New orally bioavailable 2-aminobenzamide-type histone deacetylase inhibitor possessing a (2-hydroxyethyl)(4-(thiophen-2-yl)benzyl)amino group.
New 2-aminobenzamide-type histone deacetylase (HDAC) inhibitors were synthesized. They feature a sulfur-containing bicyclic arylmethyl moiety-a surface recognition domain introduced to increase in cellular uptake-and a substituted tert-amino group which affects physicochemical properties such as aqueous solubility. Compound 22 with a (2-hydroxyethyl)(4-(thiophen-2-yl)benzyl)amino group reduced the volume of human colon cancer HCT116 xenografts in nude mice to T/C 67% by oral administration at 45mg/kg, which was comparable to the rate (T/C 62%) for a positive control, MS-275. Western blot analyses as well as cell cycle and TUNEL assays by flow cytometry suggested that the two compounds inhibited the growth of cancer cells via similar mechanisms.
Kiyokawa
Shingo
S
Department of Life Science and Biotechnology, Kansai University, Suita, Osaka 564-8680, Japan.
Hirata
Yoshiyuki
Y
Nagaoka
Yasuo
Y
Shibano
Makio
M
Taniguchi
Masahiko
M
Yasuda
Masahide
M
Baba
Kimiye
K
Uesato
Shinichi
S
D000284:Administration, Oral; D062365:Aminobenzoates / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000517:prevention & control; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D012995:Solubility; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects
D062365:Aminobenzoates; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors