Design, synthesis and antitumor activity of triphenylphosphonium-linked derivatives of quinazolinone.

Cancer is the leading cause of human death. Quinazolinone heterocyclic compounds have a variety of biological activities and have been extensively studied in recent years, especially for their potential anticancer activity. The triphenylphosphonium moiety (TPP⁺) has become a very important lipophilic cation, especially concerning its application the development of anticancer agents. In this work, we designed and synthesised 24 new TPP⁺ -conjugated quinazolinone derivatives, which have alkylated TPP⁺ at the N-3 position and different small group substitutions at the C-6 position, and their antiproliferative activity was evaluated in three cancer cell lines (human alveolar adenocarcinoma cells (A549), human hepatoblastoma cells (HepG2) and human breast cancer cells (MCF-7)) and human normal liver cells (QSG-7701). The cytotoxicity screening results showed that some derivatives exhibited effective inhibitory effects in cancer cells. Among them, the compound 5k-o showed better antiproliferative activity than the positive control drug gefitinib on MCF-7 and A549 cells. The most active compounds being 5o, with IC₅₀ values of 6.56, 14.52 and 7.51 µM in MCF-7 cells, HepG2 cells and A549 cells, respectively. Compound 5o may be a promising compound for cancer treatment worthy of further study.