RE12 derivatives displaying Vaccinia H1-related phosphatase (VHR) inhibition in the presence of detergent and their anti-proliferative activity against HeLa cells.
New derivatives of Vaccinia H1-related phosphatase (VHR) inhibitor RE12 (5) were designed by replacing the long straight alkyl chain with other hydrophobic functionalities containing two aromatic rings, with the aim of obtaining potent, cell-active inhibitors. We established a direct coupling reaction between tetronic acid derivative and thioimidate to prepare the RE derivatives 6a-6i efficiently. These compounds all showed VHR-inhibitory activity in the presence of 0.001% NP-40, whereas RE12 (5) was inactive under this condition, even at 100 μM. Further structure-activity studies focused on terminal substitution afforded trifluoromethyl derivative 6k (RE176) and nitro derivative 6l (RE177). The IC50 value of 6l in the presence of NP-40 was almost equivalent to that of RE12 (5) in its absence. Compound 6k (RE176) potently inhibited proliferation of HeLa cells.
Synthetic Organic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Frédéric
F
Thuaud
Synthetic Organic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan; Department of Applied Chemistry, School of Science and Technology, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki 214-8571, Japan; Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Shuntaro
S
Kojima
Synthetic Organic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan; RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Go
G
Hirai
Synthetic Organic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan; RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Kana
K
Oonuma
Synthetic Organic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Ayako
A
Tsuchiya
Synthetic Organic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan; Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama 338-8570, Japan.
Takako
T
Uchida
Department of Applied Chemistry, School of Science and Technology, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki 214-8571, Japan.
Teruhisa
T
Tsuchimoto
Synthetic Organic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan; Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama 338-8570, Japan; ERATO-JST, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. Electronic address: sodeoka@riken.jp.
Mikiko
M
Sodeoka
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D001596:Benzylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D003902:Detergents / Q000737:chemistry*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014616:Vaccinia virus / Q000201:enzymology*; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D001596:Benzylamines; D003902:Detergents; D004791:Enzyme Inhibitors; D014764:Viral Proteins; D010744:Phosphoric Monoester Hydrolases; D015107:4-Butyrolactone
Detergent; Enamine; Inhibitor; Protein phosphatase; Thioimidate