Synthesis and antimicrobial activity of tetrodecamycin partial structures Original Research Article

An efficient synthetic approach to the core structure 5 of the novel polyketide antibiotic tetrodecamycin (1) was developed. This approach features the acid-catalyzed cyclization of a tert-butyldimethylsilyl protected methyl α-(γ-hydroxyacyl) tetronate, leading to the novel tricyclic ring skeleton exhibited by 5, and an efficient strategy for the parallel introduction of the cis-diol and exo-methylene function. In addition to 5, diastereomer 26, analogue 6 and several derivatives (16, 27–29) were prepared and evaluated for their antibacterial activities against Staphylococcus aureus (including MRSA) and Enterococcus faecalis and for their cytotoxic activities against human leukemia cell lines (HL-60, Jurkat T-cells). While compound 5 did not inhibit the growth of the Gram-positive pathogens (MICs >128 μg mL−1), analogue 6 and 2-naphthoyl derivative 27 showed promising antibacterial activities with MICs of 4–16 μg mL−1. Remarkably, the antibacterial activity of these compounds was paralleled by cytotoxicity (IC50 10–23 μM). The reactive exo-methylene moiety was shown to be crucial, but not sufficient by its own, for both the antibacterial and the cytotoxic activities.