5-(2-aminoethyl)dibenzo[c,h][1,6]naphthyridin-6-ones: variation of n-alkyl substituents modulates sensitivity to efflux transporters associated with multidrug resistance.
5-(2-aminoethyl)dibenzo[c,h][1,6]naphthyridin-6-ones: variation of n-alkyl substituents modulates sensitivity to efflux transporters associated with multidrug resistance.
复制标题
DOI：
10.1021/jm049447z
复制
发表时间：
2005-01
影响因子：
7.3
通讯作者：
Alexander L. Ruchelman;P. Houghton;N. Zhou;Angela A. Liu;Leroy F. Liu;E. LaVoie
中科院分区：
文献类型：
--
作者：
Alexander L. Ruchelman;P. Houghton;N. Zhou;Angela A. Liu;Leroy F. Liu;E. LaVoie
5H-8，9-二甲氧基-5-(2-N，N-dimethylaminoethyl)-2，3-methylenedioxydibenzo[c，h)[1，6]萘啶-6-酮(ARC-111)具有较强的TOP1靶向活性和显著的抗肿瘤活性。在5-乙基的2-位用NH2、N-烷基、N，N-二烷基、吡咯烷基、哌啶基和哌嗪取代基合成了几个ARC-111类似物。在RPMI8402和P388肿瘤细胞及其喜树碱耐药变异体CPT-K5和P388/CPT45中，分别评估了这些结构类似物的相对TOP1靶向活性和细胞毒性。在包括NHCH_2CH3、NHCH(CH_3)_2和NHC(CH_3)_3在内的一系列N-烷基类似物中保持了较强的TOP1靶向活性。N-苄基的存在降低了TOP1的靶向活性。在一系列N-烷基-N-异丙基类似物的比较中，活性依次为CH3和GT；CH2CH3和GT；CH(CH3)2。RPMI8402和P388的细胞毒性确实与TOP1靶向活性有关。对KB3-1细胞及其变异体KB/V-1和KBH5.0也进行了细胞毒活性测定。由于KB/V-1细胞过度表达MDR1和KBH5.0细胞过度表达BCRP，这些细胞系相对于亲本细胞系的细胞毒性降低表明这些化合物是这些外排转运蛋白的底物。鉴于它们对KB/V-1细胞的毒性减弱，似乎ARC-111可能的去甲基化代谢产物，即NH2或NHCH3取代5-乙基上2-位的N(CH3)2，是MDR1的底物。而其他N-烷基类似物，包括NHC2H5、NHCH(CH3)2、NHC(CH3)3、N(CH3)2、N(CH2CH3)2、NCH3(CH(CH3)2)，以及吡咯烷基或哌啶类似物对这三种细胞株的细胞毒作用无显著差异。2-(哌嗪基)类似物对KB/V-1细胞的细胞毒性降低，提示第二个碱性氨基取代基与它们被MDR1识别为底物有关。对ARC-111及其N-脱甲基衍生物(NHCH3和NH2类似物)对SCID小鼠SJ-BT45髓母细胞瘤移植瘤的抗肿瘤活性的比较研究表明，次胺代谢产物在体内的活性至少与ARC-111相同，尽管伯胺衍生物的活性明显低于ARC-111。
5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin-6-one (ARC-111) has potent TOP1-targeting activity and pronounced antitumor activity. Several analogues of ARC-111 were synthesized with NH2, N-alkyl, N,N-dialkyl, pyrrolidinyl, piperidinyl, and piperazinyl substituents at the 2-position of the 5-ethyl group. The relative TOP1-targeting activity and cytotoxicity of these structural analogues were assessed in RPMI8402 and P388 tumor cells and their camptothecin-resistant variants CPT-K5 and P388/CPT45, respectively. Potent TOP1-targeting activity was retained within a series of mono N-alkyl analogues that included NHCH2CH3, NHCH(CH3)2, and NHC(CH3)3. TOP1-targeting activity was diminished by the presence of a N-benzyl moiety. In a comparison of a series of N-alkyl-N-isopropyl analogues, activity decreased in the order CH3 > CH2CH3 > CH(CH3)2. Cytotoxicity in RPMI8402 and P388 did correlate with TOP1-targeting activity. Cytotoxic activity was also determined in KB3-1 cells and its variants KB/V-1 and KBH5.0. As KB/V-1 cells overexpress MDR1 and KBH5.0 cells overexpress BCRP, decreased cytotoxicity in these cell lines relative to the parent cell line is indicative of compounds that are substrates for these efflux transporters. In view of their diminished cytotoxicity in KB/V-1 cells, it appears that the likely demethylated metabolites of ARC-111, i.e., where NH2 or NHCH3 replaces the N(CH3)2 at the 2-position of the 5-ethyl substituent, are substrates for MDR1. In contrast, no significant difference in cytotoxicity among these three cell lines was observed with other N-alkyl analogues, including NHC2H5, NHCH(CH3)2, NHC(CH3)3, N(CH3)2, N(CH2CH3)2, NCH3(CH(CH3)2), and either the pyrrolidinyl or the piperidinyl analogues. The 2-(piperazinyl) analogues were associated with diminished cytotoxicity in KB/V-1 cells, suggesting that the second basic amino substituent is associated with their recognition as substrates by MDR1. Comparative studies on the antitumor activity of ARC-111 and its N-demethylated derivatives (the NHCH3 and NH2 analogues) against SJ-BT45 medulloblastoma xenografts in scid mice revealed that the secondary amine metabolite is at least as active as ARC-111 in vivo, although the primary amine derivative was significantly less potent.