Chemical and Biological Aspects of Secondary Metabolites from Tongan Marine Sponges

<p>This thesis describes the isolation and structural elucidation of 17 new secondary metabolites from Tongan marine sponges including examples of alkaloids, polyketides and terpenoids. In the process of this work, 19 sponge specimens were subjected to preliminary NMR-guided investigation. Nine organisms were selected for further analysis on the basis of the structural novelty perceived within the HMBC spectrum of crude fractions generated by the first chromatographic purification of their crude extracts, and the apparent rarity of the specimen. Investigation of two different demosponge specimens afforded the γ-hydroxybutenolide sesterterpenes (23 and 24), and small quantities of the potently cytotoxic alkaloid 14-bromohomofascaplysin (29). The analysis of two samples of a dictyoceratid sponge yielded the new labdane diterpenes luakuliides A–C (33–36), characterised by a bridging hemi-acetal function on the B-ring of the labdane bicycle. Luakuliide A (33) and its methyl acetal derivative 34 were found to display interesting immunomodulatory activity. Seven new α-pyrone polyketides, lehualides E–K (69–75), were isolated from a Plakortis sp. Lehualides H–K (72–75) display a range of sulfur functionalities, the natures of which were determined by spectroscopic comparison with synthesised model compounds. Another plakinid sponge specimen contained four new polyketides (95–98), all of which possess different cyclic peroxide moieties. Cyclic peroxides 95, 97 and 98 displayed potent cytoxicity against human promyelocytic leukemia cells (HL- 60). Chemical genetic and phenoytypic profiling studies of 95 were undertaken in Saccharomyces cerevisiae yeast using the homozygous diploid and heterozygous diploid deletion libraries. These studies indicate that 95 acts to disrupt Ca2+ homeostasis, leading to elevation of intracellular Ca2 levels.</p>

Chemical and Biological Aspects of Secondary Metabolites from Tongan Marine Sponges

<p>This thesis describes the isolation and structural elucidation of 17 new secondary metabolites from Tongan marine sponges including examples of alkaloids, polyketides and terpenoids. In the process of this work, 19 sponge specimens were subjected to preliminary NMR-guided investigation. Nine organisms were selected for further analysis on the basis of the structural novelty perceived within the HMBC spectrum of crude fractions generated by the first chromatographic purification of their crude extracts, and the apparent rarity of the specimen. Investigation of two different demosponge specimens afforded the γ-hydroxybutenolide sesterterpenes (23 and 24), and small quantities of the potently cytotoxic alkaloid 14-bromohomofascaplysin (29). The analysis of two samples of a dictyoceratid sponge yielded the new labdane diterpenes luakuliides A–C (33–36), characterised by a bridging hemi-acetal function on the B-ring of the labdane bicycle. Luakuliide A (33) and its methyl acetal derivative 34 were found to display interesting immunomodulatory activity. Seven new α-pyrone polyketides, lehualides E–K (69–75), were isolated from a Plakortis sp. Lehualides H–K (72–75) display a range of sulfur functionalities, the natures of which were determined by spectroscopic comparison with synthesised model compounds. Another plakinid sponge specimen contained four new polyketides (95–98), all of which possess different cyclic peroxide moieties. Cyclic peroxides 95, 97 and 98 displayed potent cytoxicity against human promyelocytic leukemia cells (HL- 60). Chemical genetic and phenoytypic profiling studies of 95 were undertaken in Saccharomyces cerevisiae yeast using the homozygous diploid and heterozygous diploid deletion libraries. These studies indicate that 95 acts to disrupt Ca2+ homeostasis, leading to elevation of intracellular Ca2 levels.</p>

Novel Photoinduced Squalene Cyclic Peroxide Identified, Detected, and Quantified in Human Skin Surface Lipids

Skin surface lipids (SSLs) form the first barrier that protects the human organism from external stressors, disruption of the homeostasis of SSLs can result in severe skin abnormalities. One of the main causes of this disruption is oxidative stress that is primarily due to SSLs oxidation. Squalene (SQ), the most abundant lipid among SSLs, was shown to first undergo singlet molecular oxygen (1O2) oxidation to yield 6 SQ-monohydroperoxide (SQ-OOH) isomers as the primary oxidation products. However, due to the instability and lability of hydroperoxides, we found that when total SQ-OOH isomers are further photooxidized, they form a unique higher molecular weight secondary oxidation product. To generate the compound, we photooxidized total SQ-OOH isomers in the presence of ground state molecular oxygen (3O2), after its isolation and purification, we studied its structure using MS/MS, NMR, derivatization reactions, and chemical calculations. The compound was identified as 2-OOH-3-(1,2-dioxane)-SQ. Photooxidation of individual SQ-OOH isomers revealed that 6-OOH-SQ is the precursor of 2-OOH-3-(1,2-dioxane)-SQ and indicated the possibility of the formation of similar cyclic peroxides from each isomer following the same photoinduced chain reaction mechanism. An HPLC-MS/MS method was developed for the analysis of 2-OOH-3-(1,2-dioxane)-SQ and its presence on the skin was confirmed in SSLs of six healthy individuals. Its quantity on the skin correlated directly to that of SQ and was not inversely proportional to its precursor, indicating the possibility of its accumulation on the skin surface and the constant regeneration of 6-OOH-SQ from SQ’s oxidation. In general, research on lipid cyclic peroxides in the human organism is very limited, and especially on the skin. This study shows for the first time the identification and presence of a novel SQ cyclic peroxide “2-OOH-3-(1,2-dioxane)-SQ” in SSLs, shedding light on the importance of further studying its effect and role on the skin.

Elucidating the Chemiexcitation of Dioxetanones by Replacing the Peroxide Bond with S-S, N-N and C-C Bonds

Dioxetanone is one of the prototypical cyclic peroxide intermediates in several chemiluminescent and bioluminescent systems, in which thermolysis reactions allow for efficient singlet chemiexcitation. While the chemiexcitation mechanism of dioxetanone...

Withanolide-Type Steroids from Withania aristata as Potential Anti-Leukemic Agents

Leukemia is a blood or bone marrow cancer with increasing incidence in developed regions of the world. Currently, there is an ongoing need for novel and safe anti-leukemic agents, as no fully effective chemotherapy is available to treat this life-threatening disease. Herein, are reported the isolation, structural elucidation, and anti-leukemic evaluation of twenty-nine withanolide-type steroids (1–29) from Withania aristata. Among them, the new isolated withanolides, withaperoxidins A–D (1–4) have an unusual six-membered cyclic peroxide moiety on the withasteroid skeleton as a structural novelty. Their structures have been elucidated by means of spectroscopic analyses, including 2D NMR experiments. In addition, extensive structure–activity relationships and in silico ADME studies were employed to understand the pharmacophore and pharmacokinetic properties of this series of withasteroids. Compounds 15, 16, and 22 together with withaferin A (14) were identified as having improved antiproliferative effect (IC50 ranging from 0.2 to 0.7 μM) on human leukemia HL-60 cell lines compared with the reference drug, etoposide. This cytotoxic potency was also coupled with good selectivity index (SI 33.0–9.2) on non-tumoral Vero cell line and in silico drug likeness. These findings revealed that these natural withasteroids are potential candidates as chemotherapeutic agents in the treatment of leukemia.

Rapid degradation of cyclic peroxides by titanium and antimony chlorides

Rapid and safe degradation of a cyclic peroxide (TPTP) to relatively innocuous products.