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以芳香氮芥N,N-二(2-氯乙基)-1,4-苯二胺为药效基团,不同链长的萜醇和饱和醇为载体,通过氨基甲酸酯的联接方式,设计合成了6个芳香氮芥衍生物,收率在66%~90%之间,所有目标化合物的结构均经元素分析、1H NMR、13C NMR和MS测试技术确证.对K562(白血病细胞),B16(黑色素瘤)和CHO(中国仓鼠卵巢细胞)3种细胞模型进行了体外抗肿瘤活性测试,结果表明,部分化合物的活性较N,N-二(2-氯乙基)-1,4-苯二胺有明显提高,并在一定浓度范围内与商品药物美法仑(Melphalan)相当,其中法尼基修饰的化合物6e在浓度为0.1~10 μmol/L范围内,对B16细胞的体外抑制率明显优于美法仑. 相似文献
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芳胺氮芥衍生物的合成与生理活性研究 总被引:1,自引:0,他引:1
以芳香氮芥N,N-二(2-氯乙基)-1,4-苯二胺为药效基团,4位取代的苯胺和α-萘胺为载体,通过尿素的连接方式,合成了5个芳胺类氮芥衍生物,所有化合物的结构经元素分析、1HNMR、13CNMR和MS测试确证。对K562(白血病细胞),B16(黑色素瘤)和CHO(中国仓鼠卵巢癌细胞)三种细胞模型进行了体外抗肿瘤活性测试,结果表明部分化合物的活性较N,N-二(2-氯乙基)-1,4-苯二胺有明显提高,其中化合物5e在一定的浓度范围内与商品药物美法仑相当。 相似文献
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根据拼药原理,将氮芥类抗肿瘤药物的药效基团N,N-二(2-氯乙基)氨基拼接到查尔酮结构中,合成出了一系列新型含氮芥基的查尔酮衍生物3a~3r,并用1H NMR,IR,HRMS-ESI及X射线对其结构进行了确证.采用MTT法对所合成的化合物进行了体外抗肿瘤活性测试,结果表明部分化合物对所选肿瘤细胞的增殖有较强的抑制作用,其中,化合物3j和3l对K562的IC50值分别为20.01和18.6μmol/L;对HepG2的IC50值分别为43.46和21.39μmol/L.实验培养并得到了目标产物3e和3l的晶体结构,X射线分析表明化合物3e和3l都属三斜晶系,P-1空间群. 相似文献
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N-脂肪酰基乙醇胺(NAE)作为植物体内的一种内源物质, 在调节植物生长方面起着重要作用. 为了弥补其分子结构中长的脂肪链所带来的溶解性能以及在植物体内传导性能的缺陷, 我们将N-硬脂酰乙醇胺(NAE18)引入氮芥磷酸酯中, 合成了一系列标题化合物. 在合成工作中发现: 在NAE18与氮芥芳基磷酰氯的反应过程中, 4-二甲氨基吡啶(DMAP)起着关键性的催化作用. 在不加DMAP的相同实验条件下, 反应不能进行. 对所合成的标题化合物进行了植物生长调节和杀菌活性的测定, 初步生测结果表明: 经过结构修饰后, 大多数目标化合物的活性相对NAE18有所增强, 但有关生物活性仍有待进一步研究. 相似文献
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Aromatic Nitrogen Mustard‐Based Prodrugs: Activity,Selectivity, and the Mechanism of DNA Cross‐Linking
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Dr. Wenbing Chen Dr. Yanyan Han Prof. Xiaohua Peng 《Chemistry (Weinheim an der Bergstrasse, Germany)》2014,20(24):7410-7418
Three novel H2O2‐activated aromatic nitrogen mustard prodrugs ( 6 – 8 ) are reported. These compounds contain a DNA alkylating agent connected to a H2O2‐responsive trigger by different electron‐withdrawing linkers so that they are inactive towards DNA but can be triggered by H2O2 to release active species. The activity and selectivity of these compounds towards DNA were investigated by measuring DNA interstrand cross‐link (ICL) formation in the presence or absence of H2O2. An electron‐withdrawing linker unit, such as a quaternary ammonia salt ( 6 ), a carboxyamide ( 7 ), and a carbonate group ( 8 ), is sufficient to deactivate the aromatic nitrogen mustard resulting in less than 1.5 % cross‐linking formation. However, H2O2 can restore the activity of the effectors by converting a withdrawing group to a donating group, therefore increasing the cross‐linking efficiency (>20 %). The stability and reaction sites of the ICL products were determined, which revealed that alkylation induced by 7 and 8 not only occurred at the purine sites but also at the pyrimidine site. For the first time, we isolated and characterized the monomer adducts formed between the canonical nucleosides and the aromatic nitrogen mustard ( 15 ) which supported that nitrogen mustards reacted with dG, dA, and dC. The activation mechanism was studied by NMR spectroscopic analysis. An in vitro cytotoxicity assay demonstrated that compound 7 with a carboxyamide linker dramatically inhibited the growth of various cancer cells with a GI50 of less than 1 μM , whereas compound 6 with a charged linker did not show any obvious toxicity in all cell lines tested. These data indicated that a neutral carboxyamide linker is preferable for developing nitrogen mustard prodrugs. Our results showed that 7 is a potent anticancer prodrug that can serve as a model compound for further development. We believe these novel aromatic nitrogen mustards will inspire further and effective applications. 相似文献
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David E. Zacharias Jenny P. Glusker Kenneth D. Tew Beryl Hartley-Asp 《Structural chemistry》1995,6(6):371-376
Estramustine is an antimicrotubule agent that is effective against prostate cancer when used in combination with other microtubule-binding drugs. It is a derivative of estradiol and has a nitrogen mustard group attached via an intervening carbamate group. The molecular dimensions published for estramustine from crystal structure analyses (Mol. Pharmacol. 41∶569, 1992) indicate that the carbamate group modifies the mustard group by giving considerable double-bond character to the C-N bond. As a result the mustard group cannot form an active aziridine ring and therefore does not show the expected alkylating function. The substitution at O(3) of the aromatic A ring of the steroid moiety has also modified its activity as a steroid. Geometric data are presented here on a compound in which the two chlorine atoms of the mustard group of estramustine are replaced by hydroxyl groups. The question was, why does the dihydroxy derivative not show biological activity when chlorine atoms do not appear to be activated in estramustine itself? A comparison of the molecular geometries of the two compounds shows that the dimensions of the carbamate group are similar in both compounds. Therefore it appears that it is the extensive hydrogen-bonding capability of the dihydroxy compound that destroys its estramustine-like activity. In crystals of both compounds there is a hydrogen bond between O(17) -H and O(19) of another molecule, but the dihydroxy compound can form two more hydrogen bonds. This may possibly prevent it from reaching the site of action of estramustine or, if it does reach that site, cause it to behave differently. 相似文献
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《应用有机金属化学》2017,31(2)
A series of novel phosphoramide mustard sophoridinic acid analogues, consisting of nitrogen mustard group and sophoridinic acid scaffold, have been designed, synthesized and evaluated for their topoisomerase inhibitory activity as well as cytotoxicity against six tumor cell lines (SMMC‐7721, LoVo, MCF‐7, K562, S180 and H22) and a normal cell line (L929). Among the compounds tested, five were found to be potent inhibitors and exhibited potent cytotoxicity against S180 and H22 cell lines with IC50 values of 1–4 μM. Further mechanistic studies showed that this class of compounds acted as novel topoisomerase I (Topo I) catalytic inhibitors by preventing the binding of Topo I to DNA and inhibiting the cleavage of DNA, and molecular docking studies revealed that the binding energy for these compounds was comparable to that for classic Topo I inhibitors CPT and HCPT, indicating that the compounds have an interaction with DNA and Topo I. 相似文献