ChemInform Abstract: 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

Abstract

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.