This thesis represents a continuation of the work on the isolation and
structure elucidation of potential drug leads from terrestrial fungal sources
that the natural products group at the University of Canterbury has been
engaged in.
Capillary NMR spectroscopy was involved in the research as the main tool
for dereplication and elucidating the structures of novel bioactive
compounds as well as for biosynthetic studies.
Eleven new compounds including five cyclic peptides, four related pyrones
and two diketopiperazines were isolated from the extract of Aspergillus sp.
of endophyte collected from Malaysia. The five peptides F8268-A-1 to
F8268-A-5 showed excellent P388 (HCT116 (ATCC CCL-247) and human
breast cancer, MCF7 (ATCC HTB-22)) activities. Two of the peptides
F8268-A-3 and F8268-A-5 were 4,000 times more active when compared
with commercial drugs (fluorouracil, cisplatin and tamoxifen). The partial
stereochemistries of F8268-A-2 and F8268-A-3 were established by
Marfey’s method.
Four related pyrones isolated from the same extract were also shown to have
good P388 activities. They are related to the known compound NF00659A3.
The relative stereochemistries were established from NOSEY experiments
and the energy-minimised (MM2) model created using CHEM 3D software.
Two new diketopiperazines, F7474-D3 and F7474-D11, also isolated from
the Aspergillus extract did not show activity in the P388 assay. F7474-D11
contained the amino acid Me-kynurenine which is the first report of this
from a natural source. The absolute stereochemistry of F7474-D11 was
elucidated by Marfey’s method. The other diketopiperazine F7474-D3 was similar to the known compound lumpidin, and combined use of ROESY
NMR and Marfey’s method established that the constituent amino acids had
the unusual R configuration.
Dereplication has been greatly improved by the application of capillary
NMR. For example, the HPLC analysis and UV library searching of
compounds from extracts F8095 and F7855 suggested they contained related
compounds belonging to the lasiodiplodin family. However, CapNMR
spectroscopic analysis and AntiMarin database searching revealed that the
compounds from F8095 were all known polyesters while the compounds
from F7855 did belong to the lasiodiplodin family. Two new lasiodiplodins
were found in the F7855 extract,
(3R,4R)-4-hydroxy-de-O-methyl-lasiodiplodin (F7855-4) and
(E)-9-etheno-de-O-methyl-lasiodiplodin (F7855-6). The relative
stereochemistries were elucidated from NMR coupling constant analyses.
Two new dimers (F7090-A and F7090-B) were elucidated from a New
Zealand fungal endophyte. The differences between these two dimers was
their stereochemistries. F7090-A had the same stereochemistries for the
three stereocentres in both parts, while the stereochemistry of F7090-B was
different in the two parts of the dimer.
Biosynthetic studies were also carried out using CapNMR methodology. A
known compound tetrahydrofuran A and a new compound tetrahydrofuran B
from an unidentified New Zealand fungus were used for this study. For the
first time an INADEQUATE NMR experiment was successfully carried out
using CapNMR spectroscopy, thus demonstrating the capability for carrying
out biosynthetic studies on a very small scale (<200 μg of ¹³C-labelled
compound). The implementation of efficient dereplication procedures with CapNMR
methodology is paramount for those working in the field of natural products.
The recent advances that have been made in the dereplication process in the
natural products group at the University of Canterbury are given using
examples from this research and where necessary from other group
members.
| Identifer | oai:union.ndltd.org:canterbury.ac.nz/oai:ir.canterbury.ac.nz:10092/4188 |
| Date | January 2009 |
| Creators | Sun, Lin |
| Publisher | University of Canterbury. Chemistry |
| Source Sets | University of Canterbury |
| Language | English |
| Detected Language | English |
| Type | Electronic thesis or dissertation, Text |
| Rights | Copyright Lin Sun, http://library.canterbury.ac.nz/thesis/etheses_copyright.shtml |
| Relation | NZCU |
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