Anti-Inflammatory Activity of the Major Triterpenic Acids of Chios Mastic Gum and Their Semi-Synthetic Analogues

24<i>Z</i>-Masticadienonic acid (MNA) and 24<i>Z</i>-isomasticadienonic acid (IMNA) are the major triterpenic acids in Chios Mastic Gum (CMG), a resin derived from <i>Pistacia lentiscus</i> var. <i>Chia</i>. Despite their promising pharmacological potential, limited information is available due to the complexity of isolating them in pure form. This study developed a chemo-selective method for isolating MNA and IMNA and investigated their chemical transformation through isomerization of the external double bond and A-ring contraction of the triterpene scaffold. A rapid method for isolating MNA from CMG was first established, followed by a high-yield acid-catalyzed procedure to obtain both 24<i>Z</i> and 24<i>E</i> isomers of IMNA. Additionally, a basic catalyzed isomerization of IMNA led to the formation of two new compounds with A-ring contraction, which could serve as novel scaffolds for the design of new triterpene analogs. The mixture of MNA/IMNA, along with the individual compounds and their semi-synthetic analogs, exhibited significant anti-inflammatory activity. Notably, 24<i>E</i>-isomasticadienonic acid and 24<i>Z</i>-2-hydroxy-3-oxotirucalla-1,8,24-trien-26-oic acid, a previously unreported compound, significantly reduced the mRNA expression levels of <i>Tnf</i>, <i>Il6</i>, and <i>Nfkb1</i> in RAW 264.7 macrophage cells.