|Figure 1:||Triostin A (R=CH3)|
Triostin A is a natural bisintercalator belonging to the quinoxaline antibiotics. The molecule is originally isolated from Streptomyces S-2-210 and shows antitumoral properties.
It is a bicyclic octadepsipeptide composed of the amino acids alanine, d-serine, N-methyl-valine and N-methyl-cysteine which are arranged in a highly symmetrical manner. Furthermore, the intramolecular cystine bridge increases the structural rigidity. The heteroaromatic quinoxaline moieties attached to d-serine enable the molecule to intercalate into duplex DNA. The formed complex is additionally stabilized by placing its peptide backbone into the DNA minor groove GC specifically in the case of Triostin A. The intercalation induces a conformational change and therefore inhibits the DNA transcription by blocking specific enzymes.
TANDEM (Des-N-tetramethyltriostin A) is a synthetic analog and lacks Nα-methylation in the depsipetidic backbone in contrast to Triostin A. This fact causes AT-selectivity of the molecule due to the changed hydrogen bonding pattern.
|Figure 2:||Triostin A in complex with the DNA hexamer [d(GACGTC)]|
We are interested in controlling the molecular intercalation process. Therefore appropriate photoswitchable groups are introduced to create different Triostin A analogs to investigate the structural features of DNA binding abilities.
 J.P. Malkinson, M.K. Anim, M. Zloh, M. Searcey, J. Org. Chem. 2005, 70, 7654-7661.
 C. Bailly, M.J. Waring, Biochem. J. 1998, 330, 81-87.
 K.J. Addess, J.S. Sinsheimer, J. Feigon, Biochemistry 1993, 32, 2498-2508.
This project is supported by the DFG (SFB 613).
A. Zobel, K. Gaus, K. Wollschläger, J. Juodaityte, N. Sewald, "Photoswitchable Bisintercalators - Synthesis of Triostin A Analogs", 30th European Peptide Symposium, Helsinki (31.08.-05.09.08) and 9th German Peptide Symposium, Göttingen (11.-14.03.09).
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