Biosynthesis of Nonimmunosuppressive ProlylFK506 Analogues with Neurite Outgrowth and Synaptogenic Activity

• Published in: Journal of natural products (Washington, D.C.) Vol. 84; no. 2; pp. 195 - 203
• Main Authors: Jung, Jin A, Lee, Heon Joo, Song, Myoung Chong, Hwangbo, Areum, Beom, Ji Yoon, Lee, Soo Jung, Park, Dong Jin, Oh, Ji Hoon, Ha, Sang-Jun, Cheong, Eunji, Yoon, Yeo Joon
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society and American Society of Pharmacognosy 26.02.2021
• Subjects: Animals; Cells, Cultured; Fermentation; Hippocampus - cytology; Immunosuppressive Agents; Mice; Mice, Inbred ICR; Molecular Structure; Neuronal Outgrowth - drug effects; Neurons - drug effects; Pipecolic Acids; Streptomyces - metabolism; Tacrolimus - analogs & derivatives
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/acs.jnatprod.0c00767

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.