Ursolic Acid-Based Derivatives as Potential Anti-Cancer Agents: An Update

Abstract

Ursolic acid is a pharmacologically active pentacyclic triterpenoid derived from medicinal plants, fruit, and vegetables. The pharmacological activities of ursolic acid have been extensively studied over the past few years and various reports have revealed that ursolic acid has multiple biological activities, which include anti-inflammatory, antioxidant, anti-cancer, etc. In terms of cancer treatment, ursolic acid interacts with a number of molecular targets that play an essential role in many cell signaling pathways. It suppresses transformation, inhibits proliferation, and induces apoptosis of tumor cells. Although ursolic acid has many benefits, its therapeutic applications in clinical medicine are limited by its poor bioavailability and absorption. To overcome such disadvantages, researchers around the globe have designed and developed synthetic ursolic acid derivatives with enhanced therapeutic effects by structurally modifying the parent skeleton of ursolic acid. These structurally modified compounds display enhanced therapeutic effects when compared to ursolic acid. This present review summarizes various synthesized derivatives of ursolic acid with anti-cancer activity which were reported from 2015 to date.

Keywords: anti-cancer activity; derivatives/analogs; structural modification; ursolic acid.

Figure 1

Multiple molecular targets modulated by UA.

Figure 2

Structure of UA indicating the major active sites.

Scheme 1

Reagents and conditions: (a) Ac₂O, DMAP, THF, rt; (b) (COCI)₂, CH₂Cl₂. Rt; (c) HOCH₂ COOH, TEA, rt; (d) N-methylpiperazine, EDCI, DMAP, CH₂Cl₂, 0 °C to rt; (e) Benzylpiperazine, EDCI, DMAP, CH₂Cl₂, 0 °C to rt; (f) 10% Pd/C, H₂ anhydrous ethanol, rt.

Scheme 2

Reagents and conditions: (a) N-Boc-Diamine, EDCl, DMAP, CH₂Cl₂, 0 °C to rt; (b) TFA, CH₂Cl₂, 0 °C to rt.

Scheme 3

Synthetic route for compounds 10–13. Reagents and conditions: (a) NH₂NHCOOCH₃, CH(OC₂H₅)₃; Ethanol(EtOH), MeONa, reflux, 48 h; (b) Br(CH₂)nBr; Potassium carbonate (K₂CO₃), KI; (c) K₂CO₃, KI; (CH₃)₂CO, reflux, 10 h.

Figure 3

Fontana and Xu ‘s UA derivatives.

Scheme 4

Synthesis of compounds 33–35. Reagents and conditions: (a) Jones reagent acetone, 0 °C, 5 h, 90%; (b) Aldehydes, 5% NaOH, absolute EtOH, r.t 2 h, 30–75%; (c) 37% HCl, absolute EtOH, reflux, 8 h, 34–65%.

Scheme 5

Synthesis of compounds 36–38. Reagents and conditions: (a) Jones reagent acetone, 0 °C, 5 h; (b) EtOH, substituted o-amino benzaldehyde, KOH, reflux under N₂ atmosphere for 24 h.

Scheme 6

Reagents and conditions: (a) Selectfluor®, dioxane, nitromethane, 80 °C, 24 h; (b) Jones reagent, acetone, ice; (c) m-CPBA 77%, CHCl₃, r.t., 120 h; (d) p-toluenesulfonic acid monohydrate, CH₂Cl₂, r.t., 24 h; (e) R₂NH₂, dry THF, Et₃N, T3P (50 wt% in THF), ice.

Scheme 7

Reagents and conditions: (a) CuBr₂, EtOAc, MeOH, r.t., 3 h; (b) KSCN, DMSO, 90 °C, 24 h.

Scheme 8

Synthesis of UA hybrid compounds.

Figure 4

Gu’s, S. Zhang’s, Jin’s and T. Zhang’s work on UA derivatives.