Goldstein A S, Frye L L
Cogswell Lab, Renessalear Polytechnic Institute, Troy, New York 12180, USA.
J Med Chem. 1996 Dec 20;39(26):5092-9. doi: 10.1021/jm9605851.
Ergosterol, the predominant sterol of fungi, is postulated to have many cellular functions which include a bulk membrane role and a regulatory role. Studies with sterol auxotrophs show that, even in the presence of sterols which can fulfill the bulk membrane requirements, a small concentration of ergosterol is absolutely necessary for growth. The delta 5-double bond appears to be required for the regulatory role of ergosterol; therefore, development of inhibitors of the enzyme that introduce this double bond, delta 7-sterol 5-desaturase (5-desaturase), may lead to effective antifungal agents. Within is the first reported synthesis of inhibitors of fungal 5-desaturase and the development of an in vitro tritium efficacy radioassay. The inhibitors were of the general structure 7,22(E)-ergostadien-3 beta-ol with alpha-face heteroatom substituents in the vicinity of C-5. They exhibited IC50 values of 47-149 microM.
麦角固醇是真菌中的主要固醇，据推测具有多种细胞功能，包括在细胞膜中起主要作用以及发挥调节作用。对固醇营养缺陷型的研究表明，即使存在能够满足细胞膜主要需求的固醇，少量浓度的麦角固醇对于生长也是绝对必需的。麦角固醇的调节作用似乎需要δ5-双键；因此，开发引入此双键的酶（δ7-固醇5-去饱和酶，即5-去饱和酶）的抑制剂可能会产生有效的抗真菌剂。本文首次报道了真菌5-去饱和酶抑制剂的合成以及体外氚效能放射性测定法的开发。这些抑制剂的一般结构为7,22(E)-麦角二烯-3β-醇，在C-5附近的α面带有杂原子取代基。它们的IC50值为47 - 149微摩尔。
