Antitumor Agents 291 Expanded B-Ring Modification Study of 6,8,8-Triethyl Desmosdumotin B Analogues as Multidrug-Resistance Selective Agents

Abstract

Drug usefulnessis frequently obstructed by the incidence of the multidrug resistance (MDR) phenotype and severe adverse effects. Exploiting collateral sensitive(CS)agents (in this case also called MDR-selective agents), which selectively target only MDR cells, is an emerging and novel approach to overcome MDR in cancer treatment. In prior studies, we found that 4'-methyl-6,6,8-triethyldesmosdumotin B (4'-Me-TEDB, 2) is an MDR-selective synthetic flavonoid with significant in vitro anticancer activity against a MDR cell line (KB-Vin) but without activity against the parent cells (KB) as well as other non-MDR tumor cells. Our recent results suggest the absolute MDR-selectivity varies depending on the cell-line system. In order to explore this further and to better understand the critical pharmacophores, we have synthesized nine novel analogues of 2, which contain heteroaromatic as well ascycloalkyl B-rings. The new compounds were evaluated for cytotoxicity to explore the effect of B-ring modifications on MDR-selectivity. All analogues, except 7, 9 and 10, were identified as significant MDR-selective compounds. This observation solidifies the importance of the 5-hydroxy-6,8,8-trialkyl-4H-chromene-4,7(8H)-dione skeleton (AC-ring system) for the pharmacological activity and establishes the B-ring as less critical for the broader spectrum MDR-selectivity. Notably, 3-furanyl (3)and 2-thiophenyl (6)analogues displayed substantial MDR-selectivity with KB/KB-Vin ratios of >12 and 16, respectively. Furthermore, 3 and 6 also exhibited MDR-selectivity in a second set of paired cell lines, the MDR/non-MDR hepatoma-cell system. Interestingly, a cyclohexyl analogue (11) showed moderate inhibition of A549, DU145, and PC-3 cell growth, while the other compounds were inactive. These new findings are discussed in terms of current understanding of mechanism and structure-activity relationship (SAR) of our novel MDR-selective flavonoids.