use only. For a library / institutional / multi user license in respect of the Work, please contact: [email protected].

Usage Rules:

All rights reserved: The Work is the subject of copyright and Bentham Science Publishers either owns the Work (and the copyright in it) or is licensed to distribute the Work. You shall not copy, reproduce, modify, remove, delete, augment, add to, publish, transmit, sell, resell, create derivative works from, or in any way exploit the Work or make the Work available for others to do any of the same, in any form or by any means, in whole or in part, in each case without the prior written permission of Bentham Science Publishers, unless stated otherwise in this License Agreement.You may download a copy of the Work on one occasion to one personal computer (including tablet, laptop, desktop, or other such devices). You may make one back-up copy of the Work to avoid losing it. The following DRM (Digital Rights Management) policy may also be applicable to the Work at Bentham Science Publishers’ election, acting in its sole discretion:25 ‘copy’ commands can be executed every 7 days in respect of the Work. The text selected for copying cannot extend to more than a single page. Each time a text ‘copy’ command is executed, irrespective of whether the text selection is made from within one page or from separate pages, it will be considered as a separate / individual ‘copy’ command.25 pages only from the Work can be printed every 7 days.

3. The unauthorised use or distribution of copyrighted or other proprietary content is illegal and could subject you to liability for substantial money damages. You will be liable for any damage resulting from your misuse of the Work or any violation of this License Agreement, including any infringement by you of copyrights or proprietary rights.

Disclaimer:

Bentham Science Publishers does not guarantee that the information in the Work is error-free, or warrant that it will meet your requirements or that access to the Work will be uninterrupted or error-free. The Work is provided "as is" without warranty of any kind, either express or implied or statutory, including, without limitation, implied warranties of merchantability and fitness for a particular purpose. The entire risk as to the results and performance of the Work is assumed by you. No responsibility is assumed by Bentham Science Publishers, its staff, editors and/or authors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products instruction, advertisements or ideas contained in the Work.

Limitation of Liability:

In no event will Bentham Science Publishers, its staff, editors and/or authors, be liable for any damages, including, without limitation, special, incidental and/or consequential damages and/or damages for lost data and/or profits arising out of (whether directly or indirectly) the use or inability to use the Work. The entire liability of Bentham Science Publishers shall be limited to the amount actually paid by you for the Work.

General:

Any dispute or claim arising out of or in connection with this License Agreement or the Work (including non-contractual disputes or claims) will be governed by and construed in accordance with the laws of the U.A.E. as applied in the Emirate of Dubai. Each party agrees that the courts of the Emirate of Dubai shall have exclusive jurisdiction to settle any dispute or claim arising out of or in connection with this License Agreement or the Work (including non-contractual disputes or claims).Your rights under this License Agreement will automatically terminate without notice and without the need for a court order if at any point you breach any terms of this License Agreement. In no event will any delay or failure by Bentham Science Publishers in enforcing your compliance with this License Agreement constitute a waiver of any of its rights.You acknowledge that you have read this License Agreement, and agree to be bound by its terms and conditions. To the extent that any other terms and conditions presented on any website of Bentham Science Publishers conflict with, or are inconsistent with, the terms and conditions set out in this License Agreement, you acknowledge that the terms and conditions set out in this License Agreement shall prevail.

Bentham Science Publishers Ltd. Executive Suite Y - 2 PO Box 7917, Saif Zone Sharjah, U.A.E. Email: [email protected]

FOREWORD

While it is pleasing to see the continual upsurge in scientific articles describing research on drugs for cancer therapy, this increase in the literature makes it ever-harder to keep up, even with selected topics in the field. Thus it is very good to see this e-Book venture by Bentham Science Publishers, containing selected, author-updated papers originally published in Anticancer Agents in Medicinal Chemistry during 2008-2010. A particular virtue of this approach is that it obtains additional value from all the effort that is initially put into writing a review, by keeping it up-to-date and thus more useful. The present Volume 1 contains reviews of many of the classes of drugs of contemporary interest for cancer therapy, and offers a new way of keeping up with a field of interest, or being rapidly introduced to a new field. I congratulate Michelle Prudhomme, Editor-in-Chief of Anticancer Agents in Medicinal Chemistry, for this interesting new venture, which I commend to you.

PREFACE

This is the first volume of an exciting eBook series entitled Advances in Anticancer Agents in Medicinal Chemistry which will comprise a selection of the best articles published in the Bentham Science Journal Anticancer Agents in Medicinal Chemistry. These articles will be updated. In Volume 1 and 2, updated articles published during 2008-2010 are presented.

Volume 1 gathers chapters devoted to small molecule inhibitors of various proteins involved in cancer development.

The first review by Giorgio Cozza and Stefano Moro is entitled “Casein kinase 2 (CK2) inhibitors: emerging anticancer therapeutic agents”. This chapter presents this complex and multifunctional protein which plays a key role in several physiological and pathologicalprocesses. Its structure, its biological role and its implication in various diseases are described as well as the different families of inhibitors which could permit a better understanding of the cellular functions of CK2.

The second chapter by Ian Collins is devoted to Protein Kinase B (PKB) inhibitors and to the discovery of novel ATP-competitive PKB inhibitor scaffolds, as well as further exploration of the potential of peptide substrate-based inhibitors.

Dysregulation of the mammalian target of rapamycin (mTOR) pathway is frequently observed in various human cancers. The third chapter by H. Zhou and S. Huang reports the advances in the search for mTOR inhibitors as anticancer agents, rapalogs, ATP-competitive inhibitors as well as natural products.

The review of Samir. Messaoudi et al. is focused on recent advances in 90-kDa chaperone protein (Hsp90) inhibitors. Hsp90 is an emerging therapeutic target of interest for the treatment of cancer. Inhibition of Hsp90 has been shown to be effective in killing cancer cells that have developed resistance to targeted therapies such as kinase inhibitors.

The phenomenon of multidrug resistance (MDR) reflects the fact that resistance occurs against a broad diversity of drugs due to an altered membrane transport caused by increased efflux rates of the cytostatically active drugs. P-glycoprotein (P-gp) belongs to the family of transport proteins. It is overexpressed in cancer tissues. A huge interest has been devoted to the development of P-gp inhibitors. This chapter by Andreas Hilgeroth et al. reviews recent advances in P-gp inhibitor development, focusing on structure-activity relationships in the different compound classes.

The kinesin spindle protein (KSP) plays a key role during mitosis. Since mitotic kinesins are absent from post-mitotic neurons, small molecule inhibitors targeting these enzymes will not cause the neuropathic side effects of the antitubulins. Accordingly, KSP is an attractive target for the development of anticancer drugs. Two Chapters are devoted to KSP inhibitors. Yingjie Zhang and Wenfang Xu summarized the various categories of KSP inhibitors whereas the review of C.D. Cox and R.M. Garbaccio described the efforts carried out at Merck in the search for allosteric KSP inhibitors leading to the discovery of MK-0731 and analogs.

Many different types of human tumors express highly elevated levels of Cyclooxygenase 2 (COX-2), leading to the idea that increased expression of this enzyme might contribute to the carcinogenic process. Consequently, COX-2 has been considered as an attractive target for anticancer therapy. The review by A.H. Schönthal reports the recent advances in the search of COX-2 inhibitors. Celecoxib and analogs are especially developed because of their dual pharmacological potencies, inhibition of COX-2 and induction of apoptosis. They represent a novel class of promising cancer therapeutic agents.

Histone deacetylase enzymes (HDACs) are major regulators of cellular protein acetylation, especially of histone protein. Acetylation levels of histone protein are controlled by the opposing activities of histone acetyl transferase (HAT) and HDAC enzymes. Hypoacetylated histone protein has been associated with precancerous or malignant states. The chapter by Charles M. Marson is focused on the different classes of histone deacetylase inhibitors, their structure, their function and their potency to kill cancer cells.

The role of topoisomerase I inhibitors in the treatment of gliomas has expanded in recent years, especially with respect to combination therapy. Topoisomerase I (TOP1) is an enzyme critical for DNA replication and cell-cycle progression. The most studied TOP1 inhibitors are topotecan and irinitecan, derivatives of the natural compound camptothecin. Lynn G. Feun et al. reviewed the recent results in the treatment of primary CNS malignancies using TOP1 inhibitors alone or in combination with other agents.

Casein Kinase 2 (CK2) Inhibitors: Emerging Anticancer Therapeutic Agents?

Giorgio Cozza1,Stefano Moro*,2

1Dipartimento di Chimica Biologica, Università of Padova, 35121Padova, Italy; 2Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, Padova, Italy

Abstract

Protein kinase CK2 (Casein Kinase 2) is an ubiquitous, highly pleiotropic, constitutive active and essential protein kinase, with both cytosolic and nuclear localization in most mammalian cells. The holoenzyme is generally composed of two catalytic (alpha and/or alpha') and two regulatory (beta) subunits, but the free alpha/alpha' subunits are catalytically active by themselves and can be present in cells under some circumstances. CK2 catalyzes the phosphorylation of more than 300 substrates characterized by multiple acidic residues surrounding the phosphor-acceptor amino acid and, consequently, it plays a key role in several physiological and pathological processes. It’s abnormally high constitutive activity is implicated in several diseases and neoplasia, and a number of ATP competitive inhibitors of CK2 with micromolar and nanomolar in vitro activity, display a pro-apoptotic effect also in cell.

Keywords:: CK2, protein kinases, inhibitors, cancer, neurodegenerative diseases, viral infections.

*Address correspondence to Stefano Moro: Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, Padova, Italy; Tel. [phone]; Fax: [phone]; E-mail: [email protected]