- Title
- 1. Dynamin-I inhibitors from sessile marine invertebrates; 2. Chemotaxonomy of Cystophora spp.
- Creator
- Holland, Ian P.
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2011
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- A colourimetric GTPase assay was utilised to screen a marine natural products library of extracts with the goal of identifying novel dynamin-I inhibitors. Bioassay-guided fractionation of an active marine sponge (unknown Australian species) fraction led to the isolation of the methyl esters of eicosapentaenoic acid (EPA) (15) and Arachidonic acid (16). These compounds are structurally similar to the known dynamin-I inhibitors MiTMAB (1) and OcTMAB (2), however, 15 and 16 were inactive in the dynamin-I GTPase bioassay. An extract of another Australian marine sponge Psammocelmma sp. was found to possess dynamin-I inhibitory activity. Bioassay-guided fractionation led to the isolation of four new trihydroxysterols (17–20) related to aragusterol G (22). While 17 was inactive in the dynamin-I bioassay, bioassays did reveal that compounds 17–20 inhibited the growth of colorectal, breast, ovarian and prostate cancer cell lines (GI₅₀ 5–27 μM). The additional insight that these new compounds provide to previous SAR studies is also discussed. In addition, the chemistry of the brown algae Cystophora torulosa and C. xiphocarpa were investigated. It is well known that C. torulosa produces a range of secondary metabolites including resorcinols, tocotrienols, polyunsaturated alkene chains and phloroglucinols. Considering these are fairly ‘standard’ Cystophora compounds that have also been isolated from apparently closely related Cystophora species, the isolation of the previously discovered meromonoterpenes 51a, 52 and 53 was unusual. Since these meroterpenoids potentially could be used as geographic marker compounds for New Zealand populations of C. torulosa and suggest an unexpectedly close relationship with C. harvei it was judged necessary to confirm the isolation of the meromonoterpenoids from C. torulosa. Cystophora torulosa was reinvestigated with the aim of re-isolating 51a, 52 and 53. This investigation yielded many of the known C. torulosa compounds including polyenes (40 and 41), an isoprenyl chroman (48), a resorcinol (42) and fucosterol (92) but not the meromonoterpenes in question. It is apparent from comparison of the TLC profile of the crude C. torulosa extract with the isolated compounds that this investigation has not yet been exhausted and, as such, is ongoing. As the putative ancestor of the genus, C. xiphocarpa was expected to possess only the more common and wide-spread Cystophora compounds, such as phloroglucinols and tocotrienols. To date no secondary metabolites are reported from the species and it was decided to investigate the chemistry of specimens collected in Tasmania. GC-MS of the methyl esters of a transesterified triacylglycerol isolated identified at least thirteen acyl chains, 14:0, 16:3n-6, 16:0, 18:3n-6, 18:4n-3, 18:2n-6, 18:3n-3, 20:4n-6, 20:5n-3, 20:3n-6, 20:4n-3, 20:2 and 20:3n-3, indicating that the triacylglycerol mixture is comprised of at least five different compounds. Cystophora xiphocarpa also yielded a series of eight polyoxygenated steroids (94–101), which includes three pairs of diastereomers, as well as a phaeophytin. Investigation of the stereochemistry of the isolated steroids included the derivatisation of compound 94 using phosgene to form a cyclic carbonate (106), molecular modelling and coupling constant (J) analysis of each compound. As a result, the stereochemistry of only one pair of diastereomers remains undefined. Unfortunately these steroids decomposed before anticancer bioassay data could be obtained. The biosynthesis of steroids is also discussed and a biosynthetic pathway of each of the steroids identified during this research is proposed.
- Subject
- dynamin; marine natural products; steroids; bioassay-guided fractionation; stereochemistry; NMR
- Identifier
- http://hdl.handle.net/1959.13/927961
- Identifier
- uon:10299
- Rights
- Copyright 2011 Ian P. Holland
- Language
- eng
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