Phenylpyrrole-based HDAC inhibitors: synthesis, molecular modeling and biological studies. (September 2016)

• Record Type: Journal Article
• Authors: Brindisi, Margherita; Cavella, Caterina; Brogi, Simone; Nebbioso, Angela; Senger, Johanna; Maramai, Samuele; Ciotta, Alfonso; Iside, Concetta; Butini, Stefania; Lamponi, Stefania; Novellino, Ettore; Altucci, Lucia; Jung, Manfred; Campiani, Giuseppe; Gemma, Sandra
• Is Part Of: Future medicinal chemistry. Volume 8:Number 13(2016)
• Page Start: 1573
• Page End: 1587
• Publication Date: 2016-09
• Subjects: antitumor agents -- bioinformatics -- drug design -- enzyme inhibitors -- epigenetics -- HDAC; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.4155/fmc-2016-0068
• Languages: English
• ISSNs: 1756-8919

Abstract

Aim: Histone deacetylases (HDACs) regulate the expression and activity of numerous proteins involved in the initiation and progression of cancer. Currently, three hydroxamate-containing HDAC pan-inhibitors have been approved as antitumor agents.Results: We herein present the development of a series of novel phenylpyrrole-based derivatives stemmed from combined computational and medicinal chemistry efforts to rationally modulate HDAC1/6 isoform selectivity. In vitro activity on HDAC1 and HDAC6 isoforms and the effects of selected analogs on histone H3 and α-tubulin acetylation levels were determined. Cell-based data evidenced, for selected compounds, a promising antitumor potential and low toxicity on normal cells.Conclusion: The newly developed compounds represent a valuable starting point for the development of novel anticancer agents.