Selective inhibition of Class I HDACs has emerged as a promising approach for cancer therapy. Building on our previous work with Largazole (a member of the natural depsipeptide family), we have applied a similar fluorination modification to Romidepsin and synthesized its fluoro analog (12) in 12 steps. This analog exhibits potent inhibitory activity against Class I HDACs but shows no inhibitory effect on HDAC6, confirming its selectivity as a Class I HDAC inhibitor (IC50 HDAC1 0.95 nM, HDAC2 0.86, HDAC 3 1.1 nM, HDAC8 4.2 nM, HDAC6 > 103 nM). Compared with Romidepsin, compound 12 demonstrates significant growth inhibition in two cancer cell lines (NCI-H1975 and HT29) while exhibiting markedly less growth inhibition in two normal cell lines (WRL-68 and HEK293). Further studies reveal that 12 is capable of blocking the cell cycle and inducing apoptosis, thereby exerting anticancer activity. Moreover, 12 possesses metabolic stability comparable to Romidepsin. In a mouse model, 12 demonstrates strong in vivo antitumor efficacy similar to that of Romidepsin, yet with significantly reduced toxicity. These findings support the potential of this fluoro analog as a highly selective Class I HDAC inhibitor and highlight its promise as a superior alternative to Romidepsin for further development.

01 May 2025·International Journal of Biological Macromolecules

Upregulation of HDAC3 mediates behavioral impairment in the bile duct ligation model of hepatic encephalopathy

Article

Author: Elipilla, Pavani ; Rishi, Vikas ; Gupta, Shiwangi ; Aggarwal, Aanchal

Hepatic encephalopathy (HE), an outcome of chronic liver disease is characterized by behavioral impairments. The present study investigated the role of HDAC-mediated transcriptional regulation causing behavioral impairments in the bile duct ligation (BDL) model of HE. Post-BDL surgery in rats, dynamic alterations in liver function tests, liver morphology were observed. In BDL rats, histological staining in brain demonstrated reduced neuronal viability and warped neuronal architecture. Additionally, BDL animals showed impaired spatial learning, memory, and increased anxiety in the open field, Barnes maze, and Y maze tests. Further, the Golgi cox staining revealed a significantly altered spine density and spine clustering patterns of granular neuron in dentate gyrus of BDL rats. Concordantly, a significant downregulation of memory encoding genes was also observed in BDL rats that may account for aberrant behavior. Molecular analysis of modifiers, such as HDAC, showed significant changes in the expression of HDAC3 and HDAC6 in both the cortex and hippocampus of BDL rats. Upregulation of HDAC3 promoted its localization on the promoter of genes like c-Fos, NPAS4, Arc, and others, likely causing their decreased expression. Our findings suggest that increased HDAC3 activity downregulates key synaptic plasticity and memory-related genes, potentially driving neurobehavioral changes in BDL rats.

14 Feb 2025·ACS Pharmacology & Translational Science

Spirotetrahydroisoquinoline-Based Histone Deacetylase Inhibitors as New Antifibrotic Agents: Biological Evaluation in Human Fibroblasts from Bronchoalveolar Lavages of Idiopathic Pulmonary Fibrosis Patients

Article

Author: Carullo, Gabriele ; Vincenzi, Fabrizio ; Pistocchi, Anna ; Saponara, Simona ; Bargagli, Elena ; Carbone, Sabrina ; Bergantini, Laura ; Papulino, Chiara ; Scalvini, Laura ; Gangi, Sara ; Fontana, Anna ; Varani, Katia ; Mor, Marco ; Contri, Chiara ; Campiani, Giuseppe ; Benedetti, Rosaria ; Cameli, Paolo ; Lodola, Alessio ; Pezzotta, Alex ; Pasquini, Silvia ; Altucci, Lucia ; Butini, Stefania ; D’Alessandro, Miriana ; Gemma, Sandra

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.

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