Solid phase synthesis of anthraquinone peptides and their evaluation as topoisomerase I inhibitors

Abstract

Anthraquinone peptide derivatives have previously been shown to inhibit the enzyme topoisomerase I (topo I), a pharmaceutical target for the prevention of malignant carcinomas. A highly efficient procedure for the attachment of the anthraquinone moiety to the N-terminus of a peptide on a solid support is reported. This methodology provides a convenient method for the synthesis of labelled peptides, with potential applications for chemotherapy, DNA detection and protein purification. As the synthetic strategy utilizes the solid phase, it should also be amenable to the generation of combinatorial libraries. The utility of the method by synthesizing a pool of peptides and assaying for topo I inhibition is demonstrated.

Solid Phase Synthesis and Biological Activity of Tuftsin Conjugates

“…Previous studies showed that peptide−anthraquinone analogues inhibit the catalytic activity of DNA topoisomerase I and stabilize the so-called “cleavable complexes” between DNA and the enzyme . Therefore, we determined if drug−tuftsin conjugates exert a similar effect on the activity of purified types I and II DNA topoisomerases.…”

“…The condensation between leuco-1,4-dihydroxy-9,10-anthraquinone ( 1 ) and the N-termini of the peptide−resin ( 2 ) was achieved during reaction in N , N- dimethylformamide (DMF) at 120 °C under N 2 for 24 h. A 3-fold excess of leucoanthraquinone was used in the reaction. Then peptidyl-anthraquinone-resin was oxidized by air oxygen at room temperature. , To cleave the product from resin with simultaneous removal of all the side chain protecting groups, dried peptidyl-anthraquinone-resin was treated with a mixture of trifluoroacetic acid (TFA), triisopropylsilane (TIS), and water. The tuftsin conjugates were purified by solid-phase extraction (SPE) and preparative HPLC (Table ).…”

“…Previous studies showed that pepti-deÀanthraquinone analogues inhibit the catalytic activity of DNA topoisomerase I and stabilize the so-called "cleavable complexes" between DNA and the enzyme. 21 Therefore, we determined if drugÀtuftsin conjugates exert a similar effect on the activity of purified types I and II DNA topoisomerases. Our results show that none of the studied compounds, both precursor derivatives and tuftsin conjugates, significantly influenced the DNA relaxation mediated by both type I and type II DNA topoisomerases (Figure 1A, data not shown).…”

“…Then peptidyl-anthraquinone-resin was oxidized by air oxygen at room temperature. 21,22 To cleave the product from resin with simultaneous removal of all the side chain protecting groups, dried peptidyl-anthraquinoneresin was treated with a mixture of trifluoroacetic acid (TFA), triisopropylsilane (TIS), and water. The tuftsin conjugates were purified by solid-phase extraction (SPE) and preparative HPLC (Table 1).…”

Synthesis, Spectroscopy and in vitro Cytotoxicity of New Hydroxyanthraquinonato Triorganotin Compounds

“…[36] On the other hand, leucoquinizarin's peptides have been recently reported to afford topoisomerase I inhibition. [37] The chelation process of these hydroxyanthraquinones usually evolves via their tautomeric anthraquinoid structures. [38] The formation of a wide variety of metal complexes has been reported for quinizarin and anthrarufin, [39] while alizarin exhibiting linkage isomerism, acts as a chelate via the 1,2-or the 1,9-oxygen atoms and forms complexes with Ru, Cu, Ni, Hg, and a variety of transition metals.…”