Synthesis and evaluation of novel podophyllotoxin derivatives as potential antitumor agents

Cancer multidrug resistance (MDR) is a common cause of treatment failure in cancer patients. Increased expression of permeability glycoprotein (P-gp), which is also known as MDR-1, is the main cause of multidrug resistance. Podophyllotoxin derivatives hold great promise in the battle to overcome multidrug resistance, as they can induce cytotoxicity through multiple mechanisms. Here, we synthesized sixteen novel podophyllotoxin derivatives and evaluated their cytotoxicities in human cancer cell lines, HeLa, K562 and K562/A02. Some of these compounds were more potent than etoposide, a clinically relevant inhibitor of DNA repair enzymes. In particular, compound 5p exhibited the most potent activity toward drug-resistant K562/A02 cells, as it robustly inhibited tumor cell proliferation and induced apoptosis. Furthermore, preliminary investigation suggested that 5p inhibited the expression of MDR-1 in K562/A02 cells more effectively than etoposide. A novel series of podophyllotoxin derivatives were synthesized and exhibited promising in vitro cytotoxicities. Compound 5p inhibited tumor cell proliferation and induced apoptosis in K562/A02 cells. Furthermore, preliminary investigation suggested that 5p inhibited the expression of MDR-1 in K562/A02 cells. [Display omitted] •Several novel podophyllotoxin derivatives were synthesized.•Some compounds were more potent than VP-16.•Compound 5p was potently cytotoxic in multidrug resistant K562/A02 cells.•Compound 5p inhibited the expression of MDR-1 in K562/A02 cells.