(−)-Sandramycin: Total Synthesis and Characterization of DNA Binding Properties

Citations Over TimeTop 16% of 1996 papers

Abstract

Full details of the total synthesis of the potent antitumor antibiotic (−)-sandramycin (1), a cyclic decadepsipeptide possessing a 2-fold axis of symmetry, is described and constitutes the first total synthesis of a member of the growing class of naturally occurring agents now including the luzopeptins and quinaldopeptin. Key strategic elements of the approach include the late stage introduction of the heteroaromatic chromophore thereby providing access to analogs possessing altered intercalation capabilities, symmetrical pentadepsipeptide coupling and 32-membered macrocyclization conducted at the single secondary amide site in superb conversion (90%), and a convergent assemblage of the precursor pentadepsipeptide in which the potentially labile ester linkage was introduced in the final key coupling reaction. This approach also provided the cyclic decadepsipeptides 24−26 lacking both chromophores and was extended to provide 32 lacking one of the two chromophores. The characterization of the DNA-binding properties of sandramycin vs 25 and 32 is detailed. The largest share of the binding is derived from the cyclic decadepsipeptide (ΔG° = −6.0 kcal/mol) and the incremental addition of each chromophore increases the binding approximately 3.2 and 1.0 kcal/mol, respectively. This is consistent with the representation of sandramycin and the luzopeptins as minor groove binding cyclic decadepsipeptides incrementally stabilized by mono and bisintercalation. Following the same trends, sandramycin and luzopeptin A were found to be nearly equivalent, exceptionally potent cytotoxic agents (6−0.02 nM), 500−1000× more potent than the cyclic decadepsipeptide 32 possessing a single chromophore, and ≥105× more potent than the cyclic decadepsipeptides 24 and 25 lacking both chromophores. DNase I footprinting studies revealed that sandramycin and luzopeptin A behave comparably and appear to bind best to regions containing alternating A and T residues. Binding at other and perhaps all sites is observed at modest agent concentrations with a perceptible preference for 5‘-AT dinucleotide sequences many of which were preceded by a 5‘-C, i.e. 5‘-CAT. Preliminary studies of the 1:1 complex of sandramycin with 5‘-d(GCATGC)2 revealed that it maintains the 2-fold axis of symmetry of the components with the agent sandwiching the central two AT base pairs and adopting a compact conformation in which the interchromophore distance is 10.1 Å. The cyclic decadepsipeptide is positioned in the minor groove and the adopted conformation permits a rich array of complementary hydrophobic contacts extending over much of the interacting surface.

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