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Triostin A derived hybrid for simultaneous DNA binding and metal coordination.

Sachs EF, Nadler A, Diederichsen U - Amino Acids (2010)

Bottom Line: Replacing the intercalating quinoxaline moieties of triostin A by nucleobases results in a potential major groove binder.As ligand, two [1,4,7]triazacyclononane rings were bridged by a phenol.Formation of the proposed binuclear zinc complex was confirmed for the ligand and the triostin A analog/ligand construct by high-resolution mass spectrometry.

View Article: PubMed Central - PubMed

Affiliation: Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstr. 2, 37077, Göttingen, Germany.

ABSTRACT
The natural product triostin A is known as an antibiotic based on specific DNA recognition. Structurally, a bicyclic depsipeptide backbone provides a well-defined scaffold preorganizing the recognition motifs for bisintercalation. Replacing the intercalating quinoxaline moieties of triostin A by nucleobases results in a potential major groove binder. The functionalization of this DNA binding triostin A analog with a metal binding ligand system is reported, thereby generating a hybrid molecule with DNA binding and metal coordinating capability. Transition metal ions can be placed in close proximity to dsDNA by means of non-covalent interactions. The synthesis of the nucleobase-modified triostin A analog is described containing a propargylglycine for later attachment of the ligand by click-chemistry. As ligand, two [1,4,7]triazacyclononane rings were bridged by a phenol. Formation of the proposed binuclear zinc complex was confirmed for the ligand and the triostin A analog/ligand construct by high-resolution mass spectrometry. The complex as well as the respective hybrid led to stabilization of dsDNA, thus implying that metal complexation and DNA binding are independent processes.

Show MeSH
Structures of triostin A (1), TANDEM (2), aza-TANDEM (3), and hybrid of the nucleobase substituted aza-TANDEM 4 with a ligand capable of forming binuclear transition metal complexes
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Fig1: Structures of triostin A (1), TANDEM (2), aza-TANDEM (3), and hybrid of the nucleobase substituted aza-TANDEM 4 with a ligand capable of forming binuclear transition metal complexes

Mentions: DNA binding peptides have received considerable attention as promising drug candidates (Vázquez et al. 2003). Valuable lead structures in drug design are derived from peptidic natural products. Numerous methods exist for peptide modification with respect to sequence, backbone or side chains, also incorporating non-proteinogenic amino acids (Gante 1994). Next to actinomycin D as one of the most prominent examples of a DNA binding peptidic natural product used in anti-cancer therapy (Farber 1966; Lewis 1972), the quinoxaline antibiotics echinomycin, thiocoraline, and triostin A (1) are well established (Lee and Waring 1978; Waring and Wakelin 1974). Transcription and replication are efficiently blocked by these sequence-specific double strand DNA bisintercalators, thus possessing antibiotic and cytotoxic activity (Katagiri et al. 1975). The disulfide-bridged depsipeptide backbone of triostin A provides a rigid scaffold preorganizing two quinoxaline intercalators in a distance of 10.5 Å. Therefore, bisintercalation of dsDNA spanning a dinucleotide is entropically favored (Addess and Feigon 1994). In earlier studies, the peptide scaffolds of triostin A, des-N-tetramethyltriostin A (2, TANDEM) (Ciardelli and Olsen 1977), and the peptide analog aza-TANDEM (3) (Dietrich and Diederichsen 2005) were used as rigid templates for functional modification in order to generate a new class of DNA binders (Fig. 1). As part of our studies to change the DNA binding mode of triostin A and its derivatives from bisintercalation to specific major groove recognition, the rigid templating depsipeptide scaffold is used to organize nucleobases or other recognition moieties instead of the native quinoxaline moieties (Lorenz and Diederichsen 2004).Fig. 1


Triostin A derived hybrid for simultaneous DNA binding and metal coordination.

Sachs EF, Nadler A, Diederichsen U - Amino Acids (2010)

Structures of triostin A (1), TANDEM (2), aza-TANDEM (3), and hybrid of the nucleobase substituted aza-TANDEM 4 with a ligand capable of forming binuclear transition metal complexes
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3102191&req=5

Fig1: Structures of triostin A (1), TANDEM (2), aza-TANDEM (3), and hybrid of the nucleobase substituted aza-TANDEM 4 with a ligand capable of forming binuclear transition metal complexes
Mentions: DNA binding peptides have received considerable attention as promising drug candidates (Vázquez et al. 2003). Valuable lead structures in drug design are derived from peptidic natural products. Numerous methods exist for peptide modification with respect to sequence, backbone or side chains, also incorporating non-proteinogenic amino acids (Gante 1994). Next to actinomycin D as one of the most prominent examples of a DNA binding peptidic natural product used in anti-cancer therapy (Farber 1966; Lewis 1972), the quinoxaline antibiotics echinomycin, thiocoraline, and triostin A (1) are well established (Lee and Waring 1978; Waring and Wakelin 1974). Transcription and replication are efficiently blocked by these sequence-specific double strand DNA bisintercalators, thus possessing antibiotic and cytotoxic activity (Katagiri et al. 1975). The disulfide-bridged depsipeptide backbone of triostin A provides a rigid scaffold preorganizing two quinoxaline intercalators in a distance of 10.5 Å. Therefore, bisintercalation of dsDNA spanning a dinucleotide is entropically favored (Addess and Feigon 1994). In earlier studies, the peptide scaffolds of triostin A, des-N-tetramethyltriostin A (2, TANDEM) (Ciardelli and Olsen 1977), and the peptide analog aza-TANDEM (3) (Dietrich and Diederichsen 2005) were used as rigid templates for functional modification in order to generate a new class of DNA binders (Fig. 1). As part of our studies to change the DNA binding mode of triostin A and its derivatives from bisintercalation to specific major groove recognition, the rigid templating depsipeptide scaffold is used to organize nucleobases or other recognition moieties instead of the native quinoxaline moieties (Lorenz and Diederichsen 2004).Fig. 1

Bottom Line: Replacing the intercalating quinoxaline moieties of triostin A by nucleobases results in a potential major groove binder.As ligand, two [1,4,7]triazacyclononane rings were bridged by a phenol.Formation of the proposed binuclear zinc complex was confirmed for the ligand and the triostin A analog/ligand construct by high-resolution mass spectrometry.

View Article: PubMed Central - PubMed

Affiliation: Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstr. 2, 37077, Göttingen, Germany.

ABSTRACT
The natural product triostin A is known as an antibiotic based on specific DNA recognition. Structurally, a bicyclic depsipeptide backbone provides a well-defined scaffold preorganizing the recognition motifs for bisintercalation. Replacing the intercalating quinoxaline moieties of triostin A by nucleobases results in a potential major groove binder. The functionalization of this DNA binding triostin A analog with a metal binding ligand system is reported, thereby generating a hybrid molecule with DNA binding and metal coordinating capability. Transition metal ions can be placed in close proximity to dsDNA by means of non-covalent interactions. The synthesis of the nucleobase-modified triostin A analog is described containing a propargylglycine for later attachment of the ligand by click-chemistry. As ligand, two [1,4,7]triazacyclononane rings were bridged by a phenol. Formation of the proposed binuclear zinc complex was confirmed for the ligand and the triostin A analog/ligand construct by high-resolution mass spectrometry. The complex as well as the respective hybrid led to stabilization of dsDNA, thus implying that metal complexation and DNA binding are independent processes.

Show MeSH