Total syntheses of thiocoraline and BE-22179 and assessment of their DNA binding and biological properties.
Full details of the total syntheses of thiocoraline (1) and BE-22179 (2), C(2) symmetric bicyclic octadepsipeptides possessing two pendant 3-hydroxyquinoline chromophores, are described in which their relative and absolute stereochemistry were established. Key elements of the approach include the late-stage introduction of the chromophore, symmetrical tetrapeptide coupling, macrocyclization of the 26-membered octadepsipeptide conducted at the single secondary amide site following disulfide formation, and a convergent assemblage of the tetradepsipeptide with introduction of the labile thiol ester linkage in the final coupling reaction under near racemization free conditions. By virtue of the late-stage introduction of the chromophore and despite the challenges this imposes on the synthesis, this approach provides ready access to a range of key chromophore analogues. Thiocoraline and BE-22179 were shown to bind to DNA by high-affinity bisintercalation analogous to echinomycin, but with little or no perceptible sequence selectivity. Both 1 and 2 were found to exhibit exceptional cytotoxic activity (IC(50) = 200 and 400 pM, respectively, L1210 cell line) comparable to echinomycin and one analogue, which bears the luzopeptin chromophore, was also found to be a potent cytotoxic agent.
Boger
D L
DL
Contribution from the Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Ichikawa
S
S
Tse
W C
WC
Hedrick
M P
MP
Jin
Q
Q
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism*; D047630:Depsipeptides; D004448:Echinomycin / Q000378:metabolism / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology; D020128:Inhibitory Concentration 50; D051379:Mice; D010455:Peptides; D018894:Reverse Transcriptase Inhibitors; D014407:Tumor Cells, Cultured
D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D010455:Peptides; D018894:Reverse Transcriptase Inhibitors; C109005:thiocoraline; C086645:BE 22179; D004448:Echinomycin; D004247:DNA; C427203:calf thymus DNA