Inhibition of DNA-Topoisomerase I by Acylated Triterpene Saponins from Pittosporum angustifolium Lodd.

Christian Bäcker,Robert Preissner,Malgorzata N Drwal,Ulrike Lindequist

doi:10.1007/s13659-016-0087-5

Abstract

Previous phytochemical investigation of the leaves and seeds of Pittosporum angustifolium Lodd. led to the isolation and structural elucidation of polyphenols and triterpene saponins. Evaluation for cytotoxicity of isolated saponins revealed that the predominant structural feature for a cytotoxic activity are acyl substituents at the oleanane aglycon backbone. The present work reports the results of a screening of 10 selected acylated saponins for their potential to inhibit the human DNA-topoisomerase I, giving rise to IC50 values in a range of 2.8–46.5 µM. To clarify the mode of observed cytotoxic action and, moreover, to distinguish from a pure surfactant effect which is commonly accompanied with saponins, these results indicate an involvement of the topoisomerase I and its role as a possible target structure for a cytotoxic activity. In addition, computational predictions of the fitting of saponins to the topoisomerase I–DNA complex, indicate a similar binding mode to that of clinically used topoisomerase I inhibitors.Graphical Ten acylated triterpene saponins from Pittosporum angustifolium were investigated for their potential to inhibit the human DNA-topoisomerase I and computational predictions of the fitting of saponins to the topoisomerase I–DNA complex were carried out.

Highlights

Pittosporum angustifolium Lodd. (Pittosporaceae) is a small tree distributed in almost all inland areas of Australia
We have extensively investigated the phytochemistry of the seeds and leafs of P. angustifolium, resulting in the isolation and structural elucidation of five known polyphenols and 33 mono- and bisdesmosidic triterpene saponins, of which 29 were reported for the first time, possessing oleanane, rare 17,22-secooleanolic acid and taraxastane aglycones [3,4,5,6,7]
Encouraged by these outcomes, we report the results of an investigation of 10 acylated triterpene saponins (Table 1) isolated from P. angustifolium (1-10) [3, 5, 6] and partially from other Pittosporum species before (4, 8, 9) [21, 22] for their potential to inhibit the human topoisomerase I via gel based relaxation assay

Summary

Graphical Abstract

Ten acylated triterpene saponins from Pittosporum angustifolium were investigated for their potential to inhibit the human DNA-topoisomerase I and computational predictions of the fitting of saponins to the topoisomerase I– DNA complex were carried out. Preissner Structural Bioinformatics Group, Institute for Physiology, Charite – University Medicine Berlin, Lindenberger Weg 80, 13125 Berlin, Germany

Introduction

Results and Discussion

Experimental Section