Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 340-352 |
| Number of pages | 13 |
| Journal | Journal of Natural Products |
| Volume | 79 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 26 2016 |
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ASJC Scopus subject areas
- Drug Discovery
- Pharmacology
- Pharmaceutical Science
- Analytical Chemistry
- Organic Chemistry
- Molecular Medicine
- Complementary and alternative medicine
Cite this
Oxaspirol B with p97 Inhibitory Activity and Other Oxaspirols from Lecythophora sp. FL1375 and FL1031, Endolichenic Fungi Inhabiting Parmotrema tinctorum and Cladonia evansii. / Wijeratne, E. M Kithsiri; Gunaherath, G. M Kamal B; Chapla, Vanessa M.; Tillotson, Joseph; De La Cruz, Fabian; Kang, MinJing; U'Ren, Jana M.; Araujo, Angela R.; Arnold, Anne E; Chapman, Eli; Gunatilaka, Leslie.
In: Journal of Natural Products, Vol. 79, No. 2, 26.02.2016, p. 340-352.Research output: Contribution to journal › Article
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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, MinJing
AU - U'Ren, Jana M.
AU - Araujo, Angela R.
AU - Arnold, Anne E
AU - Chapman, Eli
AU - Gunatilaka, Leslie
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.
UR - http://www.scopus.com/inward/record.url?scp=84959420929&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84959420929&partnerID=8YFLogxK
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 -