Design, Synthesis, and Biological Evaluation of Novel Selenium-Containing Isocombretastatins and Phenstatins as Antitumor Agents

Two series of structurally related organoselenium compounds designed by fusing the anticancer agent methyl­(phenyl)­selane into the tubulin polymerization inhibitors isocombretastatins or phenstatins were synthesized and evaluated for antiproliferative activity. Most of these selenium containing hybrids exhibited potent cytotoxicity against a panel of cancel cell lines, with IC₅₀ values in the submicromolar concentration range. Among them, 11a, the 3-methylseleno derivative of isocombretastatin A-4 (isoCA-4) represented the most active compound with IC₅₀ values of 2–34 nM against 12 cancer cell lines, including two drug-resistant cell lines. Importantly, its phosphate salt, 11ab, inhibited tumor growth in xenograft mice models with inhibitory rate of 72.9% without apparent toxicity, which was better than the reference compounds isoCA-4P (inhibitory rate 52.2%) and CA-4P (inhibitory rate 47.6%). Mechanistic studies revealed that 11a is a potent tubulin polymerization inhibitor, which could arrest cell cycle at G₂/M phase and induce apoptosis along with the decrease of mitochondrial membrane potential. In summary, 11a could serve as a promising lead for the development of highly efficient anticancer agents.