Synthesis and Cytotoxicity of 6-Pyrrolidinyl-2-(2-substituted phenyl)-4-quinazolinones

摘要

In our continuing search for potential anticancer candidates, 2-(3-methoxyphenyl)-6-pyrrolidinyl-4-quinazolinone (JJC-1) was selected as the lead compound. Starting 5-pyrrolidinyl-2-aminobenzamide was prepared using standard methodology from 5-chlo-ro-2-nitrobenzoic acid by reaction with SOCl_2, NH_3, pyrrolidine, and H_2. The starting benzamide then was reacted with 2-substiruted benzaldehyde or benzoyl chloride in N,N-dimethylacetamide (DMAC) in the presence of NaHSO_3 at 150℃. Thermal cyclodehydration/dehydrogenation gave the target 6-pyrroli-dinyl-2-(2-substituted phenyl)-4-quinazolinones (15-22). These target compounds were assayed for their cytotoxicity in vitro against six cancer cell lines, including human monocytic leukemia cells (U937), mouse monocytic leukemia cells (WEHI-3), human hepatoma cells (HepG2, Hep3B) and human lung carcinoma cells (A549, CH27). Most of them exhibited significant cytotoxic effect toward U937 and WEHI-3 cells, with EC_(50) values ranging from 0.30 to 10.10 μM. Compound 19 was investigated further for its action mechanisms. Preliminary findings indicated that compound 19 induced G2/M arrest and apoptosis on U937 cells.