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.

中文翻译：

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Antitumor Agents 291 扩展了 6,8,8-三乙基去链丝莫丁 B 类似物作为多药耐药性选择剂的 B 环修饰研究。

多药耐药 (MDR) 表型和严重不良反应的发生率常常阻碍药物的有效性。利用仅选择性靶向 MDR 细胞的旁系敏感 (CS) 药物（在这种情况下也称为 MDR 选择性药物）是克服癌症治疗中 MDR 的新兴方法。在之前的研究中，我们发现 4'-methyl-6,6,8-triethyldesmosdumotin B (4'-Me-TEDB, 2) 是一种 MDR 选择性合成类黄酮，对 MDR 细胞系 (KB -Vin) 但对亲代细胞 (KB) 以及其他非 MDR 肿瘤细胞没有活性。我们最近的结果表明绝对 MDR 选择性取决于细胞系系统。为了进一步探索并更好地了解关键药效团，我们已经合成了 2 的九种新型类似物，它们包含杂芳族和环烷基 B 环。评估了新化合物的细胞毒性，以探索 B 环修饰对 MDR 选择性的影响。除 7、9 和 10 之外的所有类似物均被鉴定为显着的 MDR 选择性化合物。这一观察结果巩固了 5-羟基-6,8,8-三烷基-4H-色烯-4,7(8H)-二酮骨架（AC 环系统）对药理活性的重要性，并将 B 环确定为较少对更广谱的 MDR 选择性至关重要。值得注意的是，3-呋喃基 (3) 和 2-噻吩基 (6) 类似物显示出显着的 MDR 选择性，KB/KB-Vin 比率分别 >12 和 16。此外，3 和 6 在第二组配对细胞系，即 MDR/非 MDR 肝癌细胞系统中也表现出 MDR 选择性。有趣的是，环己基类似物 (11) 显示出对 A549、DU145 和 PC-3 细胞生长的中度抑制，而其他化合物则无活性。这些新发现根据目前对我们新型 MDR 选择性类黄酮的机制和构效关系 (SAR) 的理解进行了讨论。