Structure of Rapamycin: An NMR and Molecular‐Dynamics Investigation

Kessler, Horst; Haeßner, R.; Schuler, Wolfgang

doi:10.1002/hlca.19930760106

Cited by 40 publications

(34 citation statements)

References 42 publications

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“…6,7 In solution, two amide bond rotamers are observed. 8 The predominant rotamer is the trans conformation, which is consistent with the X-ray crystal structure of free or bound rapamycin. 9 -11 The ring-opened acid form of rapamycin (2 and 3) is an acyclic tertiary amide, which has been identified as the major metabolite in vitro as shown in Scheme 1.…”

Section: Introductionsupporting

confidence: 58%

An intramolecular ionic hydrogen bond stabilizes a cis amide bond rotamer of a ring‐opened rapamycin‐degradation product

Zhou

Stewart

Dhaon

2004

Magnetic Reson in Chemistry

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Rapamycin (1), a macrolide immunosuppressant, undergoes degradation into ring-opened acid products 2 and 3 under physiologically relevant conditions. The unsaturated product (3) was isolated and studied in this work. Unlike 1, which has its amide primarily in a trans conformation in solution, 3 has both cis and trans conformations in approximately a 1:1 ratio in dimethyl sulfoxide (DMSO). The amount of cis rotamer was increased dramatically in the presence of an organic base such as triethylamine. The detailed NMR results indicate that the cis rotamer is stabilized through an intramolecular ionic hydrogen bond of the carboxylate anion with the tertiary alcohol as part of a nine-membered ring system. This hydrogen bond was characterized further in organic media and the trans-cis rotamer equilibria were used to estimate the relative bond strengths in several solvents. The additional stabilization arising from this ionic hydrogen bond in the cis rotamer was determined to be 1.4 kcal mol(-1) in DMSO-d6, 2.0 kcal mol(-1) in CD3CN and 1.1 kcal mol(-1) in CD3OD.

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Section: Introductionsupporting

confidence: 58%

An intramolecular ionic hydrogen bond stabilizes a cis amide bond rotamer of a ring‐opened rapamycin‐degradation product

Zhou

Stewart

Dhaon

2004

Magnetic Reson in Chemistry

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“…This binding selectivity is unexpected, because x-ray structures of the isomerase domains of FKBP12 and FKBP52 are very similar and the active site residues have only 1 aa difference (His-87 in FKBP12 versus Ser-118 in FKBP52) (25). It therefore is likely that in the process of interfering with mTOR binding, the introduction of conformation- ally constrained substitutions at the triene of rapamycin can subtly influence the overall global population of macrolactone conformers that in turn affects immunophilin binding selectivity, given that rapamycin is well known to be a dynamic molecule that exists as a set of major and minor solution conformers because of cis-trans isomerization of the amide bond (12,26). This report presents evidence that modification distant to the FKBP-binding domain of rapamycin could generate orders of magnitude changes in immunophilin binding selectivity.…”

Section: Discussionmentioning

confidence: 99%

Binding of rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities

Ruan

Pong

Jow

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

110

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Rapamycin is an immunosuppressive immunophilin ligand reported as having neurotrophic activity. We show that modification of rapamycin at the mammalian target of rapamycin (mTOR) binding region yields immunophilin ligands, WYE-592 and ILS-920, with potent neurotrophic activities in cortical neuronal cultures, efficacy in a rodent model for ischemic stroke, and significantly reduced immunosuppressive activity. Surprisingly, both compounds showed higher binding selectivity for FKBP52 versus FKBP12, in contrast to previously reported immunophilin ligands. Affinity purification revealed two key binding proteins, the immunophilin FKBP52 and the ␤1-subunit of L-type voltage-dependent Ca 2؉ channels (CACNB1). Electrophysiological analysis indicated that both compounds can inhibit L-type Ca 2؉ channels in rat hippocampal neurons and F-11 dorsal root ganglia (DRG)/neuroblastoma cells. We propose that these immunophilin ligands can protect neurons from Ca 2؉ -induced cell death by modulating Ca 2؉ channels and promote neurite outgrowth via FKBP52 binding.immunophilin ͉ L-type voltage-gated calcium channel ͉ natural products ͉ neurodegeneration ͉ stroke

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“…Notice that the trans form dominates in rapamycin solutions. 34 The NMR spectra of 1 in THF-d 8 /D 2 O mixture supported this conclusion (see Figure S10). Scheme 2 presents a proposed mechanism of secorapamycin degradation in aqueous solution.…”

Section: Proposed Mechanism Of Base-catalyzed Degradation Processesmentioning

confidence: 65%

Degradation of rapamycin and its ring-opened isomer: Role of base catalysis

Il’ichev¹,

Alquier²,

Maryanoff³

2007

Arkivoc

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Rapamycin is a natural macrolide immunosuppressant with a distinct mechanism of action. Quantitative analysis of rapamycin poses many challenges associated with facile degradation and the multitude of isomeric forms. The primary goal of this study was to compare degradation of rapamycin and its ring-opened isomer, secorapamycin, in aqueous solution under identical conditions. Reaction kinetics and mechanisms were studied in 30/70 vol/vol acetonitrile-water mixtures containing either MeCOONH 4 (apparent pH 7.3) or NaOH (apparent pH 12.2). Degradation kinetics was well described by the first-order rate law. For rapamycin in 237 and 23.7 mM solutions of MeCOONH 4 , apparent half-lives of 200 h and 890 h were obtained. When compared to the latter value, the rapamycin half-life was reduced by 3 orders of magnitude in the pH 12.2 solution. Under all conditions studied, secorapamycin degradation was significantly slower than that of the parent compound. Both specific and general base catalysis was observed for reactions of rapamycin and secorapamycin. Two primary products of rapamycin degradation were identified as individual isomers of secorapamycin and a hydroxy acid formed via lactone hydrolysis. No evidence for the interconversion between the products was obtained. In highly basic solutions, both products undergo fragmentation and water addition reactions.

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Structure of Rapamycin: An NMR and Molecular‐Dynamics Investigation

Cited by 40 publications

References 42 publications

An intramolecular ionic hydrogen bond stabilizes a cis amide bond rotamer of a ring‐opened rapamycin‐degradation product

An intramolecular ionic hydrogen bond stabilizes a cis amide bond rotamer of a ring‐opened rapamycin‐degradation product

Binding of rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities

Degradation of rapamycin and its ring-opened isomer: Role of base catalysis

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