Ursolic Acid and Its Derivatives as Bioactive Agents

Abstract

Non-communicable diseases (NCDs) such as cancer, diabetes, and chronic respiratory and cardiovascular diseases continue to be threatening and deadly to human kind. Resistance to and side effects of known drugs for treatment further increase the threat, while at the same time leaving scientists to search for alternative sources from nature, especially from plants. Pentacyclic triterpenoids (PT) from medicinal plants have been identified as one class of secondary metabolites that could play a critical role in the treatment and management of several NCDs. One of such PT is ursolic acid (UA, 3 β-hydroxy-urs-12-en-28-oic acid), which possesses important biological effects, including anti-inflammatory, anticancer, antidiabetic, antioxidant and antibacterial effects, but its bioavailability and solubility limits its clinical application. Mimusops caffra, Ilex paraguarieni, and Glechoma hederacea, have been reported as major sources of UA. The chemistry of UA has been studied extensively based on the literature, with modifications mostly having been made at positions C-3 (hydroxyl), C12-C13 (double bonds) and C-28 (carboxylic acid), leading to several UA derivatives (esters, amides, oxadiazole quinolone, etc.) with enhanced potency, bioavailability and water solubility. This article comprehensively reviews the information that has become available over the last decade with respect to the sources, chemistry, biological potency and clinical trials of UA and its derivatives as potential therapeutic agents, with a focus on addressing NCDs.

Keywords: biological studies; clinical trials.; derivatives; non-communicable diseases; pentacyclic triterpenoids; sources; ursolic acid.

Figure 1

Ursolic acid chemical structure.

Figure 2

Preparation of UA ester derivatives. Reagents and conditions: (a) CH₃(CH₂)_nBr, potassium carbonate (K₂CO₃), dimethylformamide ((CH₃)₂NCH); (b) Br(CH₂)_nBr, K₂CO₃, (CH₃)₂NCH; (c) Acetonitrile CH₃CN/silver nitrate (AgNO₃), COO(CH₂)_nBr. 2: R₁ = CH₂CH₃; 3: R₁ = (CH₂)₂CH₃; 4: R₁ = (CH₂)₃CH₃; 5: R₂ = (CH₂)₂ONO₂; 6: R₂ = (CH₂)₃ONO₂; 7: R₂ = (CH₂)₄ONO₂.

Figure 3

Modification of UA yielded amides and ester derivatives. Reagents and conditions: (d) anhydride/Pyridine/N, N-dimethyl-4-aminopyridine (DMAP); (e) CH₃(CH₂)_nBr, K₂CO₃, (CH₃)₂NCH; (f) rhodium carbonyl chloride ((CO)₂Cl), dichloromethane (CH₂Cl₂); (g) CH₂Cl₂, triethylamine (Et₃N), HR; (h) NaOH, methanol (CH₃OH)/tetrahydrofuran (THF). All the reactions were carried out at room temperature.

Figure 4

Some of UA derivatives. 1, 25–27; 1: R₁ = H; R₂ = H; R₃ = OH; 25: R₁ = OCCH₃; R₂ = H; R₃=OH; 26: R₁ = OCCH₃; R₂ = O; R₃ = NHC₆H₅; 27: R₁ = OCH₂CH₂CH₃; R₂ = H; R₃ = NHCH₂CO₂CH₃.

Figure 5

UA analogues. 28–29; 28: R = COH; 29: R = COCH₃.

Figure 6

Derivatives synthesized from UA.

Figure 7

Synthesized UA derivatives. 42–46; 42: R₁ = COCH₃; R₂=OH; 43: R₁ = COCH₂CH₃; R₂ = OH; 44: R₁ = COCH₂CH₂CH₃; R₂ = OH; 5: R₁ = H; R₂ = OCH₃; 46: R₁ = H; R₂ = NHCH₂CH₂CH₃.

Figure 8

Synthesis of UA derivatives; reagents and conditions: (a) acid chloride or anhydride, DMAP, pyridine, reflux; (b) chromium (III) oxide (CrO₃), sulphuric acid (H₂SO₄), acetone, 0 °C, 1 h; (c) R1-CHO, potassium hydroxide (KOH), ethanol, room temperature.

Figure 9

Some reported UA analogues.

Figure 9

Some reported UA analogues.

Figure 10

Summary of reaction scheme to yield UA analogues (78–106). Reagents and conditions: (a) Jones reagent, acetone at 0 °C for 5 h; (b) ethanol, substituted oaminobenzaldehyde, potassium hydroxide (KOH), reflux under N₂ atmospheric conditions for 24 h; (c) Thionyl chloride (SOCl₂), benzene, reflux for 3 h; RCONHNH₂, trimethylamine (Et₃N), dichloromethane (CH₂Cl₂)/ether at room temperature for 8–12 h; (d) p-Toluenesulfonic acid (TsOH), toluene, reflux for 6 h.

Figure 11

Some derivatives prepared by modification of UA with interesting potential as therapeutic agents.

Figure 11

Some derivatives prepared by modification of UA with interesting potential as therapeutic agents.