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 (IC₅₀ < 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.