Triostin A Derived Cyclopeptide as Architectural Template for the Alignment of Four Recognition Units

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.

Solution-phase synthesis and biological evaluation of triostin A and its analogues

“…(300 mL) and dried with MgSO 4 , and the solvent was removed under reduced pressure. The residue was purified by silica gel (200 g) column chromatography eluted with n-hexane/AcOEt (10 : 0, 8 : 2, 7 : 3, 6 : 4) to afford the target compound 25 8.19 g (11.0 mmol, 76% yield in 2 steps) as a pale yellow amorphous solid: R f = 0.5 (n-hexane : AcOEt = 5 : 5); 1 N-Cbz-D-Ser[N-Boc-L-Ala-N-Me-L-Cys(Bam)-N-Me-D-Val]-OAll (26). To a solution of N-Cbz-D-Ser[N-Boc-N-Me-L-Cys(Bam)-N-Me-D-Val]-OAll 25 8.19 g (11.0 mmol) in AcOEt (20 mL) was added 4 M HCl in AcOEt 20 mL (80 mmol) at 0 °C.…”

“…[17][18][19] Furthermore, various analogues of the quinoxaline antibiotics have been prepared, varying the aromatic rings or the cyclic depsipeptide backbone. [19][20][21][22][23][24][25][26][27] For many years, we have been interested in developing drugs that target tumor microenvironments such as hypoxia. 11,28,29 Our recent finding that Ec extremely reduced protein expression of HIF-1α as will be shown later encouraged us to investigate the synthesis of TA and its new analogues, and to evaluate their efficacy in HIF-1 inhibition; we predict that the cyclic octadepsipeptide scaffold may be functional to recognize not only DNA but also some upstream signal molecules for HIF-1 expression.…”

Conjugates of Classical DNA/RNA Binder with Nucleobase: Chemical, Biochemical and Biomedical Applications

“…Des-N-tetramethyl triostine A derivatives (TAN-DEM) were functionalized by the introduction of four nucleobases, ATTA and TTTT to give derivative 11 [38] (Fig. 7).…”