80494-75-3Relevant articles and documents
Investigation of the effect of different linker chemotypes on the inhibition of histone deacetylases (HDACs)
Linciano, Pasquale,Benedetti, Rosaria,Pinzi, Luca,Russo, Fabiana,Chianese, Ugo,Sorbi, Claudia,Altucci, Lucia,Rastelli, Giulio,Brasili, Livio,Franchini, Silvia
, (2020/11/24)
Histone Deacetylases (HDACs) are among the most attractive and interesting targets in anticancer drug discovery. The clinical relevance of HDAC inhibitors (HDACIs) is testified by four FDA-approved drugs for cancer treatment. However, one of the main drawbacks of these drugs resides in the lack of selectivity against the different HDAC isoforms, resulting in severe side effects. Thus, the identification of selective HDACIs represents an exciting challenge for medicinal chemists. HDACIs are composed of a cap group, a linker region, and a metal-binding group interacting with the catalytic zinc ion. While the cap group has been extensively investigated, less information is available about the effect of the linker on isoform selectivity. To this aim, in this work, we explored novel linker chemotypes to direct isoform selectivity. A small library of 25 hydroxamic acids with hitherto unexplored linker chemotypes was prepared. In vitro tests demonstrated that, depending on the linker type, some candidates selectively inhibit HDAC1 over HDAC6 isoform or vice versa. Docking calculations were performed to rationalize the effect of the novel linker chemotypes on biologic activity. Moreover, four compounds were able to increase the levels of acetylation of histone H3 or tubulin. These compounds were also assayed in breast cancer MCF7 cells to test their antiproliferative effect. Three compounds showed a significant reduction of cancer proliferation, representing valuable starting points for further optimization.
Structure-based design of a new series of d-glutamic acid based inhibitors of bacterial UDP-N-acetylmuramoyl-l-alanine: D-glutamate ligase (MurD)
Toma?i?, Tihomir,Zidar, Nace,?ink, Roman,Kova?, Andreja,Blanot, Didier,Contreras-Martel, Carlos,Dessen, Andréa,Müller-Premru, Manica,Zega, Anamarija,Gobec, Stanislav,Kikelj, Danijel,Peterlin Ma?i?, Lucija
, p. 4600 - 4610 (2011/09/14)
MurD ligase is one of the key enzymes participating in the intracellular steps of peptidoglycan biosynthesis and constitutes a viable target in the search for novel antibacterial drugs to combat bacterial drug-resistance. We have designed, synthesized, and evaluated a new series of d-glutamic acid-based Escherichia coli MurD inhibitors incorporating the 5-benzylidenethiazolidin-4- one scaffold. The crystal structure of 16 in the MurD active site has provided a good starting point for the design of structurally optimized inhibitors 73-75 endowed with improved MurD inhibitory potency (IC50 between 3 and 7 μM). Inhibitors 74 and 75 showed weak activity against Gram-positive Staphylococcus aureus and Enterococcus faecalis. Compounds 73-75, with IC 50 values in the low micromolar range, represent the most potent d-Glu-based MurD inhibitors reported to date.
Structure-activity relationship study of TXA2 receptor antagonists. 4- [2-(4-Substituted phenylsulfonylamino)ethylthio]phenoxyacetic acids and related compounds
Kawashima,Sato,Yamamoto,Shimazaki,Chiba,Satake,Iwata,Hatayama
, p. 1132 - 1136 (2007/10/02)
We have recently reported that 4-[2-(4-substituted phenylsulfonylamino)ethylthio]phenoxyacetic acids and related compounds showed potent thromboxane A2 (TXA2) receptor antagonist activity. To understand how substituents affect the bi
