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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >DNA-targeting pyrroloquinoline-linked butenone and chalcones: synthesis and biological evaluation.
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DNA-targeting pyrroloquinoline-linked butenone and chalcones: synthesis and biological evaluation.

机译：靶向DNA的吡咯并喹啉连接的丁酮和查耳酮：合成和生物学评估。

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摘要

A series of conjugates of alpha,beta-unsaturated ketone systems, phenyl-butenone and diaryl-propenones (chalcones), with the tricyclic planar pyrroloquinoline nucleus were synthesised and evaluated for their anticancer properties. The aim was to target DNA by butenone and chalcones, and determine the occurrence of interactions with the macromolecule or related functional enzymes. The ability to inhibit cell growth was assayed on three human tumor cell lines, and the capacity to form molecular complexes with DNA was studied by linear flow dichroism (LD). The effect on the activity of the nuclear enzyme DNA topoisomerase II was also investigated. A noticeable cytotoxic effect was observed for all pyrroloquinoline-conjugated compounds 5 and 7a-c, particularly against human melanoma cell line JR8 (IC(50) 1.2-3.3 microM); the unconjugated chalcones (8a-c) and butenone had a lower or no effect at the tested concentrations. LD experiments confirmed the pyrroloquinoline nucleus as an efficacious carrier for intercalative complexation with DNA. The ability of pyrroloquinoline derivatives to intercalate between base pairs appears to inhibit the relaxation of supercoiled DNA by topoisomerase II, while they induce no significant DNA cleavage. Since the concentrations inhibiting the enzyme appear relatively high with respect to cytotoxicity, the effective intercalation could affect the activity of more DNA processing enzymes and these overall nuclear effects may induce cell death.
机译：合成了一系列具有三环平面吡咯并喹啉核的α，β-不饱和酮系统，苯基丁烯酮和二芳基丙烯酮（查尔酮）共轭物，并评估了其抗癌性能。目的是通过丁烯酮和查耳酮来靶向DNA，并确定与大分子或相关功能酶相互作用的发生。在三种人类肿瘤细胞系上测定了抑制细胞生长的能力，并通过线性流二色性（LD）研究了与DNA形成分子复合物的能力。还研究了对核酶DNA拓扑异构酶II活性的影响。对于所有吡咯并喹啉缀合的化合物5和7a-c，特别是对人黑素瘤细胞系JR8（IC（50）1.2-3.3 microM）观察到了明显的细胞毒性作用。未结合的查耳酮（8a-c）和丁烯酮在测试浓度下的影响较小或没有影响。 LD实验证实吡咯并喹啉核是与DNA嵌入络合的有效载体。吡咯并喹啉衍生物插入碱基对之间的能力似乎抑制了拓扑异构酶II抑制超螺旋DNA的松弛，而它们却没有引起明显的DNA裂解。由于抑制酶的浓度相对于细胞毒性而言相对较高，因此有效的嵌入可能会影响更多DNA处理酶的活性，而这些总体核效应可能会诱导细胞死亡。

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