- Design and synthesis of 2-amino-6-(1H,3H-benzo[de]isochromen-6-yl)-1,3,5- triazines as novel Hsp90 inhibitors
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A novel series of 2-amino-1,3,5-triazines bearing a tricyclic moiety as heat shock protein 90 (Hsp90) inhibitors is described. Molecular design was performed using X-ray cocrystal structures of the lead compound CH5015765 and natural Hsp90 inhibitor geldanamycin with Hsp90. We optimized affinity to Hsp90, in vitro cell growth inhibitory activity, water solubility, and liver microsomal stability of inhibitors and identified CH5138303. This compound showed high binding affinity for N-terminal Hsp90α (Kd = 0.52 nM) and strong in vitro cell growth inhibition against human cancer cell lines (HCT116 IC50 = 0.098 μM, NCI-N87 IC50 = 0.066 μM) and also displayed high oral bioavailability in mice (F = 44.0%) and potent antitumor efficacy in a human NCI-N87 gastric cancer xenograft model (tumor growth inhibition = 136%).
- Suda, Atsushi,Kawasaki, Ken-Ichi,Komiyama, Susumu,Isshiki, Yoshiaki,Yoon, Dong-Oh,Kim, Sung-Jin,Na, Young-Jun,Hasegawa, Kiyoshi,Fukami, Takaaki A.,Sato, Shigeo,Miura, Takaaki,Ono, Naomi,Yamazaki, Toshikazu,Saitoh, Ryoichi,Shimma, Nobuo,Shiratori, Yasuhiko,Tsukuda, Takuo
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p. 892 - 905
(2014/01/23)
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- Synthesis and pharmacological activities of novel cyclic disulfide and cyclic sulfide derivatives as hepatoprotective agents
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In order to search for anti-hepatitis drugs, we synthesized a series of eight- and nine-membered cyclic disulfides (1) and six- and seven-membered cyclic sulfides (2) and evaluated them for ability to reduce mortality in the model of acute hepatic failure
- Ito,Ota,Suhara,Tabashi,Kawashima
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p. 1066 - 1073
(2007/10/02)
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- Pyridylthio-acylanilide herbicides
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Novel herbicidally active pyridylthio-acylanilides of the formula STR1 in which R1, R2 and R3, independently of one another, represent hydrogen, halogen, cyano or trifluoromethyl or alkyl, alkoxy and alkylthio having 1 to 4 carbon atoms in each case, R4 represents halogen, methyl or methoxy, n represents a number 0, 1 or 2, z represents the group (Ia) STR2 or the group (Ib) STR3 where X represents oxygen, sulphur, an N--R10 or N--O--R11 group, or X and Rg tpgether represent the STR4 radical, and the other radicals can have various meanings. Intermediates of the formulae STR5 are also new.
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