González-Cadavid N F, Herrera Quijada F
Biochem J. 1974 Feb;138(2):129-41. doi: 10.1042/bj1380129.
A new thiopseudourea, S-(10-undecen-1-yl)isothiouronium iodide (compound AHR-1911), was tested for antitumour action and shown to inhibit considerably the growth of the Walker carcinoma in rats. The mechanism of its effect on protein and nucleic acid synthesis was then studied with systems in vitro from rat liver. In incubations of liver slices, 1.4mm-compound AHR-1911 decreased by 96% the incorporation of [(14)C]leucine into microsomal proteins, and mitochondrial protein synthesis measured in the presence of cycloheximide was decreased by 44%. At lower doses, translation, as well as the incorporation of [(3)H]uridine into RNA, was also considerably impaired, compound AHR-1911 being the most active of all the thiopseudoureas tested whereas undecylenic acid and thiourea by themselves showed practically no inhibition. Protein synthesis by cytoplasmic ribosomes (microsomes and C-polyribosomes) was inhibited by compound AHR-1911 at different concentrations (72% at 0.42mm), and again the other related compounds were much less effective, with the exception of one antileukaemic thiopseudourea. The same occurred with the poly(U)-stimulated incorporation of phenylalanine. The puromycin reaction with pulse-labelled C-ribosomes was strongly inhibited, particularly when preincubation with compound AHR-1911 preceded the addition of puromycin, with no release of nascent chains by the thiopseudourea alone. In the presence of GTP and pH5 fraction, to induce translocation and transform all the ribosomes to the donor state, the percentage inhibition remained the same. The ribosomes incubated with the drug are aggregated, as shown by the polyribosome profile, but, when excess of inhibitor was removed, the activity in protein synthesis and the puromycin reaction was restored, indicating that the inhibition is not due to the polyribosomal aggregation. These results suggest that the effect on translation with both 55S and 80S ribosomes is derived from inhibition of chain elongation at the level of transpeptidation and not translocation, probably together with the interference with transcription playing a role in the antitumour activity.
一种新的硫代假脲，即S-(10-十一碳烯-1-基)异硫脲碘化物（化合物AHR-1911），进行了抗肿瘤作用测试，结果显示其能显著抑制大鼠体内Walker癌的生长。随后，利用大鼠肝脏的体外系统研究了其对蛋白质和核酸合成的作用机制。在肝切片孵育实验中，1.4mmol/L的化合物AHR-1911使[(14)C]亮氨酸掺入微粒体蛋白的量减少了96%，在环己酰亚胺存在下测得的线粒体蛋白合成减少了44%。在较低剂量时，翻译以及[(3)H]尿苷掺入RNA的过程也受到显著损害，化合物AHR-1911是所有测试的硫代假脲中活性最高的，而十一碳烯酸和硫脲本身几乎没有抑制作用。化合物AHR-1911在不同浓度下（0.42mmol/L时为72%）抑制细胞质核糖体（微粒体和C-多核糖体）的蛋白质合成，同样，除了一种抗白血病硫代假脲外，其他相关化合物的效果要差得多。聚(U)刺激的苯丙氨酸掺入也出现了同样的情况。嘌呤霉素与脉冲标记的C-核糖体的反应受到强烈抑制，特别是当在加入嘌呤霉素之前先用化合物AHR-1911预孵育时，硫代假脲单独不会释放新生链段。在存在GTP和pH5组分以诱导转位并将所有核糖体转变为供体状态时，抑制百分比保持不变。如多核糖体图谱所示，与药物孵育的核糖体发生聚集，但当去除过量抑制剂时，蛋白质合成活性和嘌呤霉素反应得以恢复，这表明抑制作用不是由于多核糖体聚集。这些结果表明，对55S和80S核糖体翻译的影响源于在转肽水平而非转位水平对链延伸的抑制，可能同时转录干扰在抗肿瘤活性中也起作用。
