Chemical\nSynthesis and Antifibrotic Properties of\n(±)-Cochlearol T, (±)-Ganocochlearin A, and (±)-Cochlearol\nY

The\ncochlearols and ganocochlearins are natural products\nwith unique\nantifibrotic and renoprotective activities in models of kidney disease.\nThey represent compelling lead compounds for pharmacological intervention\nagainst kidney disease, often characterized by renal fibrosis. We\nreport a four-step synthesis of (±)-cochlearol T (<b>1</b>) and the first reported syntheses of (±)-ganocochlearin A (<b>2</b>) and (±)-cochlearol Y (<b>3</b>) through a strategy\nthat includes a Robinson annulation and unexpected oxidative aromatization.\nWe also access tricyclic intermediate <b>12</b> that represents\na formal synthesis of ganocins A–C and ganocochlearins C–D.\nWe investigated the activity of these synthesized compounds <i>in vitro</i> by inducing fibrosis in a human kidney cell line\nwith TGF-β1. The effect on fibrosis was assessed by qPCR and\nWestern blot studies. We detected significantly lower mRNA gene and\nprotein expression of fibrosis markers for all three natural products.