Isolation, Structure Elucidation, and Antitumor Activity of Spirohexenolides A and B

摘要

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 1Dand 2DNMR 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 GI50 values spanning from 0.1 to 17 μM across the NCI 60 cell line panel. Anincreased activitywas observed in leukemia (GI50 value of 254 nMinRPMI-8226 cells), lung cancer (GI50 value of 191nMinHOP-92 cells), and colon cancer (GI50 value of 565 nMinSW-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.