Duke S S, Boots M R
J Med Chem. 1983 Nov;26(11):1556-61. doi: 10.1021/jm00365a003.
Three series of sparsomycin analogues were prepared and examined for their ability to inhibit DNA or protein synthesis in bone marrow, P388 lymphocytic leukemia, and P815 mastocytoma cells. The compounds of series I and II, distinguished by the inclusion or exclusion of a hydroxymethyl functional group, were designed to elucidate the effect on activity of replacing the oxodithioacetal side chain of sparsomycin with 4-substituted benzyl groups. The series III analogues, which excluded the hydroxymethyl group and replaced the oxodithioacetal moiety of sparsomycin with a benzyl amide group, were designed to investigate the potential interaction of an amide oxygen in contrast to the sulfoxide oxygen of sparsomycin. Overall, the bromobenzyl-substituted analogues imparted the greatest inhibitory activity in the protein synthesis assay, while the methoxybenzyl-substituted analogues displayed the least. The methylbenzyl and the unsubstituted benzyl compounds were intermediate in inhibitory potential. The activity in the protein synthesis assay may correspond to the lipophilic and electronic characteristics of the substituents on the benzyl moiety of the analogues. All of the compounds were inactive in the DNA synthesis assay.
制备了三类司帕索霉素类似物，并检测了它们抑制骨髓、P388淋巴细胞白血病和P815肥大细胞瘤细胞中DNA或蛋白质合成的能力。I类和II类化合物的区别在于是否含有羟甲基官能团，其设计目的是阐明用4-取代苄基取代司帕索霉素的氧代二硫缩醛侧链对活性的影响。III类类似物不含羟甲基，并用苄基酰胺基团取代了司帕索霉素的氧代二硫缩醛部分，旨在研究酰胺氧与司帕索霉素的亚砜氧相比的潜在相互作用。总体而言，在蛋白质合成试验中，溴苄基取代的类似物具有最大的抑制活性，而甲氧基苄基取代的类似物活性最小。甲基苄基和未取代的苄基化合物的抑制潜力居中。蛋白质合成试验中的活性可能与类似物苄基部分取代基的亲脂性和电子特性相对应。所有化合物在DNA合成试验中均无活性。
