Carmona A, Gonzalez-Cadavid N F
Chem Biol Interact. 1978 Sep;22(2-3):309-27. doi: 10.1016/0009-2797(78)90135-7.
In order to assess the role played respectively by the pseudothiourea group and the alkylic chain in the inhibition of protein synthesis and tumour growth caused by compound AHR-1911, a series of eight related substances were studied. The blockade of protein synthesis on liver and Walker carcinoma ribosomes and on suspensions of Walker carcinoma cells, depended essentially on the length of the alkylic chain and the substitution in C-1. The minimum chain was 9 carbons and a plateau in the activity was reached at 11 carbons. Replacement of the thiourea group in C-1 by an NH2 group did not change the pattern. A double bond in the distal section of the chain (AHR-1911) increased inhibition on intact cells with a parallel decrease in cytotoxicity, and reduced the aggregation of ribosomes, protein synthesis factors and other proteins. The antitumor effect depends on the pseudothiourea group and is not caused primarily by interference with protein synthesis. Aminoacyl tRNA binding and transfer appeared to be targets of AH4-1911, but this did not affect significantly tRNA change or nascent peptide release. Drug binding to ribosomes and their subsequent aggregation can be regulated by K+ concentration and temperature. It is assumed that the inhibition of protein synthesis is caused by AHR-1911 effects on elongation factors, impairing their interaction with ribosomes.
为了评估假硫脲基团和烷基链在化合物AHR-1911抑制蛋白质合成及肿瘤生长过程中分别所起的作用，研究了一系列8种相关物质。对肝脏和Walker癌核糖体以及Walker癌细胞悬液中蛋白质合成的阻断，主要取决于烷基链的长度和C-1位的取代情况。最短链长为9个碳原子，在11个碳原子时活性达到平稳状态。将C-1位的硫脲基团替换为NH2基团，模式未发生改变。链远端部分的双键（AHR-1911）增强了对完整细胞的抑制作用，同时细胞毒性平行降低，并减少了核糖体、蛋白质合成因子及其他蛋白质的聚集。抗肿瘤作用取决于假硫脲基团，并非主要由干扰蛋白质合成所致。氨酰tRNA的结合与转移似乎是AH4-1911的作用靶点，但这对tRNA变化或新生肽释放没有显著影响。药物与核糖体的结合及其随后的聚集可受K+浓度和温度调节。据推测，蛋白质合成的抑制是由AHR-1911对延伸因子的作用引起的，损害了它们与核糖体的相互作用。
