Structural Basis for Peptidomimicry by the Effector Element of Rapamycin

Odagaki, Y.; Clardy, Jon

doi:10.1021/ja972098w

Cited by 13 publications

(12 citation statements)

References 22 publications

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“…The biological activities of rapamycin and temsirolimus are dependent on the binding of the left-hand portion (C 8 -C 31 , the "binding domain") of the molecule to FKBP12 to form a complex that in turn binds the mTOR protein through the remaining portion of the molecule (the "effector domain" (Odagaki et al, 1997;Sedrani et al, 1999). The inhibition of the mTOR pathway by FKBP12-rapamycin (or temsirolimus) blocks multiple downstream signals and leads to a general antiproliferative effect.…”

Section: Cai Et Almentioning

confidence: 99%

In Vitro Metabolic Study of Temsirolimus: Preparation, Isolation, and Identification of the Metabolites

Cai¹,

Tsao²,

Ruppen³

2007

Drug Metab Dispos

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ABSTRACT:The in vitro metabolism of temsirolimus, (rapamycin-42-[2,2-bis-(hydroxymethyl)]-propionate), an antineoplastic agent, was studied using human liver microsomes as well as recombinant human cytochrome P450s, namely CYP3A4, 1A2, 2A6, 2C8, 2C9, 2C19, and 2E1. Fifteen metabolites were detected by liquid chromatography (LC)-tandem mass spectrometry (MS/MS or MS/MS/MS). CYP3A4 was identified as the main enzyme responsible for the metabolism of the compound. Incubation of temsirolimus with recombinant CYP3A4 produced most of the metabolites detected from incubation with human liver microsomes, which was used for large-scale preparation of the metabolites. By silica gel chromatography followed by semipreparative reverse-phase high-performance liquid chromatography, individual metabolites were separated and purified for structural elucidation and bioactivity studies. The minor metabolites (peaks 1-7) were identified as hydroxylated or desmethylated macrolide ring-opened temsirolimus derivatives by both positive and negative mass spectrometry (MS) and MS/MS spectroscopic methods. Because these compounds were unstable and only present in trace amounts, no further investigations were conducted. Six major metabolites were identified as 36-hydroxyl temsirolimus (M8), 35-hydroxyl temsirolimus (M9), 11-hydroxyl temsirolimus with an opened hemiketal ring (M10 and M11), Noxide temsirolimus (M12), and 32-O-desmethyl temsirolimus (M13) using combined LC-MS, MS/MS, MS/MS/MS, and NMR techniques. Compared with the parent compound, these metabolites showed dramatically decreased activity against LNCaP cellular proliferation.Temsirolimus (sirolimus-42-[2,2-bis-(hydroxymethyl)]-propionate) is an ester analog of rapamycin (Fig. 1), a natural macrolide antibiotic with antifungal, antitumor, and immunosuppressive activities (Sehgal et al., 1994). Temsirolimus has demonstrated significant inhibition of tumor growth both in vitro and in vivo. It binds to the cytoplasmic protein FKBP, forming a complex that antagonizes the mammalian target of rapamycin (mTOR) signaling pathway (Peralba et al., 2003), which consequently inhibits many of the downstream processes affected by mTOR kinase activity, including transcriptional and translational control of important cell cycle regulators, resulting in cell cycle arrest (Sehgal 1995). Temsirolimus is currently in phase III clinical development for the treatment of renal cancer.Although CYP3A4 had been identified as the major enzyme involved in the formation of the main metabolite of rapamycin, 41-Odesmethyl rapamycin (Christiants et al., 1992;Sattler et al., 1992; Wang et al., 1994), little additional information about rapamycin metabolism has been reported because of the complexity of the metabolic profile and the instability of the metabolites. Thus, the objective of this study was to identify the human P450 enzymes involved in temsirolimus metabolism, isolate and characterize the major metabolites, and evaluate their antitumor activities. Materials and MethodsChemicals and Reagents. Temsiro...

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Section: Cai Et Almentioning

confidence: 99%

In Vitro Metabolic Study of Temsirolimus: Preparation, Isolation, and Identification of the Metabolites

Cai¹,

Tsao²,

Ruppen³

2007

Drug Metab Dispos

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“…The mimicking of natural peptides, both structurally and functionally, with artificial oligomers is referred to as peptidomimicry . The end products are called peptidomimetics .…”

Section: Introductionmentioning

confidence: 99%

“…The mimicking of natural peptides, both structurally and functionally, with artificial oligomers is referred to as peptidomimicry. [1][2][3][4][5][6] The end products are called peptidomimetics. [7][8][9] Various strategies, such as cyclization of linear peptides, [10][11][12] replacing the natural amino acids with unnatural ones, [13][14][15][16] substitution of the amide functionality with other functional groups etc., [17] have been applied to construct peptide mimetics.…”

Section: Introductionmentioning

confidence: 99%

“…Ball and stick conformation of trimeric diammonium trifluoroacetate salts (single crystal X-ray structures), 1 R 2 S 1 R * 2TFA (top left, for clarity, TFA was omitted) is helical and (1 R )3 (top right) is extended. Middle: Stereo diagram of the X-ray crystal structure of 2 R (1 R t-Boc)2 showing hydrogen bonding between extended conformations. Bottom: Line structure of 2 R (1 R t-Boc)2 .…”

mentioning

confidence: 99%

“…Middle: Stereo diagram of the X-ray crystal structure of 2 R (1 R t-Boc)2 showing hydrogen bonding between extended conformations. Bottom: Line structure of 2 R (1 R t-Boc)2 .…”

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confidence: 99%

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Peptidomimicry with C₂‐Symmetric Oligourea Derivatives of 1,2‐Diaminocyclohexane and 1,2‐Diphenyl‐1,2‐diaminoethane: Chirality and Chain Length‐Dependent Conformation

et al. 2018

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To study whether C2 symmetric oligoureas form secondary structures such as sheets and helices/turns to serve as peptidomimetics, conformations of oligoureas composed of 1,2‐diaminocyclohexane and 1,2‐diphenyl‐1,2‐diaminoethane were investigated using X‐ray diffraction, UV, CD and NMR spectroscopic methods. Alternating heterochiral diamines in these chains strongly favored helical conformations. The conformations of C2‐symmetric chains of homochiral diamines were more conditional, giving indications of conditional extended and helical structure.

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Immunosuppressive Agents for the Prevention of Transplantation Rejection

Pitts

2010

Burger's Medicinal Chemistry and Drug Discovery

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This chapter will focus on “small” molecule therapeutics that demonstrate useful immunosuppressant activity including established classes such as calcineurin inhibitors (cyclosporin A and tacrolimus), mTOR ( m ammalian t arget o f r apamycin ) agents (sirolimus, everolimus), and antiproliferative/antimetabolite agents (azathioprine, mycophenolic acid derivatives). This chapter will also introduce some agents with newer pharmacology mechanisms such as sphingosine receptor modulation (FTY720), inhibition of JAK3 (CP‐690,550), and inhibition of PKC θ (AEB071). Other agents useful in organ transplantation including glucocorticoids (such as prednisone and dexamethasone), nitrogen mustards (such as cyclophosphamide), and biologic agents (such as muromonab‐CD3, basiliximab, and daclizumab) are discussed elsewhere.

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Structural Basis for Peptidomimicry by the Effector Element of Rapamycin

Cited by 13 publications

References 22 publications

In Vitro Metabolic Study of Temsirolimus: Preparation, Isolation, and Identification of the Metabolites

In Vitro Metabolic Study of Temsirolimus: Preparation, Isolation, and Identification of the Metabolites

Peptidomimicry with C₂‐Symmetric Oligourea Derivatives of 1,2‐Diaminocyclohexane and 1,2‐Diphenyl‐1,2‐diaminoethane: Chirality and Chain Length‐Dependent Conformation

Immunosuppressive Agents for the Prevention of Transplantation Rejection

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Structural Basis for Peptidomimicry by the Effector Element of Rapamycin

Cited by 13 publications

References 22 publications

In Vitro Metabolic Study of Temsirolimus: Preparation, Isolation, and Identification of the Metabolites

In Vitro Metabolic Study of Temsirolimus: Preparation, Isolation, and Identification of the Metabolites

Peptidomimicry with C2‐Symmetric Oligourea Derivatives of 1,2‐Diaminocyclohexane and 1,2‐Diphenyl‐1,2‐diaminoethane: Chirality and Chain Length‐Dependent Conformation

Immunosuppressive Agents for the Prevention of Transplantation Rejection

Contact Info

Product

Resources

About

Peptidomimicry with C₂‐Symmetric Oligourea Derivatives of 1,2‐Diaminocyclohexane and 1,2‐Diphenyl‐1,2‐diaminoethane: Chirality and Chain Length‐Dependent Conformation