Synthesis and Antiproliferative Evaluation of a New Formyl Derivative of Carnosic Acid

The abietane-type diterpenoid family has long attracted natural product, biochemical, organic, and medicinal chemists due to continuous discoveries regarding their isolation, characterization, pharmacology, biosynthesis, and chemical synthesis. Over the past decade, our group has conducted numerous studies focusing on the semisynthesis and biological screening of various aromatic abietanes. Their unique tricyclic scaffold and potential for selective chemical functionalization make them attractive building blocks for developing bioactive molecules. The availability of chiral natural (+)-carnosic acid at a low price encouraged us to use it as a starting material.

In this work, we disclose how a simple modification to the carbon skeleton of carnosic acid, specifically the introduction of a formyl group, yields a more potent analogue, methyl 11,12-di-O-methyl-14-formylcarnosate, in a panel of solid tumor cell lines. The structural characterization was elucidated by extensive 1H, 13C, and 2D-NMR analysis. Preliminary biological evaluation across several tumor cell lines showed relevant antiproliferative activity. Notably, this formyl derivative demonstrated six-fold greater potency than cisplatin and etoposide in T47D (breast) and WiDr (colon) cells.