Synthesis and cytotoxic evaluation of malachite green derived oleanolic and ursolic acid piperazineamides

Sander Friedrich,Sophie Hoenke,Ratna Kancana Wolfram,Immo Serbian,René Csuk

doi:10.1007/s00044-020-02536-1

Sander Friedrich, Sophie Hoenke + Show 3 more

Open Access

https://doi.org/10.1007/s00044-020-02536-1

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Abstract

The coupling of acetylated piperazinylamide spacered triterpenoic oleanolic acid and ursolic acid with meta or para substituted carboxylated malachite green analogs gave conjugates 10, 11, 15, and 16 that were cytotoxic for several human tumor cell lines. Especially, an oleanolic acid-derived compound 10 was cytotoxic for MCF-7 human breast carcinoma cells (EC50 = 0.7 μM). These derivatives represent first examples of triterpenoic acid derivatives holding a cationic scaffold derived from malachite green.

Highlights

Chemotherapeutic treatment of cancer represents still a scientific challenge
In extension of these findings and due to the close structural similarity between malachite green (A) and rhodamine B (B, Fig. 1) we became interested in the synthesis and biological evaluation of conjugates holding a cationic triphenylmethane moiety especially of scaffolds of the “malachite green type”, i.e., 1 and 2; these scaffolds differ from malachite green by the presence of an additional carboxyl group; the latter is necessary for the attachment to the triterpene-spacer adduct
Coupling of acetylated triterpenoic oleanolic acid and ursolic acid holding a piperazinylamide spacer with meta or para substituted carboxylated malachite green analogs gave conjugates [10, 11, 15], and 16, respectively. These compounds were cytotoxic for several human tumor cell lines

Summary

Introduction

Chemotherapeutic treatment of cancer represents still a scientific challenge. nowadays many patients suffering from cancer can be cured or—at least—their life span can be increased. Several molecules holding a cationic residue are cytotoxic and seem to target the mitochondria, such as ammonium (Biedermann et al 2010; Kataev et al 2014) or phosphonium salts (Spivak et al 2013, 2017) of more complex molecules These compounds are mitocans (“mitochondrially targeted anticancer drugs”). While “simple” quaternary ammonium salts (Biedermann et al 2010; Kataev, Strobykina, and Zakharova 2014) were only of moderate cytotoxicity with their EC50 values being in the same potency range as phosphonium salts (Spivak et al 2017, 2013), hybrids consisting of a suitable pentacyclic triterpene, an amine spacer and a BODIPY-FL group (Brandes et al 2020; Krajcovicova et al 2018) held lower EC50 values against a variety of different human cancer cell lines. EC50 values in the low micromolar (Kahnt et al 2018; Wolfram et al 2018a, 2018b) and even nano-molar range (Sommerwerk et al 2017) were reported for these conjugates

Results and discussion

Conclusion

Compliance with ethical standards