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Triostin a derived cyclopeptide as architectural template for the alignment of four recognition units.

Kotyrba UM, Pröpper K, Sachs EF, Myanovska A, Joppe T, Lissy F, Sheldrick GM, Koszinowski K, Diederichsen U - ChemistryOpen (2014)

Bottom Line: The DNA bisintercalator triostin A is structurally based on a disulfide-bridged depsipeptide scaffold that provides preorganization of two quinoxaline units in 10.5 Å distance.Triostin A analogues are synthesized with nucleobase recognition units replacing the quinoxalines and containing two additional recognition units in between.The new tetra-nucleobase binders are synthesized as aza-TANDEM derivatives lacking the N-methylation of triostin A and based on a cyclopeptide backbone.

View Article: PubMed Central - PubMed

Affiliation: Institute of Organic and Biomolecular Chemistry, Georg-August-University Göttingen Tammannstrasse 2, 37077 Göttingen (Germany) E-mail: udieder@gwdg.de.

ABSTRACT
The DNA bisintercalator triostin A is structurally based on a disulfide-bridged depsipeptide scaffold that provides preorganization of two quinoxaline units in 10.5 Å distance. Triostin A analogues are synthesized with nucleobase recognition units replacing the quinoxalines and containing two additional recognition units in between. Thus, four nucleobase recognition units are organized on a rigid template, well suited for DNA double strand interactions. The new tetra-nucleobase binders are synthesized as aza-TANDEM derivatives lacking the N-methylation of triostin A and based on a cyclopeptide backbone. Synthesis of two tetra-nucleobase aza-TANDEM derivatives is established, DNA interaction analyzed by microscale thermophoresis, cytotoxic activity studied and a nucleobase sequence dependent self-aggregation investigated by mass spectrometry.

No MeSH data available.


Related in: MedlinePlus

UV melting curves of 1 (ATTA, —) and 2 (TTTT, —).
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fig05: UV melting curves of 1 (ATTA, —) and 2 (TTTT, —).

Mentions: Based on the rigid and well-defined topology offered by the aza-TANDEM backbone, the four nucleobases seem well oriented and preorganized for interaction with a complementary strand. Thus, four base pairs should be sufficient to provide high duplex or aggregate stabilities. Nevertheless, aza-TANDEM derivative 1 (ATTA) lacks a proper self-pairing sequence complementarity, and consequently, no indication for aggregation was indicated by thermal UV denaturation studies (Figure 5). In contrast, the temperature-dependent UV spectrum for aza-TANDEM derivative 2 (TTTT) clearly implies base pair recognition and self-aggregation with a stability higher than 60 °C. This sequence-dependent self-aggregation fits nicely to the hypothesis of a linear alignment of thymine nucleobases on an organizing and templating aza-TANDEM backbone.


Triostin a derived cyclopeptide as architectural template for the alignment of four recognition units.

Kotyrba UM, Pröpper K, Sachs EF, Myanovska A, Joppe T, Lissy F, Sheldrick GM, Koszinowski K, Diederichsen U - ChemistryOpen (2014)

UV melting curves of 1 (ATTA, —) and 2 (TTTT, —).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4232271&req=5

fig05: UV melting curves of 1 (ATTA, —) and 2 (TTTT, —).
Mentions: Based on the rigid and well-defined topology offered by the aza-TANDEM backbone, the four nucleobases seem well oriented and preorganized for interaction with a complementary strand. Thus, four base pairs should be sufficient to provide high duplex or aggregate stabilities. Nevertheless, aza-TANDEM derivative 1 (ATTA) lacks a proper self-pairing sequence complementarity, and consequently, no indication for aggregation was indicated by thermal UV denaturation studies (Figure 5). In contrast, the temperature-dependent UV spectrum for aza-TANDEM derivative 2 (TTTT) clearly implies base pair recognition and self-aggregation with a stability higher than 60 °C. This sequence-dependent self-aggregation fits nicely to the hypothesis of a linear alignment of thymine nucleobases on an organizing and templating aza-TANDEM backbone.

Bottom Line: The DNA bisintercalator triostin A is structurally based on a disulfide-bridged depsipeptide scaffold that provides preorganization of two quinoxaline units in 10.5 Å distance.Triostin A analogues are synthesized with nucleobase recognition units replacing the quinoxalines and containing two additional recognition units in between.The new tetra-nucleobase binders are synthesized as aza-TANDEM derivatives lacking the N-methylation of triostin A and based on a cyclopeptide backbone.

View Article: PubMed Central - PubMed

Affiliation: Institute of Organic and Biomolecular Chemistry, Georg-August-University Göttingen Tammannstrasse 2, 37077 Göttingen (Germany) E-mail: udieder@gwdg.de.

ABSTRACT
The DNA bisintercalator triostin A is structurally based on a disulfide-bridged depsipeptide scaffold that provides preorganization of two quinoxaline units in 10.5 Å distance. Triostin A analogues are synthesized with nucleobase recognition units replacing the quinoxalines and containing two additional recognition units in between. Thus, four nucleobase recognition units are organized on a rigid template, well suited for DNA double strand interactions. The new tetra-nucleobase binders are synthesized as aza-TANDEM derivatives lacking the N-methylation of triostin A and based on a cyclopeptide backbone. Synthesis of two tetra-nucleobase aza-TANDEM derivatives is established, DNA interaction analyzed by microscale thermophoresis, cytotoxic activity studied and a nucleobase sequence dependent self-aggregation investigated by mass spectrometry.

No MeSH data available.


Related in: MedlinePlus