Bierer D E, Dener J M, Dubenko L G, Gerber R E, Litvak J, Peterli S, Peterli-Roth P, Truong T V, Mao G, Bauer B E
Shaman Pharmaceuticals, Inc., South San Francisco, California 94080-4812, USA.
J Med Chem. 1995 Jul 7;38(14):2628-48. doi: 10.1021/jm00014a016.
The first structure-activity study involving the 1,2-dithiin class of compounds (1,2-dithiacyclohexadienes) is herein reported. A series of 3,6-disubstituted 1,2-dithiins was synthesized from dithiins 1d and 1e and evaluated as antifungal agents. A new and versatile synthesis of dithiins 1d and 1e is reported which is amenable to scale-up at the kilogram level. The novelty of the process derives from the use of beta-mercaptopropionitrile as the thiophile, relying on a beta-elimination strategy and subsequent oxidation to create the 1,2-dithiin ring. Optimal geometries of dithiins 1d, 18i, and 45 and model dithiin 61 were determined by molecular mechanics and Hartree-Fock molecular orbital calculations. Two possible mechanisms of action are presented for the 1,2-dithiin class of compounds to explain their observed antifungal activities against Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus.
本文报道了首例涉及1,2 - 二硫环化合物（1,2 - 二硫杂环己二烯）的构效关系研究。由二硫环化合物1d和1e合成了一系列3,6 - 二取代的1,2 - 二硫环，并对其作为抗真菌剂进行了评估。报道了一种新型且通用的二硫环化合物1d和1e的合成方法，该方法适合扩大到千克级规模。该工艺的新颖之处在于使用β - 巯基丙腈作为亲硫试剂，依靠β - 消除策略及后续氧化来构建1,2 - 二硫环。通过分子力学和哈特里 - 福克分子轨道计算确定了二硫环化合物1d、18i、45以及模型二硫环化合物61的最佳几何结构。针对1,2 - 二硫环类化合物提出了两种可能的作用机制，以解释其对白色念珠菌、新型隐球菌和烟曲霉所观察到的抗真菌活性。
