Among substituted 9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4,5,8-tetraones, the lead antitumor triptycene bisquinone TT24 blocks nucleoside transport, induces apoptotic DNA fragmentation and decreases the viability of L1210 leukemic cells in the nanomol
Among substituted 9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4,5,8-tetraones, the lead antitumor triptycene bisquinone TT24 blocks nucleoside transport, induces apoptotic DNA fragmentation and decreases the viability of L1210 leukemic cells in the nanomol
复制标题
在取代的 9,10-二氢-9,10-[1,2]苯蒽-1,4,5,8-四酮中，主要抗肿瘤药物三蝶烯双醌 TT24 可阻断核苷转运，诱导细胞凋亡 DNA 断裂并降低 L1210 白血病细胞的活力
DOI：
10.1097/00001813-200207000-00003
复制
发表时间：
2002
影响因子：
2.3
通讯作者：
Perchellet,Jean-Pierre
中科院分区：
文献类型：
--
作者：
Perchellet,ElisabethM;Sperfslage,BonnieJ;Wang,Yang;Huang,Xiaodong;Tamura,Masafumi;Hua,DuyH;Perchellet,Jean-Pierre
与它们无活性的母体化合物三甲烯（代号TT0）相比，几种新的合成类似物（代号TT）具有抗白血病活性，并在体外对柔红霉素（DAU）耐药的肿瘤亚群有效。在各种取代的9,10 -二氢- 9,10 -[1,2]苯蒽- 1,4,5,8 -四酮中，共鉴定出6种先导抗肿瘤化合物，其代号分别为TT2、TT13、TT16、TT19、TT21和TT24。这些有效的抗肿瘤三联结构具有双醌功能，以及各种溴、甲氧基、甲胺和/或二甲胺取代，在氨基功能上有或没有更长的烷基链。与蒽环类醌类抗生素DAU一样，这些三环烯（TT）双醌类也能抑制DNA合成并诱导与其细胞毒性活性相关的DNA切割，但它们还具有阻断嘌呤和嘧啶核苷的细胞运输的额外优势，这是DAU所不能做到的。完整的染色质沉淀和琼脂糖凝胶电泳表明，TT双醌和DAU诱导DNA断裂的能力是双相的，随着药物暴露时间的增加，峰值向低浓度转移。最有效的抗肿瘤铅化合物TT24在24 h诱导DNA分裂的方式与DAU相同（在1.6 μ M下响应的峰值相似），并且在第4天对L1210肿瘤细胞的活性几乎与DAU相同（TT24和DAU的IC 50值分别为48和25 nM）。放线菌素D、环己亚胺、苯氧羰基- vala - asp -氟甲基酮、苯氧羰基- il - glu - thr - asp -氟甲基酮、n - toyl - l-苯丙氨酸氯甲基酮和znso4抑制了TT24诱导DNA断裂的机制，提示TT双醌类通过caspase和核酸内切酶激活来触发细胞凋亡。由于TT24在DAU的纳摩尔范围内具有细胞毒性，但在野生型和多药耐药肿瘤细胞中可能具有比DAU更多功能的作用机制，因此这类抑制核苷转运的dna损伤醌类抗肿瘤药物可能有价值开发新的多药化疗手段。
In contrast to their inactive parent compound triptycene (code name TT0), several new synthetic analogs (TT code number) have antileukemic activities and remain effective in daunorubicin (DAU)-resistant tumor sublines in vitro. Among variously substituted 9, 10-dihydro-9, 10-[1, 2] benzenoanthracene-1, 4, 5, 8-tetraones, a total of six lead antitumor compounds have been identified, and their code names are TT2, TT13, TT16, TT19, TT21 and TT24. These active antitumor triptych structures have bisquinone functionality, and various bromo, methoxy, methylamino and/or dimethylamino substitutions with or without longer alkyl chains on the amino function. Like the anthracycline quinone antibiotic DAU, these triptycene (TT) bisquinones also inhibit DNA synthesis and induce DNA cleavage in relation with their cytotoxic activities, but have the additional advantage of blocking the cellular transport of purine and pyrimidine nucleosides, an effect which DAU cannot do. As demonstrated by intact chromatin precipitation and agarose gel electrophoresis, the ability of TT bisquinones and DAU to induce DNA fragmentation is biphasic with a peak that shifts to lower concentrations with increasing times of drug exposure. The most effective lead antitumor compound, TT24, induces DNA cleavage in the same concentration-dependent manner as DAU at 24 h (similar peak in response to 1.6 μ M) and is nearly equipotent to DAU against L1210 tumor cell viability at day 4 (IC 50 values of TT24 and DAU: 48 and 25 nM, respectively). The mechanism by which TT24 induces DNA fragmentation is inhibited by actinomycin D, cycloheximide, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, benzyloxycarbonyl-Ile-Glu-Thr-Asp-fluoromethyl ketone, N-tosyl-L-phenylalanine chloromethyl ketone and ZnSO 4, suggesting that TT bisquinones trigger apoptosis by caspase and endonuclease activation. Since TT24 is cytotoxic in the nanomolar range of DAU, but might have a more versatile mechanism of action than DAU in wild-type and multidrug-resistant tumor cells, this new class of DNA-damaging quinone antitumor drugs inhibiting nucleoside transport might be valuable to develop new means of polychemotherapy.