Structure-activity relationship of triazacycloalkanes for reversal of antitumor multidrug resistance

我们合成了7个无环亚乙基二磺酰胺和12个1，5-双（芳烃磺酰基）-1，3，5-三氮杂环庚烷，并比较了它们对体外多药耐药和过表达多药转运蛋白P-糖蛋白（P-gp）的P388/ADR多药耐药细胞中长春碱（VLB）蓄积的影响。任何具有4-甲氧基苯基、吡啶基、喹啉基或异喹啉基的无环二磺酰胺几乎不影响P388/ADR细胞对VLB的敏感性，和具有这样的芳基的环状二磺酰胺仅略微增加对VLB的敏感性。氯苯基或萘基适度增强VLB的作用，这些化合物对VLB的细胞内积累具有相似的作用，最大作用为在1，5-双（1-萘磺酰基）-1，3，5-三氮杂环庚烷（B3）的情况下观察到。B3可增强P388/ADR细胞中长春新碱、阿霉素、柔红霉素和放线菌素D的活性，但对敏感的P388细胞无此作用。B3对P388/ADR细胞P-gp含量无影响。B3对P388/ADR荷瘤小鼠的寿命无任何联合作用。

We synthesized seven acyclic ethylenedisulfonamides and twelve 1,5-bis (arenesulfonyl)-1,3,5-triazacycloheptanes, and compared the effects on in vitro multidrug resistance and on intracellular accumulation of vinblastine (VLB) in P388/ADR multidrug-resistant cells which overexpress a multidrug transporter P-glycoprotein (P-gp). Any acyclic disulfonamides having 4-methoxyphenyl, pyridyl, quinolyl, or isoquinolyl groups hardly influenced the sensitivity to VLB in P388/ADR cells, and cyclic disulfonamides having such aryl groups only slightly increased the sensitivity to VLB.Acyclic or cyclic disulfonamides having 4-chlorophenyl or naphthyl groups moderately enhanced the effect of VLB.These compounds showed similar effects on intracellular accumulation of VLB.The maximum effect was observed in the case of 1,5-bis (1-naphthalenesulfonyl)-1,3,5-triazacycloheptane (B3). B3 enhanced the activity of vincristine, adriamycin, daunomycin, or actinomycin D in P388/ADR cells but not in sensitive P388 cells. The content of P-gp in P388/ADR cells was not affected by B3. B3 did not show any combined effects on the life-span of P388/ADR-bearing mice.