Design and Synthesis of Structurally Modified Analogs of 24Z-Isomasticadienonic Acid with Enhanced Anti-Proliferative Activity.

Τriterpenic acids represent a prominent class of bioactive compounds, with a wide range of biological properties, including anti-inflammatory, antiviral, and anticancer effects. Among them, 24Z-isomasticadienonic acid (IMNA), a major constituent of Chios Mastic Gum, has attracted little attention compared with other well-studied triterpenes such as oleanolic or betulinic acid, largely because its isolation in sufficient purity and quantity was only recently achieved. In this study, a series of IMNA analogs was synthesized through targeted modifications at the A-ring. These included the introduction of heteroatoms at position 2, the incorporation of heterocyclic rings such as an oxazole and a thiazole, and rearrangements of the ring structure. The new compounds were evaluated for their antiproliferative activity against a diverse panel of cancer cell lines (Capan-1, HCT-116, LN-229, NCI-H460, DND-41, HL-60, K-562, Z-138). Among the synthesized analogs, compounds 3, 7 and 9 demonstrated selective anticancer activity toward the Capan-1 cell line, whereas compounds 6 and 10 exhibited broad-spectrum cytotoxic effects across multiple cancer cell lines. Overall, these findings highlight IMNA as a promising scaffold for anticancer drug design and demonstrate the value of A-ring modifications in improving activity and selectivity.