Quinoxapeptin B

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.

Full details of the total syntheses of luzopeptin A-C and quinoxapeptin A-C, C₂-sym. cyclic depsidecapeptides bearing two pendant heterocyclic chromophores, are disclosed and serve to establish the quinoxapeptin relative and absolute configuration.Key elements of the approach include the late-stage introduction of the chromophore and penultimate L-Htp acylation permitting the divergent synthesis of the luzopeptins, quinoxapeptins, and structural analogs from a common advanced intermediate.Sym. pentadepsipeptide coupling and macrocyclization of the 32-membered ring conducted at the single secondary amide site provided the common cyclic decadepsipeptide.The convergent preparation of the required pentadepsipeptide with installation of the labile ester in the final coupling was achieved under surprisingly effective racemization-free conditions.The quinoxapeptins were shown to bind to DNA by high-affinity bis-intercalation analogous to sandramycin and the luzopeptins.Significant similarities in the DNA binding of sandramycin and luzopeptin A were observed, and these compounds proved distinguishable from the quinoxapeptins, indicating that the structural alterations in the chromophore impact the affinity and selectivity more than the changes in the decadepsipeptide.The luzopeptins proved to be more potent cytotoxic agents than the corresponding quinoxapeptin, but the quinoxapeptins proved to be more potent inhibitors of HIV-1 reverse transcriptase.In addition, a well-defined potency order was observed in the cytotoxic assays (A > B > C) in which the distinctions were extraordinarily large, with the removal of each L-Htp acyl substituent resulting in a 100-1000-fold reduction in potency.An equally well-defined but reverse potency order was observed in HIV-1 reverse transcriptase inhibition (C > B > A).Thus, the non-naturally occurring synthetic precursor quinoxapeptin C was found to exhibit the most potent HIV-1 reverse transcriptase inhibition in the series and to lack a dose-limiting in vitro cytotoxic activity, making it the most attractive member of the series examined