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Synthesis of o ‐[ N ‐(Substituted benzoyl)‐ N ‐methylamino]phenyl Disulfides by the Spontaneous Coupling of N ‐Methyl‐2‐mono(substituted phenyl)benzothiazolines in Solution and Their VEGF Inhibitory Activities
Author(s) -
TANG Jian,
ZHANG BeiNa,
GE Mei,
ZHU Li,
WANG Yang,
CHEN Ying,
XIA Peng
Publication year - 2008
Publication title -
chinese journal of chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.28
H-Index - 41
eISSN - 1614-7065
pISSN - 1001-604X
DOI - 10.1002/cjoc.200890263
Subject(s) - chemistry , acetone , in vitro , medicinal chemistry , alcohol , stereochemistry , organic chemistry , biochemistry
The solid N ‐methyl‐2‐mono(substituted phenyl)benzothiazolines ( 1 ) are stable and can be stored in atmosphere, whereas they present different behavior in different solvents. They are relatively stable in alcohol and DMSO‐H 2 O. However, in other organic solvents such as acetone, CH 2 Cl 2 , CHCl 3 , EtOAc etc. , the oxidation‐coupling reactions occurred spontaneously to give the corresponding disulfide dimers 2 . The substituents at 2‐phenyl rings, reaction temperature and the acidities of the solutions exerted obvious impacts on the reaction rates and yields of 2 . 12 samples of N ‐methyl‐2‐(substituted phenyl)benzothiazolines ( 1 ) and 11 dimers 2 were evaluated in vitro vascular endothelial growth factor (VEGF) inhibitory activity in human breast cancer cell MDA‐MB‐231 with 2‐methoxyestradiol (2‐ME) as the positive reference and most of them showed potent VEGF inhibitory activity with the EC 50 values of sub‐millimolar range. Among them, the compounds 1l , 1i , and 2d showed potent VEGF inhibitory activities and selectivities with EC 50 values of 0.07, <0.12, and 0.03 mmol/L and SI values of 25, >32 and >32, respectively, which were about 10 times of those of 2‐ME (EC 50 =0.49 mmol/L, SI=3.37). The results further demonstrated that the scaffolds of 1 and 2 were privileged and merited further investigation as VEGF inhibitors.