Idiopathic pulmonary fibrosis (IPF) is a rare interstitial lung disease typified by a progressive fibrosing phenotype. IPF has been associated with aberrant HDAC activity, particularly HDAC6. Combining synthetic and modeling studies, a new family of spirotetrahydroisoquinoline-capped histone deacetylase inhibitors 5a-o was developed. These analogues were prepared via the three-component Castagnoli-Cushman reaction (CCR) as the key step. Structure-activity relationship (SAR) studies identified 5n (fibrostat) as a preferential HDAC6 inhibitor with a suitable degree of selectivity compared to HDAC1, HDAC3, HDAC5, HDAC8, HDAC10, and HDAC11. 5n was able to negatively modulate the expression of fibrotic markers, fibronectin and collagen 1, in fibroblasts derived from bronchoalveolar lavages of IPF patients. In another ex vivo IPF human model, 5n (fibrostat) reduced the expression of fibronectin and negatively affected the expression of collagen 1 and vimentin, the latter being associated with invasiveness. Finally, fibrostat did not show toxicity in rat-perfused heart and zebrafish larvae.
Fontana, A., Bergantini, L., Carullo, G., Scalvini, L., D'Alessandro, M., Papulino, C., et al. (2024). Spirotetrahydroisoquinoline-Based Histone Deacetylase Inhibitors as New Antifibrotic Agents: Biological Evaluation in Human Fibroblasts from Bronchoalveolar Lavages of Idiopathic Pulmonary Fibrosis Patients. ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE [10.1021/acsptsci.4c00456].
Spirotetrahydroisoquinoline-Based Histone Deacetylase Inhibitors as New Antifibrotic Agents: Biological Evaluation in Human Fibroblasts from Bronchoalveolar Lavages of Idiopathic Pulmonary Fibrosis Patients
Fontana, Anna;Bergantini, Laura;Carullo, Gabriele;D'Alessandro, Miriana;Cameli, Paolo;Gangi, Sara;Saponara, Simona;Gemma, Sandra
;Bargagli, Elena;Butini, Stefania;Campiani, Giuseppe
2024-01-01
Abstract
Idiopathic pulmonary fibrosis (IPF) is a rare interstitial lung disease typified by a progressive fibrosing phenotype. IPF has been associated with aberrant HDAC activity, particularly HDAC6. Combining synthetic and modeling studies, a new family of spirotetrahydroisoquinoline-capped histone deacetylase inhibitors 5a-o was developed. These analogues were prepared via the three-component Castagnoli-Cushman reaction (CCR) as the key step. Structure-activity relationship (SAR) studies identified 5n (fibrostat) as a preferential HDAC6 inhibitor with a suitable degree of selectivity compared to HDAC1, HDAC3, HDAC5, HDAC8, HDAC10, and HDAC11. 5n was able to negatively modulate the expression of fibrotic markers, fibronectin and collagen 1, in fibroblasts derived from bronchoalveolar lavages of IPF patients. In another ex vivo IPF human model, 5n (fibrostat) reduced the expression of fibronectin and negatively affected the expression of collagen 1 and vimentin, the latter being associated with invasiveness. Finally, fibrostat did not show toxicity in rat-perfused heart and zebrafish larvae.File | Dimensione | Formato | |
---|---|---|---|
Spirotetrahydroisoquinoline-Based Histone Deacetylase Inhibitors as New Antifibrotic Agents.pdf
non disponibili
Descrizione: free full text (temporaneo) sul sito dell'editore
Tipologia:
PDF editoriale
Licenza:
NON PUBBLICO - Accesso privato/ristretto
Dimensione
8.17 MB
Formato
Adobe PDF
|
8.17 MB | Adobe PDF | Visualizza/Apri Richiedi una copia |
Spirotetrahydroisoquinoline-Based Histone-Fontana-2024-PostPrint.pdf
embargo fino al 01/12/2025
Descrizione: Accepted Manuscript
Tipologia:
Post-print
Licenza:
PUBBLICO - Pubblico con Copyright
Dimensione
1.66 MB
Formato
Adobe PDF
|
1.66 MB | Adobe PDF | Visualizza/Apri Richiedi una copia |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
https://hdl.handle.net/11365/1283334