Separating the immunosuppressive activity of FK506 (1) from its neurotrophic activity is required to develop FK506 analogues as drugs for the treatment of neuronal diseases. Two new FK506 analogues, 9-deoxo-36,37-dihydro-prolylFK506 (2) and 9-deoxo-31-O-demethyl-36,37-dihydro-prolylFK506 (3) containing a proline moiety instead of the pipecolate ring at C-1 and modifications at the C-9/C-31 and C-36–C-37 positions, respectively, were biosynthesized, and their biological activities were evaluated. The proline substitution in 9-deoxo-36,37-dihydroFK506 and 9-deoxo-31-O-demethyl-36,37-dihydroFK506 reduced immunosuppressive activity by more than 120-fold, as previously observed. Compared with FK506 (1), 2 and 3 exhibited ∼1.2 × 105- and 2.2 × 105-fold reductions in immunosuppressive activity, respectively, whereas they retained almost identical neurite outgrowth activity. Furthermore, these compounds significantly increased the strength of synaptic transmission, confirming that replacement of the pipecolate ring with a proline is critical to reduce the strong immunosuppressive activity of FK506 (1) while enhancing its neurotrophic activity.

中文翻译：

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具有神经突生长和突触活性的非免疫抑制性 ProlylFK506 类似物的生物合成

需要将 FK506 ( 1 )的免疫抑制活性与其神经营养活性分开，以开发 FK506 类似物作为治疗神经元疾病的药物。两种新的 FK506 类似物，9-deoxo-36,37-dihydro-prolylFK506 ( 2 ) 和 9 -deoxo -31-O-demethyl-36,37-dihydro-prolylFK506 ( 3 ) 含有脯氨酸部分而不是哌啶环分别合成了 C-1 和 C-9/C-31 和 C-36-C-37 位置的修饰，并评估了它们的生物活性。如前所述，9-deoxo-36,37-dihydroFK506 和 9-deoxo-31-O-demethyl-36,37-dihydroFK506 中的脯氨酸取代将免疫抑制活性降低了 120 倍以上。与 FK506 ( 1 )相比，2和3 的免疫抑制活性分别降低了 1.2 × 105 和 2.2 × 105 倍，而它们保留了几乎相同的神经突生长活性。此外，这些化合物显着增加了突触传递的强度，证实了用脯氨酸替换哌可酸环对于降低 FK506 ( 1 )的强免疫抑制活性同时增强其神经营养活性至关重要。