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首页> 外文期刊>Bioorganic and Medicinal Chemistry >Synthesis and biological evaluation of new symmetrical derivatives as cytotoxic agents and apoptosis inducers.
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Synthesis and biological evaluation of new symmetrical derivatives as cytotoxic agents and apoptosis inducers.

机译：新型对称衍生物作为细胞毒剂和细胞凋亡诱导剂的合成及生物学评价。

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Based on the research of less toxic anticancer therapies, we have looked for novel compounds with anticancer activity based on a proapoptotic mechanism. The described compounds are derivatives of ether, carbamate, urea, amide, or amine. Some of the prepared compounds decreased cell viability of various tumor cell lines in a time- and dose-dependent manner, and also induced DNA fragmentation, which indicated cell apoptosis. The potential antitumoral activity of the compounds was evaluated in vitro by examining their cytotoxic effects against human mama, colon, and bladder cancer cell lines (MD-MBA-231, HT-29, and T-24). Compounds showing cytotoxic activity were subjected to an apoptosis assay. In addition, some of the synthesized compounds provoked a rapid and dose-dependent increase in the level of caspase-3, an enzyme, which is considered to be one of the principal executing caspases in which all of the biochemical routes involved in the apoptosis response converge. The most promising compounds, with respect to cytotoxicity and apoptosis induction capability, were the 4-nitrophenylcarbamate derivative of 2,2'-methylenebis(4-chlorophenyl) 3c, the naphthylurea derivative 4d, and the n-propylurea derivative 4c, from 4,4'-methylenebisphenyl, all of which displayed cytotoxic activity and showed very interesting levels of apoptosis. Furthermore, good levels of apoptosis induction were achieved for 3a and 4b in the T-24 cell line. Therefore, compounds such as 7b, a pyrido[2,3-d]pyrimidine derivative, show a significant in vitro cytotoxicity, with IC(50) values between 3 and 8mum in the three cell lines tested. This compound also produced a rapid and dose-dependent increase of the caspase-3 level and induced apoptosis in HT-29 cells. Other profiles have been found, such as those presented by 5c and 7c, which are cytotoxic and apoptotic but do not provoke an increase in the level of caspase-3, or those presented by 1c, 1d, and 2a, which are cytotoxic, without showing any other activity. The different types of behavior of each compound are not necessarily parallel in the three cell lines tested. A great number of these compounds of interest show no cytotoxicity in nontumoral human cells such as CRL-8799, a nontumoral line of mama. Subsequent modulation of these lead structures permits advances in the design of potent cytotoxic and proapoptotic anticancer drugs.
机译：基于对毒性较小的抗癌疗法的研究，我们已经基于促凋亡机制寻找了具有抗癌活性的新型化合物。所描述的化合物是醚，氨基甲酸酯，尿素，酰胺或胺的衍生物。一些制备的化合物以时间和剂量依赖性方式降低了各种肿瘤细胞系的细胞生存力，并且还诱导了DNA断裂，这表明细胞凋亡。通过检查化合物对人妈妈，结肠和膀胱癌细胞系（MD-MBA-231，HT-29和T-24）的细胞毒作用，在体外评估了该化合物的潜在抗肿瘤活性。对显示出细胞毒性活性的化合物进行凋亡测定。另外，一些合成的化合物引起了caspase-3（一种被认为是主要执行的半胱天冬酶之一）的水平的快速且剂量依赖性的增加，在该酶中，所有生化途径均参与凋亡反应。汇合。就细胞毒性和细胞凋亡诱导能力而言，最有前途的化合物是2,2'-亚甲基双（4-氯苯基）3c的4-硝基苯基氨基甲酸酯衍生物，萘并脲衍生物4d和正丙基脲衍生物4c（由4， 4'-亚甲基双苯基，所有这些均显示出细胞毒活性，并显示出非常有趣的凋亡水平。此外，在T-24细胞系中3a和4b达到了良好的凋亡诱导水平。因此，化合物（例如7b，一种吡啶并[2,3-d]嘧啶衍生物）显示出显着的体外细胞毒性，在所测试的三种细胞系中IC（50）值在3至8mum之间。该化合物还导致caspase-3水平快速且剂量依赖性增加，并诱导HT-29细胞凋亡。还发现了其他特征，例如由5c和7c呈现的那些具有细胞毒性和凋亡但不会引起caspase-3水平的升高，或者由1c，1d和2a呈现的具有细胞毒性，但没有显示任何其他活动。在测试的三种细胞系中，每种化合物的不同类型的行为不一定平行。大量这些目标化合物在非肿瘤人类细胞（如CRL-8799）中没有显示出细胞毒性，CRL-8799是非肿瘤细胞。这些前导结构的后续调节使得有效的细胞毒性和促凋亡抗癌药物的设计得以发展。

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