Abstract
This study focused on the substitution effect at position C7 of 1-arylsulfonyl-5-(N-hydroxyacrylamide)indolines. Compound 9, (E)-3-(7-amino-1-(4-methoxyphenylsulfonyl)indolin-5-yl)-N-hydroxyacrylamide, displayed 4- to 14-fold more potent antiproliferative activity than vorinostat (SAHA, 1). Notably, 9 possessed specific histone deacetylase (HDAC) inhibitory activity toward HDAC1 and HDAC2, but had no effect on HDAC6, indicating that 9 has the potential to be developed as a class I HDAC inhibitor. In a xenograft tumor model, 9 suppressed the growth of HCT116 cells at 100 mg kg(−1), which led to a TGI (tumor growth inhibition) of 40.3%. Taken together, the C7 substitutions have a crucial effect on class I HDACs, which is beneficial for synthesizing efficient anticancer agents.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antineoplastic Agents / chemical synthesis
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology*
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
Dose-Response Relationship, Drug
-
Drug Screening Assays, Antitumor
-
HCT116 Cells
-
HeLa Cells
-
Histone Deacetylase Inhibitors / chemical synthesis
-
Histone Deacetylase Inhibitors / chemistry
-
Histone Deacetylase Inhibitors / pharmacology*
-
Histone Deacetylases / metabolism*
-
Humans
-
Hydroxamic Acids / chemical synthesis
-
Hydroxamic Acids / chemistry
-
Hydroxamic Acids / pharmacology*
-
Male
-
Mice
-
Mice, Nude
-
Molecular Structure
-
Neoplasms, Experimental / drug therapy
-
Neoplasms, Experimental / pathology
-
Structure-Activity Relationship
-
Sulfonamides / chemical synthesis
-
Sulfonamides / chemistry
-
Sulfonamides / pharmacology*
Substances
-
3-(7-amino-1-(4-methoxyphenylsulfonyl)indolin-5-yl)-N-hydroxyacrylamide
-
Antineoplastic Agents
-
Histone Deacetylase Inhibitors
-
Hydroxamic Acids
-
Sulfonamides
-
Histone Deacetylases