Synthesis and cytotoxic evaluation of novel 2,3-di-O-alkyl derivatives of l-ascorbic acid

A new series of 2,3-di-O-alkyl derivatives of 5,6-O-isopropylidene-l-ascorbic acid were synthesized using phase transfer catalysis in aqueous media. These derivatives were screened for their superoxide radical scavenging activity and anticancer activity against human breast cancer cell line (MCF-7), leukemic cell line (HL-60), and cervical cell line (HeLa). All these derivatives exhibited enhanced scavenging effect than l-ascorbic acid except for the 4-fluorobenzyl or 2/4-chlorobenzyl alkyl group either at 3-O and/or 2-O position displayed pro-oxidant activity. These pro-oxidant derivatives (2c–e, m) exhibited potent anticancer activities against all the cell lines (IC₅₀ = 25.79–57.21 μM). However, these compounds were also cytotoxic to human normal leukemic macrophages THP-1. On the other hand, antioxidant derivatives displayed albeit slight (2k, IC₅₀ = 57.96–63.45 μM), but selective inhibitory effect toward all tumor cell lines. Thus, pro-oxidant and antioxidant properties can be used to predict the cytotoxic selectivity of drug against normal and cancer cells.