점액세균 Sorangium cellulosum이 생산하는 신규 spiroketal 화합물, Spirodienal D의 구조 및 생물활성

Abstract

Myxobacteria are a rich source of natural products with biological activity. In particular, strains belong to the genus Sorangium proved to be unusually rich in secondary metabolites. So far, about 100 different core structures and 500 variants have been characterized. The search for novel compounds strongly depends on the availability of novel strains.

During the last 3 years, we have isolated 96 strains of Sorangium cellulosum from soil samples collected at different areas in Korea. The strains were all used in our screening for secondary metabolites. We looked for biological effects as well as for new signals in the HPLC-diode array analysis of the culture extracts.

Previous studies in our lab have demonstrated that a newly isolated strain KM0141 produced three new antibiotics, each containing a spiroketal moiety.

In our search for additional antibiotics from the strain, a co-metabolite named Spirodienal D(1) was observed in very low yield.

Pooled wet cell mass and adsorbent Amberlite XAD-16 from several fermentations(about 350L) of S. cellulosum KM0141, were extracted with acetone. Spirodienal D(1) was isolated as colorless oil after extraction, solvent partitioning, and silica gel chromatography. The crude product was further purified by HPLC to give 3.9mg of 1.

The structure of 1 was elucidated by 2D-NMR and mass spectroscopy. The relative stereochemistry of the spiroketal ring was determined on the basis of 1H-1H coupling constants and NOE correlations.

Spirodienals A-D were evaluated for cytotoxic activity against several human cancer lines using doxorubicin as a reference by SRB method. All these compounds demonstrated potent cytotoxicities against human cancer cells, having IC50 values ranging from 0.053μM to 0.878 μM.

Interestingly, the cytotoxic activities of Spirodienals A-D against human colon cancer cells(HCT-15) were 2 to 7 times stronger than that of doxorubicin in terms of IC50.