Structures of quinoxaline antibiotics

Abstract

The crystal structures of three quinoxaline antibioticsechinomycin 2QN, triostin C and the C222~ form of triostin A -have been determined, and the structure of the P212121 form of triostin A has been re-refined against our previously reported data. The molecular conformations are compared with those deduced from NMR data and those reported for two complexes of triostin A with oligonucleotides. Although the depsipeptide ring conformations are basically similar, the effective twofold molecular symmetry is violated by the folding of one of the quinoxaline chromophores in echinomycin 2QN and by a rotation of one of the ester planes with the formation of an intramolecular hydrogen bond in triostin C. In the oligonucleotide complexes of triostin A the chirality of the disulfide bridge is inverted. The alanine NH groups are involved in intermolecular hydrogen bonds in all four structures, and (except in echinomycin 2QN) the stacking of the chromophores in the crystal emulates the intercalation involved in DNA complex formation. In echinomycin 2QN, the antibiotic molecules are hydrogen bonded to form a helix along the crystallographic 65 screw axes, with a channel of disordered solvent running through the middle of the helix. Crystal data: (1), echinomycin 2QN,

DNA recognition by quinoxaline antibiotics: use of base-modified DNA molecules to investigate determinants of sequence-specific binding of triostin A and TANDEM

“…The same conclusion applies for triostin A, which is structurally close to echinomycin and binds equally well to CpG sites. The biosynthetic bis-quinoline analogue of echinomycin called 2QN [35] behaves similarly (C. Bailly and M. J. Waring, unpublished work). Therefore there is no doubt that the 2-amino group of guanine constitutes a key structural element in the mechanism of DNA recognition by the quinoxaline family of antibiotics.…”

Biosynthetic Modularity Rules in the Bisintercalator Family of Antitumor Compounds

“…This depends just on the presence of d -Ser, l -Cys or d -DABA ( d -diaminobutyric acid) in the first amino acid position, respectively [21,24,25]. This will generate a cyclic depsipeptide (SW-163, triostin, echinomycin, sandramycin, luzopeptin, quinoxapeptin), thiodepsipeptide (thiocoraline, BE-22179, Scheme 3) or peptide (quinaldopeptin, Scheme 4) scaffold, accordingly [12,13].…”

Syntheses of Triostin A Antibiotic and Nucleobase‐Functionalized Analogs as New DNA Binders

“…Starting with Z--Ser(tBu)-OH (8) and Fmoc--Ser(tBu)-OH (9), [19][20][21] we prepared the trichloroethanol (Tce) esters and subsequently deprotected the side chains (Scheme 1). The Tce group increased the solubility of all the depsipeptides in organic solvents and enabled the isolation of the free amines by extraction with ethyl acetate.…”

“…[7] Our interest in triostin A is based on the unique characteristic of the depsipeptide scaffold to provide recognition units in a preorganized orientation. [8][9][10] Besides bisintercalation, the distance of 10.5 Å for the parallel-oriented recognition units generally allows for DNA recognition by hydrogen bonding with the nucleobases in the major or minor groove. The major groove -presenting the Hoogsteen base-pair site -should especially be a target for specific differentiation between the canonical nucleobase pairs.…”

“…This approach requires orthogonal protection of the amino groups of the triostin A scaffold and was used previously to synthesize triostin A backbone analogs, like TANDEM (des-N-tetramethyltriostin) and des-N-(tetramethyl)azatriostin. [8][9][10]18,19] The solution-phase peptide synthesis of triostin A is described. Furthermore, four triostin derivatives 2-5 were prepared containing nucleobases as recognition units in different combinations.…”