Synthesis, in vitro and in vivo biological evaluation, docking studies, and structure--activity relationship (SAR) discussion of dipeptidyl boronic acid proteasome inhibitors composed of beta-amino acids.
A series of novel dipeptidyl boronic acid proteasome inhibitors composed of beta-amino acids were synthesized, in vitro and in vivo biologically evaluated, and theoretically modeled for the first time. From the screened racemic compounds in enzyme, 4i was the most active. The IC(50) value of its pure enantiomer 4q was 9.6 nM, 36-fold more active than its isomer 4p and as active as the marketed bortezomib in inhibiting human 20S proteasome. This candidate also showed good activities with IC(50) values nearly less than 5 microM against several human solid and hematologic tumor cell lines. Safety evaluation in vivo with zebrafish and Sprague-Dawley (SD) rats showed that the candidate 4q was less toxic than bortezomib. Pharmacokinetic profiles suggested candidate 4q showed a more plasma exposure and longer half-life than bortezomib. Docking results indicated that 4q nearly interacted with 20S proteasome in a similar way as bortezomib.
Jiangsu Simcere Pharmaceutical Research Institute and Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18 Xuan Wu Avenue, Xuan Wu District, Nanjing 210042, PRC. zhyqscu@hotmail.com
Yongqiang
Y
Zhu
Xinrong
X
Zhu
Gang
G
Wu
Yuheng
Y
Ma
Yuejie
Y
Li
Xin
X
Zhao
Yunxia
Y
Yuan
Jie
J
Yang
Sen
S
Yu
Feng
F
Shao
Runtao
R
Li
Yanrong
Y
Ke
Aijun
A
Lu
Zhenming
Z
Liu
Liangren
L
Zhang
D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001897:Boronic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006207:Half-Life; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D016019:Survival Analysis; D018675:Toxicity Tests; D015027:Zebrafish
D000596:Amino Acids; D001897:Boronic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex