Natural products are well known for their biological relevance, high degree of three-dimensionali... more Natural products are well known for their biological relevance, high degree of three-dimensionality and access to areas of largely unexplored chemical space. To shape our understanding on the interaction between natural products and protein targets in the post-genomic era, we have used native mass spectrometry to investigate 62 potential protein targets for malaria using a natural product-based fragment library. We reveal here 97 low molecular natural products identified as binding partners of 32 of the putative malarial targets. Eighty-one (81) fragments have direct growth inhibition on Plasmodium falciparum at concentrations that are promising for development of Fragment Hits against these protein targets. This adds a fragment library to the published HTS active libraries in the public domain.
Antibiotics have revolutionised medicine in many aspects, and their discovery is considered a tur... more Antibiotics have revolutionised medicine in many aspects, and their discovery is considered a turning point in human history. However, the most serious consequence of the use of antibiotics is the concomitant development of resistance against them. The marine environment has proven to be a very rich source of diverse natural products with significant antibacterial, antifungal, antiviral, antiparasitic, antitumour, anti-inflammatory, antioxidant, and immunomodulatory activities. Many marine natural products (MNPs)-for example, neoechinulin B-have been found to be promising drug candidates to alleviate the mortality and morbidity rates caused by drug-resistant infections, and several MNP-based anti-infectives have already entered phase 1, 2, and 3 clinical trials, with six approved for usage by the US Food and Drug Administration and one by the EU. In this Review, we discuss the diversity of marine natural products that have shown in-vivo efficacy or in-vitro potential against drug-re...
A study of the chemical constituents from the Australian Sponge Hyrtios digitatus has provided a ... more A study of the chemical constituents from the Australian Sponge Hyrtios digitatus has provided a perspective on the connection between the chemistry and biology of the puupehenones, a unique and unusual class of merosesquiterpenes. In this study, a new tetracyclic merosesquiterpene, 19-methoxy-9,15-ene-puupehenol (1) was isolated from the marine sponge Hyrtios digitatus along with the known 20-methoxy-9,15-ene-puupehenol (2). Their structures were elucidated on the basis of spectroscopic data (¹H and (13)C NMR) in combination with experimental electronic circular dichroism (ECD) data. Compounds 1 and 2 are active at 1.78 μM and 3.05 μM, respectively, on Scavenger Receptor-Class B Type 1 HepG2 (SR-B1 HepG2) stable cell lines, targeting atherosclerosis disease.
The sole species of the vascular plant family Austrobaileyaceae, Austrobaileya scandens, is endem... more The sole species of the vascular plant family Austrobaileyaceae, Austrobaileya scandens, is endemic to the tropical rainforest of northeastern Queensland, Australia. A single lead-like enhanced fraction of A. scandens showed potent inhibition against human prostate cancer PC3 cells. Chemical investigation of this plant resulted in the isolation of two new aryltetralin lignans, austrobailignans 8 and 9 (1 and 2), and the synthetic compound nicotlactone B (3), newly identified as a natural product together with nine known lignans (4-12). Their structures were established on the basis of spectroscopic analyses. Absolute configurations of the new compounds were determined by quantum chemical electronic circular dichroism (ECD) calculations employing time-dependent density functional theory. The ECD calculations were also used to assign the absolute configuration of marphenol K (4) and revise the absolute configuration of kadsurindutin C (20). Ten out of the 12 isolated compounds inhibit...
The red alga Ptilonia australasica is endemic to Australian temperate waters. Chemical investigat... more The red alga Ptilonia australasica is endemic to Australian temperate waters. Chemical investigation of P. australasica led to the identification of four new polybrominated compounds, ptilones A-C (1-3) and australasol A (4). Their planar structures were established by extensive NMR and MS analyses. The low H/C ratio and the presence of a large number of heteroatoms made the structure elucidation challenging. The absolute configurations of 1, 2, and 4 were determined by quantum chemical ECD calculations employing time-dependent density functional theory. Ptilones A-C (1-3) show unique 4-ethyl-5-methylenecyclopent-2-enone (1 and 2) and 2-methyl-6-vinyl-4H-pyran-4-one (3) skeletons not previously reported in algal metabolites. Ptilone A displayed the most potent cytotoxicity against the human prostate cancer PC3 cells with an IC50 value of 0.44 μM and induced the PC3 cell cycle arrest in the G0/G1 phase.
Cnemidocarpa stolonifera is an underexplored marine tunicate that only occurs on the tropical to ... more Cnemidocarpa stolonifera is an underexplored marine tunicate that only occurs on the tropical to subtropical East Coast of Australia, with only two pyridoacridine compounds reported previously. Qualitative analysis of the lead-like enhanced fractions of C. stolonifera by LC-MS dual electrospray ionization coupled with PDA and ELSD detectors led to the identification of three new natural products, stolonines A-C (1-3), belonging to the taurine amide structure class. Structures of the new compounds were determined by NMR and MS analyses and later verified by total synthesis. This is the first time that the conjugates of taurine with 3-indoleglyoxylic acid, quinoline-2-carboxylic acid and β-carboline-3-carboxylic acid present in stolonines A-C (1-3), respectively, have been reported. An immunofluorescence assay on PC3 cells indicated that compounds 1 and 3 increased cell size, induced mitochondrial texture elongation, and caused apoptosis in PC3 cells.
Extracts from dried leaf and stems of Elaeodendron australe var. integrifolium (Celastraceae) col... more Extracts from dried leaf and stems of Elaeodendron australe var. integrifolium (Celastraceae) collected in South East Queensland, Australia, were active in an assay that measured Ca(2+) driven expression of IL-2/luciferase designed to identify inhibitors of the ICRAC channel. Bioassay-guided isolation using C18 and polyamide column chromatography, HPLC (Phenyl and C18) and centrifugal partition chromatography (CPC) led to the isolation of digitoxigenin (1) and three cardenolide glycosides, glucoside 2, quinovoside 3 and the new natural product xyloside 4, as the active components with low nM activity in the reporter assay.
Two consecutive prefractionated fractions of the Australian marine sponge extract, Pipestela cand... more Two consecutive prefractionated fractions of the Australian marine sponge extract, Pipestela candelabra, were identified to be selectively active on the human prostate cancer cells (PC3) compared to the human neonatal foreskin fibroblast non-cancer cells (NFF). Twelve secondary metabolites were isolated in which four compounds are new small peptides. Their structures were characterized by spectroscopic and chemical analysis. These compounds inhibited selectively the growth of prostate cancer cells with IC 50 values in the picomolar to sub-micromolar range. Structure-activity relationship of these compounds is discussed.
The X-ray crystal structure of the adduct between the zinc metalloenzyme carbonic anhydrase II (C... more The X-ray crystal structure of the adduct between the zinc metalloenzyme carbonic anhydrase II (CA, EC 4.2.1.1) with the recently discovered natural product coumarin derivative 6-(1S-hydroxy-3methylbutyl)-7-methoxy-2H-chromen-2-one showed the coumarin hydrolysis product, a cis-2-hydroxycinnamic acid derivative, and not the parent coumarin, bound within the enzyme active site. The bound inhibitor exhibits an extended, two-arm conformation that effectively plugs the entrance to the enzyme active site with no interactions with the catalytically crucial zinc ion. The inhibitor is sandwiched between Phe131, with which it makes an edge-to-face stacking, and Asn67/Glu238sym, with which it makes several polar and hydrogen bonding interactions. This unusual binding mode, with no interactions between the inhibitor molecule and the active site metal ion is previously unobserved for this enzyme class and presents a new opportunity for future drug design campaigns to target a mode of inhibition that differs substantially from classical inhibitors such as the clinically used sulfonamides and sulfamates. Several structurally simple coumarin scaffolds were also shown to inhibit all 13 catalytically active mammalian CA isoforms, with inhibition constants ranging from nanomolar to millimolar. The inhibition is time dependent, with maximum inhibition being observed after 6 h.
The authors describe first a proof-of-concept experiment to show direct affinity screening using ... more The authors describe first a proof-of-concept experiment to show direct affinity screening using electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR-MS) is a rapid and informative approach for natural product extract screening. The study used 10 alkaloid-enriched plant extracts and 8 desalted marine extracts spiked with specific inhibitors of bovine carbonic anhydrase II (bCAII; EC4.2.1.1) as a model set. The spiked extracts were incubated with bCAII and then analyzed by ESI-FTICR-MS. The noncovalent complexes were detected, and the specific inhibitors were reidentified in the spiked natural product extracts. There was no interference from the desalted/alkaloid-enriched extracts to the formation of the noncovalent complexes. The method allowed quick identification of the molecular mass of the bound ligand. The authors then applied the screening to identify active compounds in natural product extracts. They employed direct infusion and onlin...
The natural product, convolutamine I (1), has anti-trypanosomal activity however it has a high mo... more The natural product, convolutamine I (1), has anti-trypanosomal activity however it has a high molecular weight of 473 due to a presence of 3 bromine atoms. The synthesis of the natural product convolutamine I (1) together with its analogues are presented. A SAR study against Trypanosoma brucei brucei led to compounds with improved physico-chemical properties: lower molecular weight and lower log P while maintaining potency (with a slight 2-fold improvement).
Bioorganic & Medicinal Chemistry Letters, 2010
Two of the four parameters in the &am... more Two of the four parameters in the 'rule of five', molecular weight and logP, which can be detected and predicted by mass spectrometry and compound retention on reversed-phase HPLC, were used as guidelines in natural product isolation. A new aporphine alkaloid, (6aR)-normecambroline (1), was isolated from the bark of Neolitsea dealbata (R. Br.) Merr. Its structure was determined on the basis of NMR, MS and CD analysis. It is the first time the absolute configuration of the roemerine-N-oxide was assigned for both roemerine-N(α)-oxide (3) and roemerine-N(β)-oxide (4). Physico-chemical property evaluation demonstrated all alkaloids had no Lipinski violation. Compound 1 inhibited selectively against cervical cancer cells (HeLa) with an IC(50) of 4.0 μM.
Biochemical and Biophysical Research Communications, 2010
R-(-)-b-O-methylsynephrine (OMe-Syn) is an active compound isolated from a plant of the Rutaceae ... more R-(-)-b-O-methylsynephrine (OMe-Syn) is an active compound isolated from a plant of the Rutaceae family. We conducted cell proliferation assays on various cell lines and found that OMe-Syn more strongly inhibited the growth of human umbilical vein endothelial cells (HUVECs) than that of other normal and cancer cell lines tested. In angiogenesis assays, it inhibited vascular endothelial growth factor (VEGF)-induced invasion and tube formation of HUVECs with no toxicity. The anti-angiogenic activity of OMe-Syn was also validated in vivo using the chorioallantonic membrane (CAM) assay in growing chick embryos. Expression of the growth factors VEGF, hepatocyte growth factor, and basic fibroblast growth factor was suppressed by OMe-Syn in a dose-dependent manner. Taken together, our results indicate that this compound could be a novel basis for a small molecule targeting angiogenesis.
The rapid economic development of Vietnam triggers a number of challenges in all sectors includin... more The rapid economic development of Vietnam triggers a number of challenges in all sectors including infrastructure design and execution. New development plans and lack of space in densely populated and economically valuable areas creates a need for complex engineering solutions to meet the demand. The present research is a case study investigating reengineered vast natural slope to meet all requirements for geotechnical safety such as maximum displacements and factor of safety. Complex ground conditions and significant dimensions of the slope made the entire structure very likely to cause major risk for the future development plan of the site. Due to complex conditions, the slope was divided into 4 main sections. Each section was reinforced using a combination of soil nails, ground anchors, drainage systems and micro piles, of 19m for a single pile. Due to very much limited space available new geometry of the slope was designed for inclination reaching 1:0.3. Based on numerical model...
Natural products are well known for their biological relevance, high degree of three-dimensionali... more Natural products are well known for their biological relevance, high degree of three-dimensionality and access to areas of largely unexplored chemical space. To shape our understanding on the interaction between natural products and protein targets in the post-genomic era, we have used native mass spectrometry to investigate 62 potential protein targets for malaria using a natural product-based fragment library. We reveal here 97 low molecular natural products identified as binding partners of 32 of the putative malarial targets. Eighty-one (81) fragments have direct growth inhibition on Plasmodium falciparum at concentrations that are promising for development of Fragment Hits against these protein targets. This adds a fragment library to the published HTS active libraries in the public domain.
Antibiotics have revolutionised medicine in many aspects, and their discovery is considered a tur... more Antibiotics have revolutionised medicine in many aspects, and their discovery is considered a turning point in human history. However, the most serious consequence of the use of antibiotics is the concomitant development of resistance against them. The marine environment has proven to be a very rich source of diverse natural products with significant antibacterial, antifungal, antiviral, antiparasitic, antitumour, anti-inflammatory, antioxidant, and immunomodulatory activities. Many marine natural products (MNPs)-for example, neoechinulin B-have been found to be promising drug candidates to alleviate the mortality and morbidity rates caused by drug-resistant infections, and several MNP-based anti-infectives have already entered phase 1, 2, and 3 clinical trials, with six approved for usage by the US Food and Drug Administration and one by the EU. In this Review, we discuss the diversity of marine natural products that have shown in-vivo efficacy or in-vitro potential against drug-re...
A study of the chemical constituents from the Australian Sponge Hyrtios digitatus has provided a ... more A study of the chemical constituents from the Australian Sponge Hyrtios digitatus has provided a perspective on the connection between the chemistry and biology of the puupehenones, a unique and unusual class of merosesquiterpenes. In this study, a new tetracyclic merosesquiterpene, 19-methoxy-9,15-ene-puupehenol (1) was isolated from the marine sponge Hyrtios digitatus along with the known 20-methoxy-9,15-ene-puupehenol (2). Their structures were elucidated on the basis of spectroscopic data (¹H and (13)C NMR) in combination with experimental electronic circular dichroism (ECD) data. Compounds 1 and 2 are active at 1.78 μM and 3.05 μM, respectively, on Scavenger Receptor-Class B Type 1 HepG2 (SR-B1 HepG2) stable cell lines, targeting atherosclerosis disease.
The sole species of the vascular plant family Austrobaileyaceae, Austrobaileya scandens, is endem... more The sole species of the vascular plant family Austrobaileyaceae, Austrobaileya scandens, is endemic to the tropical rainforest of northeastern Queensland, Australia. A single lead-like enhanced fraction of A. scandens showed potent inhibition against human prostate cancer PC3 cells. Chemical investigation of this plant resulted in the isolation of two new aryltetralin lignans, austrobailignans 8 and 9 (1 and 2), and the synthetic compound nicotlactone B (3), newly identified as a natural product together with nine known lignans (4-12). Their structures were established on the basis of spectroscopic analyses. Absolute configurations of the new compounds were determined by quantum chemical electronic circular dichroism (ECD) calculations employing time-dependent density functional theory. The ECD calculations were also used to assign the absolute configuration of marphenol K (4) and revise the absolute configuration of kadsurindutin C (20). Ten out of the 12 isolated compounds inhibit...
The red alga Ptilonia australasica is endemic to Australian temperate waters. Chemical investigat... more The red alga Ptilonia australasica is endemic to Australian temperate waters. Chemical investigation of P. australasica led to the identification of four new polybrominated compounds, ptilones A-C (1-3) and australasol A (4). Their planar structures were established by extensive NMR and MS analyses. The low H/C ratio and the presence of a large number of heteroatoms made the structure elucidation challenging. The absolute configurations of 1, 2, and 4 were determined by quantum chemical ECD calculations employing time-dependent density functional theory. Ptilones A-C (1-3) show unique 4-ethyl-5-methylenecyclopent-2-enone (1 and 2) and 2-methyl-6-vinyl-4H-pyran-4-one (3) skeletons not previously reported in algal metabolites. Ptilone A displayed the most potent cytotoxicity against the human prostate cancer PC3 cells with an IC50 value of 0.44 μM and induced the PC3 cell cycle arrest in the G0/G1 phase.
Cnemidocarpa stolonifera is an underexplored marine tunicate that only occurs on the tropical to ... more Cnemidocarpa stolonifera is an underexplored marine tunicate that only occurs on the tropical to subtropical East Coast of Australia, with only two pyridoacridine compounds reported previously. Qualitative analysis of the lead-like enhanced fractions of C. stolonifera by LC-MS dual electrospray ionization coupled with PDA and ELSD detectors led to the identification of three new natural products, stolonines A-C (1-3), belonging to the taurine amide structure class. Structures of the new compounds were determined by NMR and MS analyses and later verified by total synthesis. This is the first time that the conjugates of taurine with 3-indoleglyoxylic acid, quinoline-2-carboxylic acid and β-carboline-3-carboxylic acid present in stolonines A-C (1-3), respectively, have been reported. An immunofluorescence assay on PC3 cells indicated that compounds 1 and 3 increased cell size, induced mitochondrial texture elongation, and caused apoptosis in PC3 cells.
Extracts from dried leaf and stems of Elaeodendron australe var. integrifolium (Celastraceae) col... more Extracts from dried leaf and stems of Elaeodendron australe var. integrifolium (Celastraceae) collected in South East Queensland, Australia, were active in an assay that measured Ca(2+) driven expression of IL-2/luciferase designed to identify inhibitors of the ICRAC channel. Bioassay-guided isolation using C18 and polyamide column chromatography, HPLC (Phenyl and C18) and centrifugal partition chromatography (CPC) led to the isolation of digitoxigenin (1) and three cardenolide glycosides, glucoside 2, quinovoside 3 and the new natural product xyloside 4, as the active components with low nM activity in the reporter assay.
Two consecutive prefractionated fractions of the Australian marine sponge extract, Pipestela cand... more Two consecutive prefractionated fractions of the Australian marine sponge extract, Pipestela candelabra, were identified to be selectively active on the human prostate cancer cells (PC3) compared to the human neonatal foreskin fibroblast non-cancer cells (NFF). Twelve secondary metabolites were isolated in which four compounds are new small peptides. Their structures were characterized by spectroscopic and chemical analysis. These compounds inhibited selectively the growth of prostate cancer cells with IC 50 values in the picomolar to sub-micromolar range. Structure-activity relationship of these compounds is discussed.
The X-ray crystal structure of the adduct between the zinc metalloenzyme carbonic anhydrase II (C... more The X-ray crystal structure of the adduct between the zinc metalloenzyme carbonic anhydrase II (CA, EC 4.2.1.1) with the recently discovered natural product coumarin derivative 6-(1S-hydroxy-3methylbutyl)-7-methoxy-2H-chromen-2-one showed the coumarin hydrolysis product, a cis-2-hydroxycinnamic acid derivative, and not the parent coumarin, bound within the enzyme active site. The bound inhibitor exhibits an extended, two-arm conformation that effectively plugs the entrance to the enzyme active site with no interactions with the catalytically crucial zinc ion. The inhibitor is sandwiched between Phe131, with which it makes an edge-to-face stacking, and Asn67/Glu238sym, with which it makes several polar and hydrogen bonding interactions. This unusual binding mode, with no interactions between the inhibitor molecule and the active site metal ion is previously unobserved for this enzyme class and presents a new opportunity for future drug design campaigns to target a mode of inhibition that differs substantially from classical inhibitors such as the clinically used sulfonamides and sulfamates. Several structurally simple coumarin scaffolds were also shown to inhibit all 13 catalytically active mammalian CA isoforms, with inhibition constants ranging from nanomolar to millimolar. The inhibition is time dependent, with maximum inhibition being observed after 6 h.
The authors describe first a proof-of-concept experiment to show direct affinity screening using ... more The authors describe first a proof-of-concept experiment to show direct affinity screening using electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR-MS) is a rapid and informative approach for natural product extract screening. The study used 10 alkaloid-enriched plant extracts and 8 desalted marine extracts spiked with specific inhibitors of bovine carbonic anhydrase II (bCAII; EC4.2.1.1) as a model set. The spiked extracts were incubated with bCAII and then analyzed by ESI-FTICR-MS. The noncovalent complexes were detected, and the specific inhibitors were reidentified in the spiked natural product extracts. There was no interference from the desalted/alkaloid-enriched extracts to the formation of the noncovalent complexes. The method allowed quick identification of the molecular mass of the bound ligand. The authors then applied the screening to identify active compounds in natural product extracts. They employed direct infusion and onlin...
The natural product, convolutamine I (1), has anti-trypanosomal activity however it has a high mo... more The natural product, convolutamine I (1), has anti-trypanosomal activity however it has a high molecular weight of 473 due to a presence of 3 bromine atoms. The synthesis of the natural product convolutamine I (1) together with its analogues are presented. A SAR study against Trypanosoma brucei brucei led to compounds with improved physico-chemical properties: lower molecular weight and lower log P while maintaining potency (with a slight 2-fold improvement).
Bioorganic & Medicinal Chemistry Letters, 2010
Two of the four parameters in the &am... more Two of the four parameters in the 'rule of five', molecular weight and logP, which can be detected and predicted by mass spectrometry and compound retention on reversed-phase HPLC, were used as guidelines in natural product isolation. A new aporphine alkaloid, (6aR)-normecambroline (1), was isolated from the bark of Neolitsea dealbata (R. Br.) Merr. Its structure was determined on the basis of NMR, MS and CD analysis. It is the first time the absolute configuration of the roemerine-N-oxide was assigned for both roemerine-N(α)-oxide (3) and roemerine-N(β)-oxide (4). Physico-chemical property evaluation demonstrated all alkaloids had no Lipinski violation. Compound 1 inhibited selectively against cervical cancer cells (HeLa) with an IC(50) of 4.0 μM.
Biochemical and Biophysical Research Communications, 2010
R-(-)-b-O-methylsynephrine (OMe-Syn) is an active compound isolated from a plant of the Rutaceae ... more R-(-)-b-O-methylsynephrine (OMe-Syn) is an active compound isolated from a plant of the Rutaceae family. We conducted cell proliferation assays on various cell lines and found that OMe-Syn more strongly inhibited the growth of human umbilical vein endothelial cells (HUVECs) than that of other normal and cancer cell lines tested. In angiogenesis assays, it inhibited vascular endothelial growth factor (VEGF)-induced invasion and tube formation of HUVECs with no toxicity. The anti-angiogenic activity of OMe-Syn was also validated in vivo using the chorioallantonic membrane (CAM) assay in growing chick embryos. Expression of the growth factors VEGF, hepatocyte growth factor, and basic fibroblast growth factor was suppressed by OMe-Syn in a dose-dependent manner. Taken together, our results indicate that this compound could be a novel basis for a small molecule targeting angiogenesis.
The rapid economic development of Vietnam triggers a number of challenges in all sectors includin... more The rapid economic development of Vietnam triggers a number of challenges in all sectors including infrastructure design and execution. New development plans and lack of space in densely populated and economically valuable areas creates a need for complex engineering solutions to meet the demand. The present research is a case study investigating reengineered vast natural slope to meet all requirements for geotechnical safety such as maximum displacements and factor of safety. Complex ground conditions and significant dimensions of the slope made the entire structure very likely to cause major risk for the future development plan of the site. Due to complex conditions, the slope was divided into 4 main sections. Each section was reinforced using a combination of soil nails, ground anchors, drainage systems and micro piles, of 19m for a single pile. Due to very much limited space available new geometry of the slope was designed for inclination reaching 1:0.3. Based on numerical model...
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