Synthesis of o-N-(Substituted benzoyl)-N-methylaminophenyl Disulfides by the Spontaneous Coupling of N-Methyl-2-mono(substituted phenyl)benzothiazolines in Solution and Their VEGF Inhibitory Activities

摘要

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-H2O. However, in other organic solvents such as acetone, CH2Cl2, CHCl3, 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 sam-ples of N-methyl-2-(substituted phenyi)benzothiazolines (1) and 11 dimers 2 were evaluated in vitro vascular endo-thelial growth factor (VEGF) inhibitory activity in human breast cancer cell MDA-MB-231 with 2-methoxyestra-diol (2-ME) as the positive reference and most of them showed potent VEGF inhibitory activity with the EC50 values of sub-millimolar range. Among them, the compounds 11, li, and 2d showed potent VEGF inhibitory activities and selectivities with EC50 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 (EC50=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.