Jones S R, Kinney W A, Zhang X, Jones L M, Selinsky B S
Department of Chemistry, Villanova University, Pennsylvania 19085, USA.
Steroids. 1996 Oct;61(10):565-71. doi: 10.1016/s0039-128x(96)00114-6.
Analogs of the aminosterol antimicrobial agent squalamine have been synthesized beginning from hyodeoxycholic acid. After carboxylic acid esterification and oxidation of both alcohol functions to ketones, the A/B ring junction was converted from cis to trans by acid-catalyzed isomerization. Different polyamines were added to the 3-keto group by reductive amination, yielding both the 3 alpha and 3 beta addition products. The synthetic products exhibited potent, broad-spectrum antimicrobial activity similar to that of the parent compound. Changing the identity of the polyamine or the stereochemistry of addition has little effect upon antimicrobial activity but appears to change the selectivity of the agents. The analogs are synthesized with high yield from inexpensive starting materials and are promising alternatives to squalamine as potential antibiotics.
已从猪去氧胆酸开始合成氨甾醇类抗菌剂角鲨胺的类似物。在将羧酸酯化并将两个醇官能团氧化为酮后，通过酸催化异构化将A/B环连接从顺式转变为反式。通过还原胺化将不同的多胺添加到3-酮基上，得到3α和3β加成产物。合成产物表现出与母体化合物相似的强效、广谱抗菌活性。改变多胺的种类或加成的立体化学对抗菌活性影响很小，但似乎会改变药剂的选择性。这些类似物由廉价的起始原料高产率合成，作为潜在的抗生素，有望成为角鲨胺的替代品。
