Retention of Immunosuppressant Activity in an Ascomycin Analogue Lacking a Hydrogen-Bonding Interaction with FKBP12

Abstract

C24-Deoxyascomycin was prepared in a two-step process from ascomycin and evaluated for its immunosuppressant activity relative to ascomycin and FK506. An intermediate in the synthetic pathway, Delta(23,24)-dehydroascomycin, was likewise evaluated. Despite lacking the hydrogen-bonding interactions associated with the C24-hydroxyl moiety of ascomycin, C24-deoxyascomycin was found to be equipotent to the parent compound both in its immunosuppressive potency and in its interaction with the immunophilin, FKBP12. Conversely, Delta(23,24)-dehydroascomycin which also lacks the same hydrogen-bonding interactions did not exhibit this potency. NMR studies were conducted on the FKBP12/C24-deoxyascomycin complex in an attempt to understand this phenomenon at the molecular level. The NMR structures of the complexes formed between FKBP12 and ascomcyin or C24-deoxyascomcyin were very similar, suggesting that hydrogen-bonding interactions with the C24 hydroxyl moiety are not important for complex formation.

Evaluation, synthesis and characterization of tacrolimus impurities

“…7 23,24-anhydro tacrolimus 5 was prepared, in 27% yield, by treatment of 1 with p-toluensulfonic acid in toluene at reflux, similarly to a described synthesis of 23,24-anhydro ascomycin. 8 A characteristic vicinal NMR coupling constant (J) value (16 Hz) of H-23 and H-24 at 6.35 and 7.09 p.p.m., respectively, (see Table 2) was accounted for a E configuration of the 23,24 double bond of synthesized 5. Because chemical-physical properties of 5 were not reported, it was characterized by means of 1 H NMR, MS and FT-IR analyses and the results are collected in Tables 2 and 3.…”

Opportunities and Challenges of Small Molecule Induced Targeted Protein Degradation

“…This protein interacts with calcium channel receptor (Nissin receptors) and keeps the calcium channel in a stable closed state. When FKBP12 dissociates from RyRs, RyRs opens and releases calcium ions, thereby realizing the regulation of important functions of the body through the calcium signaling pathway ( Andrus and Schreiber, 1993 ; Holt et al, 1993 ; Teague and Stocks, 1993 ; Huse et al, 1999 ; Wiedeman et al, 1999 ). One of the important functions of FKBP12 is to participate in the development of the heart and to play an important regulatory role in the phenotypic differentiation of cardiomyocytes, the formation of heart structures and the initiation of heart beats.…”

Natural products as immunosuppressive agents

“…Of particular interest was the fact that 24deoxyascomycin 13 had a similar potency to ascomycin both as an immunosuppressant and also in its interaction with FKBP-12, suggesting that H-bonding with the C24 hydroxy of the natural product is not important for binding to FKBP12. 45 Oligomycin F 14 from an unidentified species of Streptomyces had an IC 50 of 0.1 µg ml Ϫ1 in the mixed lymphocyte reaction in response to the mitogen concavalin A. It is also highly active against a variety of pathogenic fungi of plants.…”