Discovery of a Potent Antisarcopenia Drug Molecular Scaffold Derived from Ligusticum chuanxiong and Its Photochemical Synthesis.

Sarcopenia is a growing public health crisis with an unmet need for effective pharmacotherapies. Ligusticum chuanxiong (L. chuanxiong), commonly known as Chuanxiong in China, is a medicinal plant widely utilized for conditions involving muscle wasting and weakness. Herein, we report the discovery of a novel antisarcopenia molecular scaffold from L. chuanxiong, designated as phenylpropanephthalide, which structurally integrates (Z)-ligustilide (6) and (E)-ferulic acid (7). Phenylpropanephthalides A-E (1-5) represent a new category of phthalides in nature, constituting a new chemical subclass of L. chuanxiong constituents. Their structures and absolute configurations were elucidated through comprehensive NMR spectroscopy, X-ray crystallography, and ECD calculations. Photocycloaddition experiments enabled the efficient synthesis of 1-4, and mechanistic studies, supported by DFT calculations, revealed that their formation proceeds via a regio-divergent [2 + 2] photocyclization, which is critically dependent on a supramolecularly preorganized ground-state complex between 6 and 7. Systematic evaluation identified compound 4 as the most promising candidate, exhibiting potent antisarcopenia activity both in vitro using C2C12 myoblasts and in vivo in a Caenorhabditis elegans model. The discovery of phenylpropanephthalide D (4) provides a compelling lead compound and a novel molecular scaffold for the treatment of sarcopenia.