Pastwa E, Ciesielska E, Piestrzeniewicz M K, Denny W A, Gniazdowski M, Szmigiero L
Department of General Chemistry, Institute of Physiology and Biochemistry, Medical University of Lódź, Poland.
Biochem Pharmacol. 1998 Aug 1;56(3):351-9. doi: 10.1016/s0006-2952(98)00030-6.
An antitumor drug N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) and its three close structural analogs N-[2-(hydroxyethylamino)ethyl]acridine-4-carboxamide (DACAH), N-[2-(dimethylamino)ethyl]-9-aminoacridine-4-carboxamide (amino-DACA), and N-[2-(hydroxyethylamino)ethyl]-9-aminoacridine-4-carboxamide (amino-DACAH) were studied for their ability to inhibit RNA synthesis in vitro and to form topoisomerase II-mediated DNA lesions in relation to cell-killing activity. All tested compounds induced chromatin lesions characteristic of topoisomerase II-blocking drugs (DNA breaks and DNA-protein cross-links) in treated cells, but were much less active than reference antileukemic acridine m-AMSA (4'-(9-acridinylamino)-methanesulfon-m-anisidide). The ability to form these lesions was dependent on the structure of the 4-carboxamide side-chain, which seems to be an important factor affecting the drug transport rate through cell membrane. A 4-carboxamide chain with an N-2-(dimethylamino)ethyl moiety resulted in more efficient transport through cell membranes, higher cytotoxicity, and DNA-damaging activity. The mode of action of acridine-4-carboxamides was further elucidated by their incubation with cells in the presence of antitopoisomerase II agents of a known mechanism of inhibition. These were: bisdioxopiperazine (ICRF-187), a catalytic inhibitor of topoisomerase II, and etoposide (VP-16), an inducer of a cleavable complex of the enzyme with DNA. The cytotoxicity of DACA and its analogs was not antagonized by preincubating cells with ICRF-187. All tested acridines protected cells against DNA breakage induced by VP-16, but the extent of protection varied significantly. Amino-DACA, which easily penetrates cell membrane, fully inhibited DNA break formation, whereas other analogs exhibited a low degree of protection when used at high concentration. Our results suggest that the acridine-4-carboxamides discussed here are poor topoisomerase II poisons and that this enzyme is not their main target.
研究了一种抗肿瘤药物N-[2-(二甲基氨基)乙基]吖啶-4-甲酰胺（DACA）及其三种结构相近的类似物N-[2-(羟乙氨基)乙基]吖啶-4-甲酰胺（DACAH）、N-[2-(二甲基氨基)乙基]-9-氨基吖啶-4-甲酰胺（氨基-DACA）和N-[2-(羟乙氨基)乙基]-9-氨基吖啶-4-甲酰胺（氨基-DACAH）在体外抑制RNA合成以及形成拓扑异构酶II介导的DNA损伤与细胞杀伤活性之间的关系。所有测试化合物在处理的细胞中均诱导出拓扑异构酶II阻断药物特有的染色质损伤（DNA断裂和DNA-蛋白质交联），但活性远低于参考抗白血病吖啶m-AMSA（4'-(9-吖啶基氨基)-甲磺酰基间茴香胺）。形成这些损伤的能力取决于4-甲酰胺侧链的结构，这似乎是影响药物通过细胞膜转运速率的一个重要因素。带有N-2-(二甲基氨基)乙基部分的4-甲酰胺链导致通过细胞膜的转运更有效，细胞毒性更高，以及具有DNA损伤活性。通过在已知抑制机制的抗拓扑异构酶II药物存在下将吖啶-4-甲酰胺与细胞一起孵育，进一步阐明了其作用方式。这些药物是：双二氧哌嗪（ICRF-187），一种拓扑异构酶II的催化抑制剂，以及依托泊苷（VP-16），一种该酶与DNA可裂解复合物的诱导剂。用ICRF-187预孵育细胞不会拮抗DACA及其类似物的细胞毒性。所有测试的吖啶都能保护细胞免受VP-16诱导的DNA断裂，但保护程度差异很大。容易穿透细胞膜的氨基-DACA完全抑制DNA断裂的形成，而其他类似物在高浓度使用时表现出低程度的保护作用。我们的结果表明，本文讨论的吖啶-4-甲酰胺是较差的拓扑异构酶II毒物，并且该酶不是它们的主要靶点。
