Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
Anticancer Agents Med Chem ; 19(4): 546-556, 2019.
Article in English | MEDLINE | ID: mdl-30426904

ABSTRACT

BACKGROUND: Histone Deacetylase (HDAC) inhibitors represent an extensive class of targeted anticancer agents. Among the most explored structure moieties, hydroxybenzamides and hydroxypropenamides have been demonstrated to have potential HDAC inhibitory effects. Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as givinostat (ITF2357) and belinostat (PXD-101). AIMS: This study aims at developing novel HDAC inhibitors bearing N-hydroxybenzamides and Nhydroxypropenamides scaffolds with potential cytotoxicity against different cancer cell lines. METHODS: Two new series of N-hydroxybenzamides and N-hydroxypropenamides analogues (4a-j, 6a-j) designed based on the structural features of nexturastat A, AR-42, and PXD-101, were synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines (SW620 (colorectal adenocarcinoma), PC3 (prostate adenocarcinoma), and NCI-H23 (adenocarcinoma, non-small cell lung cancer). Molecular simulations were finally carried out to gain more insight into the structure-activity relationships. RESULTS: It was found that the N-hydroxypropenamides (6a-e) displayed very good HDAC inhibitory potency and cytotoxicity. Various compounds, e.g. 6a-e, especially compound 6e, were up to 5-fold more potent than suberanilohydroxamic acid (SAHA) in terms of cytotoxicity. These compounds also comparably inhibited HDACs with IC50 values in the sub-micromolar range. Docking experiments showed that these compounds bound to HDAC2 at the enzyme active binding site with the same binding mode of SAHA, but with higher binding affinities. CONCLUSIONS: The two series of N-hydroxybenzamides and N-hydroxypropenamides designed and synthesized were potential HDAC inhibitors and antitumor agents. Further development of these compounds should be warranted.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzamides/chemistry , Benzamides/pharmacology , Drug Design , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans
2.
Med Chem ; 11(8): 725-35, 2015.
Article in English | MEDLINE | ID: mdl-26133355

ABSTRACT

Histone deacetylases (HDAC) are currently a group of validated targets for anticancer drug discovery and development. In our research program to find novel small molecules targeting these enzymes, we designed and synthesized two series of 3-hydroxyimino-2-oxoindoline- and 3- methoxyimino-2-oxoindoline-based N-hydroxypropenamides (3a-g, 6a-g). The results show that these propenamides potently inhibited HDAC2 with IC50 values in sub-micromolar range, approximately 10-fold lower than that of SAHA (also known as suberoylanilohydroxamic acid). Evaluation of cytotoxicity of these compounds in three human cancer cell lines revealed that most of the synthesized compounds were up to 5-fold more cytotoxic than SAHA. Docking studies showed that the compounds bound to HDAC2 at the binding site with higher binding affinities compared to SAHA. Our present results demonstrate that these novel 3-substituted-2-oxoindoline-based N-hydroxypropenamides are potential for further development as anticancer agents.


Subject(s)
Acrylamides/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Histone Deacetylase 2/antagonists & inhibitors , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylase Inhibitors/pharmacology , Hydroxamic Acids/pharmacology , Indoles/chemistry , Indoles/pharmacology , Acrylamides/chemical synthesis , Acrylamides/chemistry , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Histone Deacetylase 2/metabolism , Histone Deacetylase Inhibitors/chemical synthesis , Humans , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/chemistry , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship
SELECTION OF CITATIONS
SEARCH DETAIL
...