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首页> 外文期刊>Bioorganic and Medicinal Chemistry Letters >Sequential cytotoxicity: a theory examined using a series of 3,5-bis(benzylidene)-1-diethylphosphono-4-oxopiperidines and related phosphonic acids.
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Sequential cytotoxicity: a theory examined using a series of 3,5-bis(benzylidene)-1-diethylphosphono-4-oxopiperidines and related phosphonic acids.

机译：顺序细胞毒性：使用一系列3,5-双（亚苄基）-1-二乙基膦酰基-4-氧代哌啶和相关的膦酸研究的理论。

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摘要

The concept of sequential cytotoxicity, which states that successive chemical attacks on cellular constituents can be more deleterious to neoplasms than normal cells, was evaluated using a series of 3,5-bis(benzylidene)-1-diethylphosphono-4-oxopiperidines 1 and related phosphonic acids 2, which were screened against a panel of malignant and normal cell lines. The compounds proved to be not only potent cytotoxins (71% of the CC(50) figures are submicromolar) but to display greater cytotoxicity to the neoplastic cells. QSAR revealed that both cytotoxic potencies and selective toxicity were increased by a rise in the electron-withdrawing properties and a decrease in the hydrophobicity of the aryl substituents. Utilisation of the PL10 concept and evaluation of druglike properties revealed 1c as the lead tumour-specific cytotoxin. This molecule activated caspase-3 in HL-60 cells but not in the HSC-2 cell line. While 1c caused internucleosomal DNA fragmentation in HL-60 cells, it did not elicit this effect in either HSC-2 and HSC-4 cells. Clearly 1c exerts its cytotoxic potencies by different mechanisms and such pleiotropy is likely the principal reason for the remarkable display of preferential toxicity towards malignant cells of the compounds in series 1 and 2.
机译：使用一系列3,5-双（亚苄基）-1-二乙基膦酰基-4-氧代哌啶1和相关药物评估了连续细胞毒性的概念，该概念表明连续的化学成分对细胞成分的化学攻击比正常细胞对肿瘤更有害。膦酸2，针对一组恶性和正常细胞系进行了筛选。该化合物不仅被证明是有效的细胞毒素（CC（50）数据的71％为亚微摩尔），而且对肿瘤细胞显示出更大的细胞毒性。 QSAR显示，吸电子性能的提高和芳基取代基的疏水性的降低都增加了细胞毒性和选择性毒性。 PL10概念的利用和对类药物性质的评估揭示了1c作为主要的肿瘤特异性细胞毒素。该分子在HL-60细胞中激活caspase-3，但在HSC-2细胞中不激活。尽管1c在HL-60细胞中引起核小体间DNA断裂，但在HSC-2和HSC-4细胞中均未引起这种作用。显然，1c通过不同的机制发挥其细胞毒性作用，而这种多效性可能是显着显示系列1和2中化合物对恶性细胞优先毒性的主要原因。

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