Abstract
Biological target: 12-Aza-epothilones (azathilones) induce tubulin polymerization, thereby disturbing microtubule function and inhibiting mitosis and cell growth at nM concentrations. They show low susceptibility to P-glycoprotein-mediated efflux and are thus active on multidrug resistant cells.
Therapeutic profile: The compounds are potential anticancer agents.
Synthetic highlights: Natural macrocyclic compounds have been subjected to both extensive and peripheral structural modifications in the search for new lead compounds. An example of the former is the antibiotic azithromycin, whereas 12-aza-epothilones must be approached by total synthesis. This total synthesis of epothilones involves ring closure metathesis using heteroleptic complexes as catalysts and has proved to be an efficient approach to “non-natural, macrocyclic natural products”. In one of the critical steps of this pathway to azathilones, creative site-selective diimide reduction of an allylic C=C bond was applied.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Bollag DM, McQueney PA, Zhu J, Hensens O (1995) Cancer Res 55:2325–2333
Girth K, Bedorf N, Hofle G, Irschik H, Reichenbach H (1996) J Antibiot 49:560–566
Hofle G, Rechenbach H (2005) Epothilone, a Myxobacterial Metabolite with Promising Antitumor Activity. In: Cragg GM, Kingston DGI, Newman DG (eds) Anticancer agents from natural products. Taylor & Francis, Boca Raton, FL, pp 413–450
Kowalsk RJ, Giannakakou P, Hamel E (1997) J Biol Chem 272:2534–2541
Nikolau KC, Ritzen A, Namoto K (2001) JCS Chem Commun: 1523–1535
Bertinato P, Sorensen EJ, Meng D, Danishefsky SJ (1996) J Org Chem 61:8000–8001
Nikolau KC, Winssinger N, Pastor J, Ninkovic S, Sarabia F, He Y, Vourloumis D, Tang Z, Li T, Giannakakou P, Hamel E (1997) Nature 387:268–272
Wartmann M, Altmann K-H (2002) Curr Med Chem Anticancer Agents 2:123–128
Altmann K-H, Bold G, Caravatti G, Florsheimer A, Gugnano V, Wartmann M (2000) Biorg Med Chem 10:2675–2678
Carlomagno T, Blommers MJJ, Meiler J, Jahnke W, Schupp TT, Peterson F, Schinzer D, Altmann K-H, Griesinger C (2003) Angew Chem Int Ed 42:2511–2515
Goodin S, Kane MP, Rubin EH (2004) J Clin Oncol 22:2015–2025
Forli S, Manetti F, Altmann K-H, Botta M (2010) ChemMedChem 5:35–40
Hofle G, Bedorf M, Steinmetz H, Schomburg D, Gerth K, Reichenbach H (1996) Angew Chem Int Ed 35:1567–1569
Nettles JH, Li H, Cornett B, Krahn JM, Smyder JP, Downing KH (2004) Science 305:866–869
Nikolaou KC, Scarpelli R, Bollbuck B, Werschkun B, Pereira MMA, Wartmann M, Altmann K-H, D Zaharevitz, Gussio R, Giannakakou P (2000) Chem Biol 7:593–599
Gertsch J, Feyen F, Butzberger A, Gerber B, Pfeiffer B, Altmann K-H (2009) Chembiochem 10:2513–2521
Burke MD, Schreiber SL (2004) Angew Chem Int Ed 43:46–58
Breinbauer R, Vetter IR, Waldmann H (2002) Angew Chem Int Ed 41:2878–2890
Koch MA, Waldmann H (2005) Drug Discov Today 10:471–483
Tietze LF, Bell HP, Chandrasekar S (2003) Angew Chem Int Ed 42:3996–4028
Kobrehel G, Radobolja G, Tamburašev Z, Đokic S, (PLIVA) (1982). 11-Aza-10-deoxo-10-dihydroerythromycin A and derivatives thereof as well a process for their preparation. US 4 328 334
Đokic S, Kobrehel G, Lazarevski G, Lopotar N, Tamburašev Z, Kamenar B, Nagl A, Vicković I (1986) J Chem Soc Perkin Trans I: 1881–1990
Retsema J, Girard A, Schelkly W, Manousos M, Anderson M, Bright G, Borovoy R, Brenan L, Mason R (1987) Antimicrob Agent Chemother 31:1939–1947
Altmann K-H, Florsheimer A, Bold G, Caravatti G, Wartmann M (2004) Chimia 58:686–690
Cachoux F, Scgaal F, Teichert A, Wagner T, Altmann K-H (2004) Synlett; 2709–2712
Feyen F, Gertsch J, Wartmann M, Altmann K-H (2006) Angew Chem Int Ed 52:5880–5885
Feyen F, Cachoux F, Gertsch J, Wartmann M, Altmann K-H (2008) Acc Chem Res 41:21–31
Feyen F, Jantsch A, Hauenstein K, Pfeiffer B, Altmann K-H (2008) Tetrahedron 64:7920–7928
Altmann K-H, Bold G, Caravatti G, Denni D, Florsheimer A, Schmidt A, Rihs G, Wartmann M (2002) Helv Chim Acta 85:4086–4110
Altmann K-H, Feyen F, Gertch J (ETH, Zurich), WO 2007/110214 A1.
Nguyen ST, Johnson LK, Grubbs RH, Ziller JW (1992) J Am Chem Soc 114:3974–3975
Nguyen ST, Grubbs RH, Ziller JW (1993) J Am Chem Soc 115:9858–9859
Furstner A (ed) (1998) Alkene metathesis in organic synthesis. Springer, Berlin
Furstner A (2000) Angew Chem Int Ed 39:3912–3043
Herrison J-L, Chauvin Y (1970) Macromol Chem 141:161–176
Dias EL, Nguyen ST, Grubbs RH (1997) J Am Chem Soc 119:3887–3897
Cucculu ME, Li C, Nolan SP, Nguyen ST, Grubbs RH (1998) Organometallics 17:5565–5568
Kuzniwesky CN, Gertsch J, Wartmann M, Altmann K-H (2008) Org Lett 10:1183–1186
Altmann K-H (2005) Curr Pharm Des 11:1595–1613
Fischer H, Gibian H (1941) Liebigs Ann Chem 548:183–194
Fischer H, Gibian H (1942) Liebigs Ann Chem 550:208–251
Corey EJ, Mock WL, Pasto DJ (1961) Tetrahedron Lett: 347–352
Balu EJ, Hochheimer EF, Unger HJ (1961) J Chem Phys 34:1060–1068
Tang HR, McKee ML, Stanbury DM (1995) J Am Chem Soc 117:8967–8973
Pasto DJ, Taylor TT (1991) Org React 40:91–155
Rivkin A, Yoshimura F, Gabarda AE, Cho YS, Chou T-C, Dog H, Danishefsky SJ (2004) J Am Chem Soc 126:10913–10922
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
Copyright information
© 2011 Springer Basel AG
About this chapter
Cite this chapter
Šunjić, V., Parnham, M.J. (2011). 12-Aza-Epothilones. In: Signposts to Chiral Drugs. Springer, Basel. https://doi.org/10.1007/978-3-0348-0125-6_16
Download citation
DOI: https://doi.org/10.1007/978-3-0348-0125-6_16
Published:
Publisher Name: Springer, Basel
Print ISBN: 978-3-0348-0124-9
Online ISBN: 978-3-0348-0125-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)