Erx

7.04.3.6 Conclusion

The clinical effectiveness of the taxanes has paved the way for the more recently discovered nontaxane microtubule-stabilizing agents. These new compounds, most discovered in the last 10 years, have provided new avenues for research in cancer chemotherapy, as well as significant challenges to the synthetic community to supply sufficient quantities of these frequently complex structures. The early clinical success of the epothilones is an encouraging first step toward the introduction of a nontaxane microtubule stabilizer into widespread clinical use. The advancement of discodermolide toward clinical evaluation is further cause for optimism. Total synthesis has played a key role in the advancement of discodermolide through preclinical evaluation. Furthermore, totally synthetic material will be used in clinical trials. The complexity of this undertaking illustrates what may be the single biggest challenge for further evaluation of other microtubule-stabilizing natural products, that being the lack of adequate supplies of material. Biotechnology and heterologous expression of biosynthetic machinery of these natural products can alleviate this issue, as is the case with the epothilones. The discoveries of a small number of simple, synthetic materials that show cytotoxiciy and function as microtubule stabilizers may serve to promote additional medicinal chemistry efforts on these structures.

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Brian R Hearn, PhD, is a scientist in the chemistry department at Kosan Biosciences. He joined Kosan in 2003 and worked on the total synthesis and semisynthesis of a number of polyketide natural products and their analogs. Prior to Kosan, he completed an NIH postdoctoral fellowship with Prof Paul A Wender at Stanford University, CA, USA. He obtained his PhD from the University of Notre Dame under the supervision of Prof Richard E Taylor.

Simon J Shaw, PhD, is a scientist in the chemistry department of Kosan Biosciences. Since joining the department in 2001, he has been involved in research in the areas of infectious disease and cancer. Prior to joining Kosan, he spent 2 years in the laboratories of Prof Dan Kahne as a postdoctoral scholar. He received a PhD from Imperial College, London, under the direction of Prof Donald Craig.

Biographies

David C Myles, PhD, is Executive Director, Chemistry of Kosan Biosciences. Prior to joining Kosan in May 2001, he was Associate Director, Organic and Medicinal Chemistry at Chiron Corporation where he was involved in research directed toward the development of new antiviral, antibacterial, and anticancer agents. From 1991 to 1998, he held a faculty position in the Department of Chemistry and Biochemistry at the University of California, Los Angeles, CA. From 1989 through 1991, he held the NIH/Lawton Chiles Biotechnology Fellowship in the Department of Chemistry at Harvard University, MA, where he studied organic synthesis using biocatalysts. He earned his PhD in 1989 from Yale University.

© 2007 Elsevier Ltd. All Rights Reserved Comprehensive Medicinal Chemistry II

No part of this publication may be reproduced, stored in any retrieval system or transmitted ISBN (set): 0-08-044513-6 in any form by any means electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without permission in writing from the publishers ISBN (Volume 7) 0-08-044520-9; pp. 81-110

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