Oleanolic Acid Dimers with Potential Application in Medicine-Design, Synthesis, Physico-Chemical Characteristics, Cytotoxic and Antioxidant Activity

Abstract

The present work aimed to obtain a set of oleanolic acid derivatives with a high level of cytotoxic and antioxidant activities and a low level of toxicity by applying an economical method. Oleanolic acid was alkylated with α,ω-dihalogenoalkane/α,ω-dihalogenoalkene to obtain 14 derivatives of dimer structure. All of the newly obtained compounds were subjected to QSAR computational analysis to evaluate the probability of the occurrence of different types of pharmacological activities depending on the structure of the analysed compound. All dimers were tested for cytotoxicity activity and antioxidant potential. The cytotoxicity was tested on the SKBR-3, SKOV-3, PC-3, and U-87 cancer cell lines with the application of the MTT assay. The HDF cell line was applied to evaluate the tested compounds' Selectivity Index. The antioxidant test was performed with a DPPH assay. Almost all triterpene dimers showed a high level of cytotoxic activity towards selected cancer cell lines, with an IC₅₀ value below 10 µM. The synthesised derivatives of oleanolic acid exhibited varying degrees of antioxidant activity, surpassing that of the natural compound in several instances. Employing the DPPH assay, compounds 2a, 2b, and 2f emerged as promising candidates, demonstrating significantly higher Trolox equivalents and highlighting their potential for pharmaceutical and nutraceutical applications. Joining two oleanolic acid residues through their C-17 carboxyl group using α,ω-dihalogenoalkanes/α,ω-dihalogenoalkenes resulted in the synthesis of highly potent cytotoxic agents with favourable SIs and high levels of antioxidant activity.

Keywords: SAR; antioxidant activity; cytotoxic activity; oleanolic acid; oleanolic acid dimers; triterpene dimers; triterpenes.

Figure 1

One of the sources of oleanolic acid (1) and the structure of this compound.

Figure 2

Synthesis of OADs 2a–2n.

Figure 3

The ability of OADs 2a–2n and oleanolic acid (1, OA) to inhibit the DPPH radical, expressed as Trolox equivalent.

Figure 4

Standard curve for DPPH radical inhibition by Trolox.

Figure 5

The dependency between the melting point of OADs 2a–2n and the amount of carbon atoms in the linker joining two triterpene moieties. Legend: OA—oleanolic acid (reference compound); sat.—saturated linker; unsat.—unsaturated linker; init. m.p.—initial melting point; fin. m.p.—final melting point.