Synthesis of oxygenated oleanolic and ursolic acid derivatives with anti-inflammatory properties

Abstract

The scalable syntheses of four oxygenated triterpenes have been implemented to access substantial quantities of maslinic acid, 3-epi-maslinic acid, corosolic acid, and 3-epi-corosolic acid. Semi-syntheses proceed starting from the natural products oleanolic acid and ursolic acid. Proceeding over five steps, each of the four compounds can be synthesized on the gram scale. Divergent diastereoselective reductions of α-hydroxy ketones provided access to the four targeted diol containing compounds from two precursors of the oleanane or ursane lineage. These compounds were subsequently evaluated for their ability to inhibit inflammatory gene expression in a mouse model of chemically induced skin inflammation. All compounds possessed the ability to inhibit the expression of one or more inflammatory genes induced by 12-O-tetradecanoylphorbol-13 acetate in mouse skin, however, three of the compounds, corosolic acid, 3-epi-corosolic acid and maslinic acid were more effective than the others. The availability of gram quantities will allow further testing of these compounds for potential anti-inflammatory activities as well as cancer chemopreventive activity.

Keywords: 3-epi-Corosolic acid; 3-epi-Maslinic acid; Cancer; Chemoprevention; Corosolic acid; Maslinic acid; Mouse; Natural product; Skin inflammation; Synthesis; Triterpene.

Figure 1

Structures of oleanane and ursane carbocyclic cores and oleanolic acid, and ursolic acid.

Figure 2

Structures of maslinic, 3-epi-maslinic, corosolic, and 3-epi-corosolic acids.

Figure 3

Syntheses of maslinic acid and 3-epi-maslinic acid proceeding from oleanolic acid.

Figure 4

Synthesis of corosolic acid and 3-epi-corosolic acid proceeding from ursolic acid.

Figure 5

Effect of triterpenes found in P. frutescens in TPA-induced inflammatory gene expression in mouse skin. Quantitative mRNA expression (assessed by qRT-PCR) of IL-1α, IL-1β, IL-6, and IL-23 was normalized to GADPH and to the value in acetone treated mice which was set to a value of 1. The graphs represent means ±SEM. For statistical analysis, the Mann-Whitney U test was used. *, significantly greater (p ≤ 0.05) than acetone-treated group; **, significantly lower (p ≤ 0.05) than TPA-treated group; ^#, significantly lower (p ≤ 0.05) than UA + TPA group; and ^‡, significantly greater (p ≤ 0.05) than UA + TPA group. T; TPA, UA; ursolic acid, OA; oleanolic acid, CA; corosolic acid, 3-epi-CA; 3-epi-corosolic acid, MA; maslinic acid, and 3-epi-MA; 3-epi-maslinic acid.