Hocart S J, Nekola M V, Coy D H
Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
J Med Chem. 1987 Oct;30(10):1910-4. doi: 10.1021/jm00393a038.
The solid-phase reductive alkylation of the Lys side chain in positions 6 (D) and 8 (L) and position 8 alone of the LH-RH antagonist [N-Ac-D-Nal,D-Ph2,3,D-Arg6,Phe7,D-Ala10]LH-RH was investigated in an attempt to reduce the histamine-releasing activity inherent to most potent antagonists while retaining high antiovulatory activity. The protected parent analogues were prepared by conventional solid-phase peptide synthesis. After selective removal of the Lys Fmoc side chain protection, the resin-bound peptides were readily and conveniently alkylated at the epsilon amino groups with various aldehydes and ketones in the presence of NaBH3CN. The analogues were then cleaved from the resin with simultaneous deprotection by anhydrous hydrogen fluoride and purified to homogeneity in two stages: gel permeation followed by preparative reversed-phase liquid chromatography. The analogues were assayed in standard rat antiovulatory and in vitro histamine-release assays.
研究了促黄体生成素释放激素（LH-RH）拮抗剂[N-乙酰基-D-萘丙氨酸，D-二苯基丙氨酸，3，D-精氨酸6，苯丙氨酸7，D-丙氨酸10]LH-RH中第6位（D）和第8位（L）以及仅第8位赖氨酸侧链的固相还原烷基化反应，目的是在保留高抗排卵活性的同时，降低大多数强效拮抗剂固有的组胺释放活性。通过常规固相肽合成制备了受保护的母体类似物。选择性去除赖氨酸Fmoc侧链保护基后，在NaBH3CN存在下，树脂结合的肽很容易且方便地在ε-氨基处用各种醛和酮进行烷基化。然后用无水氟化氢同时进行脱保护，将类似物从树脂上裂解下来，并分两个阶段纯化至均一性：凝胶渗透，然后进行制备型反相液相色谱。在标准大鼠抗排卵和体外组胺释放试验中对类似物进行了测定。
