Nocardiopsins: new FKBP12-binding macrolide polyketides from an Australian marine-derived actinomycete, Nocardiopsis sp.
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.
Raju
Ritesh
R
Institute for Molecular Bioscience, The University of Queensland, Carmody Road, St. Lucia, Brisbane 4072, Australia.
Piggott
Andrew M
AM
Conte
Melissa
M
Tnimov
Zakir
Z
Alexandrov
Kirill
K
Capon
Robert J
RJ
D039903:Actinobacteria / Q000737:chemistry* / Q000302:isolation & purification*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000302:isolation & purification*; D007120:Immunochemistry / Q000379:methods; D007166:Immunosuppressive Agents / Q000737:chemistry*; D018942:Macrolides / Q000737:chemistry* / Q000302:isolation & purification* / Q000378:metabolism; D008386:Marine Biology; D015394:Molecular Structure; D020123:Sirolimus / Q000737:chemistry*; D016559:Tacrolimus / Q000737:chemistry*; D022061:Tacrolimus Binding Protein 1A / Q000737:chemistry* / Q000302:isolation & purification* / Q000378:metabolism
D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D018942:Macrolides; C548744:nocardiopsin A; C548743:nocardiopsin B; D022061:Tacrolimus Binding Protein 1A; D020123:Sirolimus; D016559:Tacrolimus