对卵巢癌细胞具有抗癌活性的类杂胡萝卜素。

Q2 Pharmacology, Toxicology and Pharmaceutics Open Medicinal Chemistry Journal Pub Date : 2007-10-24 DOI:10.2174/1874104500701010011
Thanh C Le, K Darrell Berlin, Stacy D Benson, Margaret A Eastman, Gianna Bell-Eunice, Anna C Nelson, Doris M Benbrook
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引用次数: 16

摘要

Flex-Het化合物10a (SHetA2-NSC 721689){[4-硝基苯基氨基][(2,2,4,4-四甲基硫代铬-6-基)氨基]甲烷-1-硫酮]}在临床前试验中显示出作为抗癌剂的前景,没有毒性、皮肤刺激或致畸性的证据。本研究的目的之一是合成一系列与SHetA2结构相关的杂类胡萝卜素,并测量结构改变对化合物对A2780卵巢癌细胞毒性活性的影响。改变包括NO2端基与CO2Et端基的活性比较,硫脲连接物与尿素连接物的活性比较,扭曲的硫铬环单元与平面喹啉环单元的活性比较。细胞毒性实验表明,硫脲连接物的效价与尿素连接物相似,NO2取代比CO2Et取代的效价略高,而用平面喹啉融合环系统取代硫代色素基团显著降低了活性。证实了化合物通过细胞凋亡产生细胞毒性的机制。提高效价的最佳结构特征组合是尿素连接物、NO2取代物和柔性硫代色素单元。通过x射线和核磁共振分析证实了活性较高的尿素衍生物中存在广泛的氢键。这是第一个例子,其中的生物活性的柔性,硫代色素单位的比较,融合芳基单位在杂类胡萝卜素分子。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Heteroarotinoids with anti-cancer activity against ovarian cancer cells.

The Flex-Het compound 10a (SHetA2-NSC 721689) {[4-nitrophenylamino][(2,2,4,4-tetramethylthiochroman-6-yl)amino]methane-1-thione]} has shown promise in preclinical testing as an anti-cancer agent without evidence of toxicity, skin irritancy, or teratogenicity. One objective of this study was to synthesize a series of heteroarotinoids structurally related to SHetA2 and to measure the effect of structural alterations on the cytotoxicity activities of the compounds on A2780 ovarian cancer cells. Alterations included comparisons of activity of an NO2 end group versus a CO2Et end group, a thiourea linker versus a urea linker, and a distorted, thiochroman ring unit versus a planar quinoline ring unit. Cytotoxicity assays demonstrated the thiourea linker compounds to be similar in potency to the urea linker counterparts, the NO2 substitutions were slightly more potent than the CO2Et substitutions, and replacement of the thiochroman group with a planar quinoline fused ring system markedly reduced activity. The mechanism of cytotoxicity through apoptosis was confirmed for the compounds. The optimal combination of structural features for enhancing potency consisted of a urea linker, a NO2 substitution, and a flexible thiochroman unit. Extensive H-bonding in the more active urea derivative was confirmed by X-ray and NMR analyses. This is the first example in which the biological activity of flexible, thiochroman units is compared to that of fused aryl units in a heteroarotinoid molecule.

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来源期刊
Open Medicinal Chemistry Journal
Open Medicinal Chemistry Journal Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
4.40
自引率
0.00%
发文量
4
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