Production of anticancer polyenes through precursor-directed biosynthesis.

Abstract

The biosynthesis of the pyrrolyl moiety of the fungal metabolite rumbrin originates from pyrrole-2-carboxylic acid. In an effort to produce novel derivatives with enhanced biological activity a series of substituted pyrrole-2-carboxylates were synthesised and incubated with the producing organism, Auxarthron umbrinum. Several 4-halo-pyrrole-2-carboxylic acids were incorporated into the metabolite yielding three new derivatives: 3-fluoro-, 3-chloro- and 3-bromo-isorumbrin, which were generated in milligram quantities enabling cytotoxicity assays to be conducted. The 3-chloro- and 3-bromo-isorumbrins had improved activity against HeLa cells compared with rumbrin; 3-bromoisorumbrin also showed dramatically improved activity towards a lung cancer cell line (A549).

• Authors: Benjamin R Clark, Stephen O'Connor, Deirdre Fox, Jacques Leroy, Cormac D Murphy
• Journal: Organic & biomolecular chemistry (Org Biomol Chem) Vol. 9 Issue 18 Pg. 6306-11 (Sep 21 2011) ISSN: 1477-0539 [Electronic] England
• PMID: 21792395 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Polyenes
• Pyrones
• Pyrroles
• rumbrin
• 2-pyrrolecarboxylic acid
• Proline

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Fungi (chemistry)
• HeLa Cells
• Humans
• Inhibitory Concentration 50
• Neoplasms (drug therapy)
• Polyenes (chemistry, pharmacology)
• Proline (analogs & derivatives, chemistry, pharmacology)
• Pyrones (chemistry, pharmacology)
• Pyrroles (chemistry, pharmacology)