Isolation, structure elucidation, and antitumor activity of spirohexenolides A and B.

Abstract

In this report, we describe the discovery of a pair of bioactive spirotetronates, spirohexenolides A (1) and B (2), that arose from the application of mutagenesis, clonal selection techniques, and media optimization to strains of Streptomyces platensis. The structures of spirohexenolides A (1) and B (2) were elucidated through X-ray crystallography and confirmed by 1D and 2D NMR studies. Under all examined culture conditions, spirohexenolide A (1) was the major metabolite with traces of spirohexenolide B (2) arising in cultures containing increased loads of adsorbent resins. Spirohexenolide A (1) inhibited tumor cell growth with GI(50) values spanning from 0.1 to 17 microM across the NCI 60 cell line panel. An increased activity was observed in leukemia (GI(50) value of 254 nM in RPMI-8226 cells), lung cancer (GI(50) value of 191 nM in HOP-92 cells), and colon cancer (GI(50) value of 565 nM in SW-620 cells) tumor cells. Metabolite 1 was fluorescent and could be examined on a confocal fluorescent microscope with conventional laser excitation and filter sets. Time lapse imaging studies indicated that spirohexenolide A (1) was readily taken up by tumor cells, appearing through the cell immediately after dosing and subcellularly localizing in the lysosomes. This activity, combined with a unique selectivity in NCI 60 cancer cell line screening, indicates that 1 warrants further chemotherapeutic evaluation.

• Authors: MinJin Kang, Brian D Jones, Alexander L Mandel, Justin C Hammons, Antonio G DiPasquale, Arnold L Rheingold, James J La Clair, Michael D Burkart
• Journal: The Journal of organic chemistry (J Org Chem) Vol. 74 Issue 23 Pg. 9054-61 (Dec 04 2009) ISSN: 1520-6904 [Electronic] United States
• PMID: 19883063 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Heterocyclic Compounds, 4 or More Rings
• spirohexenolide A
• spirohexenolide B

Topics

• Antineoplastic Agents (metabolism, pharmacokinetics, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Crystallography, X-Ray
• Drug Discovery
• Drug Screening Assays, Antitumor
• Heterocyclic Compounds, 4 or More Rings (metabolism, pharmacokinetics, therapeutic use)
• Humans
• Lysosomes (metabolism)
• Magnetic Resonance Spectroscopy
• Molecular Structure
• Mutagenesis
• Streptomyces (metabolism)