Studies in marine natural products
Author: Barrow, Colin James
Publisher: University of Canterbury. Chemistry
Type: Theses / Dissertations
Link to this item using this URL: http://hdl.handle.net/10092/8598
The bioactivity directed analysis of the extract from a sponge of the genus Sarcotragus led to the isolation of a series of bioactive sesterterpenes, of which variabilin (1a) was the major component. The sesterterpenes (29a), (30) and (31a), along with the related C₂₁ furanoterpene (32), were present in lesser amounts. The unequivocal assignment of the stereochemistry of the 20,21 double bond in variabilin as 20(Z) was achieved through examination of the22-O-methyl derivative (1b) of variabilin and the isolation of the variabilin isomer (29a) with the 20(E) stereochemistry. Variabilin was also isolated from a sponge of the genus lrcinia. The four related bioactive sesterterpenes (33b), (34b), (35b), and (36b) together with (31b) were isolated from a methylated extract from the same sponge. Variabilin autooxidised in the presence of light and air to form a mixture of products that underwent further oxidation on standing. The 22-O-methyl derivative (1b) of variabilin did not autooxidize but underwent oxidation in the presence of the singlet oxygen sensitizer, rose bengal. The products from this oxidation reaction were (48b), (49b), (50b), (51b), (52b), (53b), (50b), (61b), (62b), (63b), (64b) and (65b) and these were the same as the products from the variabilin autooxidation with the exception of the methyl group at C₂₂. Variabilin autooxidation was shown to occur through the production of singlet oxygen and subsequent oxygen addition to the furan moiety. The production of singlet oxygen occurred through a sensitization mechanism involving the variabilin tetronic acid moiety. To investigate structure-bioactivity relationships in variabilin and related sesterterpenes, derivatization of the furan and tetronic acid moieties in variabilin was carried out. 22-O-Me variabilin (1b), in contrast to variabilin, reacted favourably under most furan reaction conditions and so a number of reactions were carried out on (1b) also. Hydrogenation of variabilin gave the cytotoxic compound (73). Dials-Alder addition of DMAD to variabilin gave the cytotoxic compounds (74a) and (75a) and acylation gave the cytotoxic compounds (81) and (82). Reduction of these acylation products gave the cytotoxic derivatives (83) and (84). The non-cytotoxic compound (85) was formed on reaction of p-bromobenzoylchloride with variabilin. Dials-Alder addition of DMAD to 22-O-Me variabilin gave the cytotoxic compounds (74b) and (75b) and addition of 4-phenyl-1,2,4-triazoline-3,5-dione (phenyl-TD) (78) gave the potential antiviral compounds (76) and (77). A cytotoxic sesquiterpene (86) with a tricyclo[18.104.22.168.²,⁵]dodecane skeleton has been isolated from the extract of a New Zealand Eurypon sp. of sponge. Two derivatives, (87) and (88), of this sesquiterpene have also been isolated, probably as artefacts arising during the isolation procedure. The structure of a spirosesquiterpene (89), also obtained from the sponge extract, has been determined. Previously published nmr assignments for β-caryophyllene alcohol (90) have been revised. Three further compounds, labeled unknowns a-c, were isolated, but their structures were not determined. One of these unknowns (unknown a) was probably a sesquiterpene, and was shown to be cytotoxic, while the remaining two (unknowns band c) gave spectroscopic data which indicated that while they were very closely related to one another, they were not sesquiterpenes. Bioassay directed isolations of the active components from a new sponge, genus Chondropsis, and the bryozoan, Margaretta barbata, were attempted. The bryozoan, Margaretta barbata had previously been shown to exhibit significant in vivo P388 activity. For the Chondropsis species the components responsible for the observed biological activity appeared to be very minor components of the overall sponge and isolation of the active compounds was not achieved. For the bryozoan the more polar active material was present in reasonable abundance and a compound (unknown d) giving in vitro P388 activity was isolated. However full characterisation of this compound was not achieved. The compound, or compounds, responsible for the biological activity shown by the less polar material were not isolated. Sterols were shown to be major components of the non-polar organic material in both the sponge and bryozoan species studied. For the Chondropsis sponge the major sterol component was identified as 24-methylene-cholesterol (92). For the bryozoan, Margaretta barbata, the major sterol was identified as cholesterol (93) with 24-methylene-cholesterol (92) and cholest-4-en-3-one (94) also being identified. The major organic water soluble compound was identified as homarine (95).
Copyright: Copyright Colin James Barrow