Author: Publisher:
ISBN:
Category :
Languages : en
Pages :
Book Description
Design, Synthesis and Biological Evaluation of Novel Hydroxamic Acid Based Histone Deacetylase 6 Selective Inhibitors Bearing Phenylpyrazol Scaffold as Surface Recognition Motif
Author: The Design, Synthesis, and Biological Evaluation of Selective Histone Deacetylase (HDAC) Inhibitors
Author: Joseph KnoffPublisher:
ISBN:
Category : Chemistry, Organic
Languages : en
Pages : 0
Book Description
Histone deacetylase (HDAC) proteins have become an important target for the treatment of several diseases including cancers, neurodegenerative diseases and inflammatory diseases. Four such inhibitors are approved by the FDA as anti-cancer drugs, but unfortunately, they inhibit numerous HDAC isoforms which leads to side effects in clinical settings. In this work, we have developed multiple libraries of chemical biology tools that selectively inhibit a small number of HDAC proteins with the goal of decreasing the possible therapeutic side effects related to non-selective inhibition. With this, our strategy was to develop novel libraries of HDAC inhibitors based on two new types of metal binding groups that are not present in any of the FDA approved inhibitors. Several benzamide type HDAC inhibitors were synthesized across two projects, with the same goal of selectively inhibiting HDAC1. The synthesized compounds were tested in vitro and in cellular assays to determine isoform selectivity and toxicity to cancer cells. The compounds that displayed the highest selectivity in these two projects were the p-chloro N-(2-aminophenyl) benzamide, and the tryptophanyl aminobiphenyl amide, Bnz-3. These two compounds displayed 16.8- and 29-fold selectivity for HDAC1 over HDAC2, while being between 17- and 320-fold selective for HDAC1 over HDACs3-9. Furter validation of these findings was performed via docking analysis. A new series of compounds combining the unique findings of both libraries was proposed with extensive support from computational methods. In addition, another compound library bearing the trifluoromethyl ketone (TFMK) binding group was designed and synthesized, with preliminary findings of in vitro experiments detailed herin. The TFMK analogs of the FDA approved inhibitor SAHA made use of a modified metal binding group to promote selectivity for the lesser studied class IIa HDAC isoforms HDAC4, 5, 7, and 9. Docking studies of the TFMK SAHA analogs with modifications at the C2-, C3-, and C4- positions show promise towards promoting selective inhibition of class IIa HDAC isoforms. Both classes of inhibitors can be used lead compounds and as chemical tools to aid in the elucidation of the functions of specific HDAC isoforms as they relate to cancer biology.
Design, Synthesis and Biological Evaluation of Histone Deacetylase (HDAC) Inhibitors
Author: Ahmed NegmeldinPublisher:
ISBN:
Category : Biochemistry
Languages : en
Pages : 352
Book Description
The dual HDAC6/8 selective inhibitors can be used as lead compounds and as a chemical tool to study HDAC related cancer biology. The observed enhancement of selectivity upon modifying the linker region of the non-selective inhibitor SAHA shows that modifying current drugs, like SAHA, could lead to substantial improvement in its pharmacodynamic properties.
Design, Synthesis and Biological Evaluation of Anti-cancer and Anti-parasitic Histone Deacetylase Inhibitors
Author: Katharina StenzelO-alkyl Imidate Formation Via Staudinger Ligation
Author: José A. RestituyoPublisher:
ISBN:
Category : Genetic regulation
Languages : en
Pages : 214
Book Description
Author: 
Author: 余兆武
Author: Elena Maria Loi
Author: Dmitrii V. Kalinin
Author: Ruomeng Wang