Dl. Boger et al., Total syntheses of thiocoraline and BE-22179 and assessment of their DNA binding and biological properties, J AM CHEM S, 123(4), 2001, pp. 561-568
Full derails of the total: syntheses of thiocoraline (1) and BE-22179 (2),
C-2 symmetric bicyclic octadepsipeptides: possessing two pendant 3-hydroxyq
uinoline chromophores, are described in which their relative and absolute s
tereochemistry were established. Key elements:of the approach include the l
ate-stage introduction of the chromophore, symmetrical; tetrapeptide coupli
ng, 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 c
onditions. By virtue of the late-stage introduction of the chromophore and
despite the challenges this imposes on the synthesis, this approach provide
s ready access to a range of key chromophore analogues. Thiocoraline and BE
-22179 were shown to bind to DNA by high-affinity bisintercalation analogou
s to echinomycin, but with little or no perceptible sequence selectivity. B
oth 1 and 2 were found to exhibit exceptional cytotoxic activity (IC50 = 20
0 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.