Sixteen analogues (3-16, 33, and 48) of the unique flavonoid desmosdumotin B (1) were prepared and evaluated as in vitro inhibitors of the human KB cancer cell line and its MDR subclone, KB-VIN. 6,8,8-Triethyl analogues 10- 13 showed enhanced KB-VIN selectivity. In particular, 4'-alkyl derivatives 11 (4'-Me) and 12 (4'-Et) showed significant ED 50 values of 0.03 and 0.025 microg/mL, respectively, against KB-VIN with selectivities of >460- and 320-fold compared with that of KB. This report is the first to describe compounds showing such high activity against MDR cells versus non-MDR cells. The unique activity of 1-analogues is likely MDR-mediated because cotreatment with verapamil, a P-gp inhibitor, partially reversed the selective toxicity of both 1 and 10. Interestingly, only 1-analogues with a naphthalene B-ring (8 and 14) showed significant cytotoxic activity against KB and other cancer cell lines. Thus, 1-analogues might be a new class of potent drug candidates, especially as 11 and 12 express direct selective action against tumors expressing MDR.