Synthesis and antimicrobial activity of tetrodecamycin partial structures.
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 alpha-(gamma-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 microg mL(-1)), analogue 6 and 2-naphthoyl derivative 27 showed promising antibacterial activities with MICs of 4-16 microg mL(-1). Remarkably, the antibacterial activity of these compounds was paralleled by cytotoxicity (IC(50) 10-23 microM). The reactive exo-methylene moiety was shown to be crucial, but not sufficient by its own, for both the antibacterial and the cytotoxic activities.
Paintner
Franz F
FF
Department Pharmazie-Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, Haus C, D-81377 München, Germany. franz.paintner@cup.uni-muenchen.de
Allmendinger
Lars
L
Bauschke
Gerd
G
Berns
Caroline
C
Heisig
Peter
P
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D013293:Enterococcus faecalis / Q000187:drug effects; D005663:Furans / Q000138:chemical synthesis* / Q000494:pharmacology*; D006094:Gram-Positive Bacteria / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D008826:Microbial Sensitivity Tests; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D005663:Furans; C087129:tetrodecamycin