Spirotetrahydroisoquinoline-Based\nHistone Deacetylase\nInhibitors as New Antifibrotic Agents: Biological Evaluation in Human\nFibroblasts from Bronchoalveolar Lavages of Idiopathic Pulmonary Fibrosis\nPatients

Idiopathic pulmonary fibrosis (IPF) is a rare interstitial\nlung\ndisease typified by a progressive fibrosing phenotype. IPF has been\nassociated with aberrant HDAC activity, particularly HDAC6. Combining\nsynthetic and modeling studies, a new family of spirotetrahydroisoquinoline-capped\nhistone deacetylase inhibitors <b>5a</b>–<b>o</b> was developed. These analogues were prepared via the three-component\nCastagnoli–Cushman reaction (CCR) as the key step. Structure–activity\nrelationship (SAR) studies identified <b>5n</b> (<i>fibrostat</i>) as a preferential HDAC6 inhibitor with a suitable degree of selectivity\ncompared to HDAC1, HDAC3, HDAC5, HDAC8, HDAC10, and HDAC11. <b>5n</b> was able to negatively modulate the expression of fibrotic\nmarkers, fibronectin and collagen 1, in fibroblasts derived from bronchoalveolar\nlavages of IPF patients. In another ex vivo IPF human model, <b>5n</b> (<i>fibrostat</i>) reduced the expression of\nfibronectin and negatively affected the expression of collagen 1 and\nvimentin, the latter being associated with invasiveness. Finally, <i>fibrostat</i> did not show toxicity in rat-perfused heart and\nzebrafish larvae.