Discovery of novel and highly potent anticancer agents enabled by selenium scanning of noscapine.

Herein, the structural modification of noscapine via an elegant selenium scanning strategy has been demonstrated, which enables the production of three classes of novel seleno-containing noscapinoids, namely 6', 7', and 9'-seleno-substituted noscapines. Among them, 9'-seleno-substituted noscapines exhibited superior in vitro anti-proliferative activity, and 9'-cycloheptylselenomethyl-noscapine 17a16 with a large hydrophobic cycloheptyl group showed the most potent activity and good selectivity. Unlike most of the reported noscapinoids that induce G2/M phase arrest by targeting microtubules, 17a16 exhibited a distinct ability to induce S-phase arrest and displayed superior potency in inducing apoptosis, which attribute to the activation of two parallel checkpoint pathways orchestrating DNA damage response, including DNA-PKcs-dependent p53 stabilization and ATR-Chk1 axis activation. Dissecting the upstream mechanism revealed that 17a16 targets mitochondria and induces mitochondrial dysfunction. This study elucidates the interplay of mitochondrial stress, DNA damage response, p53 and ATR-Chk1 checkpoint activation in mediating the anticancer effects of 17a16. Furthermore, 17a16 treatment significantly suppressed tumor growth in p53-deficient JeKo-1 subcutaneous xenograft model in vivo, without inducing systemic toxicity. Overall, our findings highlight 17a16 as a promising lead compound in cancer therapy and demonstrate the potential of selenium scanning as a valuable strategy for anticancer drug discovery.