Antibacterial and Cytotoxic Phenyltetracenoid Polyketides from Streptomyces morookaense .

Formicapyridine-type racemates, streptovertidines A ( 1 ) and B ( 2 ), a 7,24- seco -fasamycin, streptovertidione ( 3 ), and the fasamycin-type streptovertimycins I-T ( 4 - 15 ), together with 13 known fasamycin congeners ( 16 - 28 ), were isolated from soil-derived Streptomyces morookaense SC1169. Their structures were elucidated by extensive spectroscopic analysis and theoretical computations of ECD spectra. The fasamycin-type compounds 5 , 8 - 12 , 14 , and 15 exhibited activity against the drug-resistant bacteria MRSA and VRE (MIC: 1.25-10.0 μg/mL). All isolates, except 3 , 4 , 10 , and 24 , displayed cytotoxicity against at least one of the human carcinoma A549, HeLa, HepG2, and MCF-7 cells (IC ₅₀ < 10.0 μM), of which some were also cytotoxic to the noncancerous Vero cells. Taken together, the activity data demonstrated that the fasamycin-type compounds were more selective to the tested bacteria over the mammalian cells. Structure-activity relationship analysis suggested that chlorination at C-2 in antibacterial fasamycin-type compounds improves the activity and selectivity to the bacteria. Theoretical simulations of reaction paths and chemical reactions for conversion of 3 to 1 were carried out and supported that the pyridine ring formation in formicapyridines proceeds nonenzymatically via 1,5-dicarbonyl condensation with ammonia.