Language: English
ISBN/ISSN: 7030168194
Published on: 2006-01
Paperback
Camptothecin (CPT) is pentacyclic alkaloid isolated from wood and bark of Camptotheca acuminate. Initially it was found to be highly active in a number of mouse in vivo cancer assays Subsequently, CPT was found to possesses a novel mechanism of action involving the inhibition of DNA relaxation by DNA topoisomerase I, and more specifically the stabilization of a covalent binary complex formed between topoisomerase I and DNA. A number of CPT Analogues are in advanced clinical trial, Topotecan and CPT-11, have been approved for marketing by the FDA. Camptothecins have been playing an important role as anticancer agents in recent 20 years. This book provides a detailed discussion of recent advances in the medicinal chemistry of camptothecin, and summarizes the current status of studies of the mechanism of action of camptothecin, including topoisomerase I inhibition and additional cellular responses. A systematic evaluation of novel and important analogues of camptothecin and their contribution to the current structure-activity profile are considered, and camptothecins development and schedules of administration in clinical onlology update. This includes our study about camptothecins in recent years. To improve the water solubility, series of new derivatives of Camptothecin were prepared, and evaluated cytotoxicity by MTT and inhibitive activity of topoisomerase I by molecurlar biological method. These camptothecin derivatives have good water solubility, low toxic, and good topiosomerase I inhibitive activity. Further detail investigation is progressing in the pharmacology.
CONTENTS
CHAPTER 1 CAMPTOTHECIN AND ITS MECHANISM OF ACTION
1.1 History
1.2 Camptothecin: Mechanism of Action
1.3 Structure-Activity Relationships
1.4 The Homocamptothecin
1.5 The Future of Camptothecin
References
CHAPTER 2 WATER SOLUBLE DERIVATIVES OF CAMPTOTHECIN
WITH POTENT ANTITUMOR ACTIVITY
2.1 Synthesis of Intermediate
2.2 Synthesis of Water Soluble Derivatives of Camptothecin
2.3 Cytotoxicity of the Salt Derivatives of Camptothecin
2.4 Topoisomerase I Inhibitory Activity of the Derivatives of Camptothecin
2.5 In vivo Toxicity and Antitumor Studies
References
CHAPTER 3 WATER SOLUBLE QUATERNARY SALT DERIVATIVES OF 9-NITROCAMPTOTHECIN WITH POTENT ANTITUMOR
ACTIVITY
3.1 Synthesis of Intermediate
3.2 Synthesis of Water Soluble Quaternary Salt Derivatives of 9-nitro- camptothecin
3.3 Cytotoxicity of the 9-nitro-camptothecin Salt Derivatives
3.4 Topoisomerase I Inhibitory Activity of the Derivatives of Camptothecin
References
CHAPTER 4 OTHER DERIVATIVES OF CAMPTOTHECIN
4.1 Synthesis of Derivatives
4.2 Cytotoxicity of the Derivatives of Camptothecin
CHAPTER 5 EXPERIMENTAL SECTION
5.1 Chemistry
5.2 Biological Assay
CHAPTER 6 CAMPTOTHECINS IN CLINIC
6.1 Topotecan
6.2 Irinotecan
6.3 9-aminocamptothecin and 9-nitrocamptothecin
6.4 Exatecan and Camptothecin Glycoconjugates
References
