TY - JOUR
T1 - Oxaspirol B with p97 Inhibitory Activity and Other Oxaspirols from Lecythophora sp. FL1375 and FL1031, Endolichenic Fungi Inhabiting Parmotrema tinctorum and Cladonia evansii
AU - Wijeratne, E. M.Kithsiri
AU - Gunaherath, G. M.Kamal B.
AU - Chapla, Vanessa M.
AU - Tillotson, Joseph
AU - De La Cruz, Fabian
AU - Kang, Min Jing
AU - U'Ren, Jana M.
AU - Araujo, Angela R.
AU - Arnold, A. Elizabeth
AU - Chapman, Eli
AU - Gunatilaka, A. A.Leslie
N1 - Funding Information:
Financial support for this work was provided by Grants R01 CA090265 funded by the National Cancer Institute, P41 GM094060 funded by National Institute of General Medical Sciences, R01 ES023758 funded by National Institute of Environmental Health Sciences, and DEB-0640996 funded by National Science Foundation. We also thank University of Arizona for start-up funds (E.C.) and CAPES, Brazil, for the graduate fellowship (V.M.C.).
Publisher Copyright:
© 2016 The American Chemical Society and American Society of Pharmacognosy.
PY - 2016/2/26
Y1 - 2016/2/26
N2 - A new metabolite, oxaspirol D (4), together with oxaspirols B (2) and C (3) were isolated from Lecythophora sp. FL1375, an endolichenic fungus isolated from Parmotrema tinctorum, whereas Lecythophora sp. FL1031 inhabiting the lichen Cladonia evansii afforded oxaspirols A (1), B (2), and C (3). Of these, oxaspirol B (2) showed moderate p97 ATPase inhibitory activity. A detailed characterization of all oxaspirols was undertaken because structures proposed for known oxaspirols have involved incomplete assignments of NMR spectroscopic data leading only to their planar structures. Thus, the naturally occurring isomeric mixture (2a and 2b) of oxaspirol B was separated as their diacetates (5a and 5b) and the structures and absolute configurations of 1, 2a, 2b, 3, and 4 were determined by the application of spectroscopic techniques including two-dimensional NMR and the modified Mosher's ester method. Oxaspirol B (2) and its diacetates 5a and 5b were evaluated for their ATPase inhibitory activities of p97, p97 mutants, and other ATP-utilizing enzymes, and only 2 was found to be active, indicating the requirement of some structural features in oxaspirols for their activity. Additional biochemical and cellular assays suggested that 2 was a reversible, non-ATP competitive, and specific inhibitor of p97.
AB - A new metabolite, oxaspirol D (4), together with oxaspirols B (2) and C (3) were isolated from Lecythophora sp. FL1375, an endolichenic fungus isolated from Parmotrema tinctorum, whereas Lecythophora sp. FL1031 inhabiting the lichen Cladonia evansii afforded oxaspirols A (1), B (2), and C (3). Of these, oxaspirol B (2) showed moderate p97 ATPase inhibitory activity. A detailed characterization of all oxaspirols was undertaken because structures proposed for known oxaspirols have involved incomplete assignments of NMR spectroscopic data leading only to their planar structures. Thus, the naturally occurring isomeric mixture (2a and 2b) of oxaspirol B was separated as their diacetates (5a and 5b) and the structures and absolute configurations of 1, 2a, 2b, 3, and 4 were determined by the application of spectroscopic techniques including two-dimensional NMR and the modified Mosher's ester method. Oxaspirol B (2) and its diacetates 5a and 5b were evaluated for their ATPase inhibitory activities of p97, p97 mutants, and other ATP-utilizing enzymes, and only 2 was found to be active, indicating the requirement of some structural features in oxaspirols for their activity. Additional biochemical and cellular assays suggested that 2 was a reversible, non-ATP competitive, and specific inhibitor of p97.
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U2 - 10.1021/acs.jnatprod.5b00986
DO - 10.1021/acs.jnatprod.5b00986
M3 - Article
C2 - 26812276
AN - SCOPUS:84959420929
VL - 79
SP - 340
EP - 352
JO - Journal of Natural Products
JF - Journal of Natural Products
SN - 0163-3864
IS - 2
ER -