Total synthesis and biological evaluation of potent analogues of dictyostatin: modification of the C2-C6 dienoate region.

Abstract

By exploiting a Still-Gennari olefination of a common C11-C26 aldehyde with a C4-C10 or C1-C10 beta-ketophosphonate, three modified C2-C6 region analogues of the 22-membered macrolide dictyostatin were synthesised and evaluated in vitro for growth inhibition against a range of human cancer cell lines, including the Taxol-resistant NCI/ADR-Res cell line. 6-Desmethyldictyostatin and 2,3-dihydrodictyostatin displayed potent (low nanomolar) antiproliferative activity, intermediate between dictyostatin and discodermolide, while 2,3,4,5-tetrahydrodictyostatin showed activity comparable to discodermolide. As with dictyostatin, these simplified analogues act through a mechanism of microtubule stabilisation, G2/M arrest and apoptosis.

• Authors: Ian Paterson, Nicola M Gardner, Esther Guzmán, Amy E Wright
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 18 Issue 23 Pg. 6268-72 (Dec 01 2008) ISSN: 1464-3405 [Electronic] England
• PMID: 18951787 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Alkanes
• Antineoplastic Agents
• Carbamates
• Lactones
• Macrolides
• Pyrones
• Tubulin
• dictyostatin
• discodermolide
• Paclitaxel

Topics

• Alkanes (chemistry, pharmacology)
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Carbamates (chemistry, pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Drug Screening Assays, Antitumor
• Humans
• Lactones (chemistry, pharmacology)
• Macrolides (chemical synthesis, chemistry, pharmacology)
• Molecular Structure
• Paclitaxel (chemistry, pharmacology)
• Porifera (chemistry)
• Pyrones (chemistry, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship
• Tubulin (metabolism)