Antascomicins A, B, C, D and E. Novel FKBP12 Binding Compounds from a Micromonospora Strain.

Fehr, Theo; Sanglier, Jean‐Jacques; Schüler, W.; Gschwind, Liliane; Ponelle, Monique; Schilling, W; Wioland, C

doi:10.7164/antibiotics.49.230

Cited by 61 publications

(39 citation statements)

References 2 publications

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“…[6] SAR studies have confirmed the rare a-ketoacyl pipecolic residue as key to the immunosuppressive pharmacophore. [7] The only other known natural product members of this structure class are meridamycin, from a Venezuelan isolate of Streptomyces hygroscopius, [8] and the antascomicins, from a Chinese soil Micromonospora sp., [9] which also bind to FKBP12 but are not immunosuppressive. Recent literature reports note that FKBP-binding polyketides can exhibit separate and distinct immunosuppressive and neurotrophic pharmacologies, [10] with non-immunosuppressive inhibitors of FKBPs having potential application against important neurological disorders such as multiple sclerosis, [11] traumatic spinal cord injury [12] and Parkinsons disease.…”

Section: Resultsmentioning

confidence: 99%

Nocardiopsins: New FKBP12‐Binding Macrolide Polyketides from an Australian Marine‐Derived Actinomycete, Nocardiopsis sp.

Raju

Piggott

Conte

et al. 2010

Chemistry A European J

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A marine-derived actinomycete, Nocardiopsis sp. (CMB-M0232), obtained from a sediment sample collected at a depth of 55 m off the coast of Brisbane, Australia, yielded two new macrolide polyketides. Structures for nocardiopsins A and B were assigned by detailed spectroscopic analysis, degradation and chemical derivatization. A Marfey's analysis revealed an unexpected acid-mediated partial racemization of the L-pipecolic acid incorporated within the nocardiopsins. The scope of this racemization was assessed against a selection of natural and synthetic N-acyl pipecolic acids. While the nocardiopsins are not antibacterial, antifungal or cytotoxic, they do exhibit low-micromolar binding to the immunophilin FKBP12, consistent with their structural and biosynthetic relationship to the immunosuppressive agents FK506 and rapamycin. The nocardiopsins represent a new point of entry into what has been a valuable, exclusive and reclusive region of bioactive chemical space--that surrounding the FK506/rapamycin pharmacophore.

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Section: Resultsmentioning

confidence: 99%

Nocardiopsins: New FKBP12‐Binding Macrolide Polyketides from an Australian Marine‐Derived Actinomycete, Nocardiopsis sp.

Raju

Piggott

Conte

et al. 2010

Chemistry A European J

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“…Antascomicin B possesses structural similarities to FK506 (Prograf; Astellas Pharma, Bangkok, Thailand) and rapamycin (Rapamune; Wyeth, Madison, NJ) and exhibits potent sub-nanomolar FKBP12 binding activity, but it antagonizes the binding of the immunosuppressants rapamycin and FK-506. 348,349 Recent investigations suggested that small-molecule ligands of FKBP12 possess potent neuroprotective and neurodegenerative properties in mouse models, and they potentially can be validated as a novel drug target for the causative treatment of Parkinson's disease. 350 McIntosh et al reported recently on the synthesis of antascomicin B C22-C34 fragment 249 where directed hydrogenation was employed to set the C29 stereocenter (Scheme 29.31).…”

Section: Ir-catalyzed Hydrogenation In Stereoselective Synthesesmentioning

confidence: 99%

Stereoselective Hydrogenation ofCCBonds: Application to Drug and Natural Product Synthesis

Andrushko

2013

Stereoselective Synthesis of Drugs and Natural Products

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Asymmetric homogeneous hydrogenation is perhaps one of the most researched areas in homogeneous catalysis; thus, it is now used in numerous innovative applications in stereoselective syntheses of many chiral pharmaceutical and natural products. Metal complexes, derived from transition metals, like Rh, Ru, Ir, and so on, and chiral ligands (usually mono‐ or diphosphine ligands), are widely used as catalysts in asymmetric alkene hydrogenation as a result of their efficiency in the preparation of enantiopure compounds with excellent atom economy. This chapter provides many interesting examples of homogeneous enantio‐ and diastereoselective hydrogenation of CC bonds, highlighting the utility of these methods as useful synthetic tools for the construction of stereogenic centers in stereoselective drug and natural product syntheses.

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“…One of these effects, or the combination of both, could explain the very low immunosuppressive activity of ATG181. In any event, binding of a compound to FKBP-12 (a protein with peptidyl-prolyl isomerase activity) per se has apparently no biological consequences except for antagonizing the immunosuppressive activity of FK506, rapamycin, and everolimus; no other biological effects have been found so far for the known nonimmunosuppressive FKBP-12-binding molecules (Dumont et al, 1992;Fehr et al, 1996).…”

Section: Zollinger Et Almentioning

confidence: 99%

The Macrolide Everolimus Forms an Unusual Metabolite in Animals and Humans: Identification of a Phosphocholine Ester

Zollinger¹,

Sayer²,

Dannecker³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The immunosuppressant macrolide everolimus was found to be metabolized in animals and humans to a phosphocholine ester (ATG181), a hitherto unknown type of conjugate in xenobiotic metabolism. The structure of ATG181 was elucidated by mass spectrometry and confirmed by synthesis. ATG181 was among the most prominent metabolites of everolimus in rat, monkey, and human blood and was found also in various tissues of the rat, whereas no ATG181 was identified in the urine and feces of the species investigated. The metabolite showed binding to FK506 binding protein with a 2-to 3-fold higher affinity than everolimus. However, ATG181 exhibited only marginal in vitro immunosuppressive activity and is therefore very unlikely to contribute in a relevant manner to the immunosuppressive effect of everolimus.

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Antascomicins A, B, C, D and E. Novel FKBP12 Binding Compounds from a Micromonospora Strain.

Cited by 61 publications

References 2 publications

Nocardiopsins: New FKBP12‐Binding Macrolide Polyketides from an Australian Marine‐Derived Actinomycete, Nocardiopsis sp.

Nocardiopsins: New FKBP12‐Binding Macrolide Polyketides from an Australian Marine‐Derived Actinomycete, Nocardiopsis sp.

Stereoselective Hydrogenation ofCCBonds: Application to Drug and Natural Product Synthesis

The Macrolide Everolimus Forms an Unusual Metabolite in Animals and Humans: Identification of a Phosphocholine Ester

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