Zambias R A, Hammond M L, Heck J V, Bartizal K, Trainor C, Abruzzo G, Schmatz D M, Nollstadt K M
Merck Research Laboratories, Rahway, New Jersey 07065.
J Med Chem. 1992 Jul 24;35(15):2843-55. doi: 10.1021/jm00093a018.
The echinocandins are a well-known class of lipopeptides characterized by their potent antifungal activity against Candida species. The mechanism of action of the echinocandins is generally thought to be the inhibition of beta-1,3-glucan synthesis, an important structural component in the cell wall of Candida species. Extensive structure-activity studies on the fatty acid side chain of echinocandin B (1) led to the preparation of the clinical candidate cilofungin (4). However, little is known about the cyclic peptide. We now report the preparation, by solid-phase synthesis, of a series of simplified analogs of cilofungin in which the unusual amino acids found in the echinocandins were replaced with more readily accessible natural amino acids. The solid-phase approach to the total synthesis of these analogs allowed us to conveniently explore structural modifications that could not be accomplished by chemical modification of the natural product. The simplest analog 5 showed no biological activity. Structural complexity was then returned to the system in a systematic fashion so as to reapproach the original cilofungin structure. Antifungal activity and the inhibition of beta-1,3-glucan synthesis were monitored at each step of the process, thereby revealing the basic structure-activity relationships of the amino acids and the minimal structural requirements for biological activity in the echinocandin ring system. The results suggests that the 3-hydroxy-4-methylproline residue enhances activity but the L-homotyrosine residue is crucial for both antifungal activity and the inhibition of beta-1,3-glucan synthesis.
棘白菌素是一类著名的脂肽，其特征在于对念珠菌属具有强大的抗真菌活性。棘白菌素的作用机制通常被认为是抑制β-1,3-葡聚糖合成，这是念珠菌属细胞壁中的一种重要结构成分。对棘白菌素B（1）脂肪酸侧链的广泛构效关系研究导致了临床候选药物西洛芬净（4）的制备。然而，关于环肽的了解却很少。我们现在报告通过固相合成制备了一系列简化的西洛芬净类似物，其中棘白菌素中发现的不寻常氨基酸被更容易获得的天然氨基酸所取代。这些类似物的全合成固相方法使我们能够方便地探索通过天然产物化学修饰无法实现的结构修饰。最简单的类似物5没有显示出生物活性。然后以系统的方式恢复系统的结构复杂性，以便重新接近原始的西洛芬净结构。在该过程的每个步骤中监测抗真菌活性和β-1,3-葡聚糖合成的抑制，从而揭示棘白菌素环系统中氨基酸的基本构效关系和生物活性的最小结构要求。结果表明，3-羟基-4-甲基脯氨酸残基增强活性，但L-高酪氨酸残基对于抗真菌活性和β-1,3-葡聚糖合成抑制均至关重要。
