Synthesis and Antitumor Effect of Sophoridine Derivatives Bearing an Acyclic Aryloxy Phosphoramidate Mustard Functionality

To elevate the potency of sophoridine, phosphoramidate mustard motif was incorporated to D‐ring opened sophoridine scaffold. A series of acyclic aryloxy phosphoramidate mustard functionalized sophoridine derivatives were synthesized and screened for cytostatic activity in a range of different tumor cell lines (S180, H22, K562, MCF‐7, SMMC‐7721, and LoVo). All these compounds were shown to be more sensitive to S180 and H22 cells with IC₅₀ values ranging from 2.10 to 7.21 μM. In addition, all targeted derivatives distinctly are more cytotoxic to cancer cells than normal cell L929. Compounds 8b , 8c , 8d , and 8e displayed moderate tumor suppression without apparent organ toxicity in vivo against mice bearing H22 liver tumors. Their potential binding modes with DNA topoisomerase I complex have also been investigated.