A cytotoxic pentadecapeptide from a South African Didemnid tunicate
- Gallegos, D, Serrill, J, Parker-Nance, Shirley, Dorrington, Rosemary A, Ishmael, J, McPhail, Kerry L
- Authors: Gallegos, D , Serrill, J , Parker-Nance, Shirley , Dorrington, Rosemary A , Ishmael, J , McPhail, Kerry L
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/65935 , vital:28863 , https://doi.org/10.1055/s-0036-1596683
- Description: publisher version , The rate of discovery of new natural product chemical entities has plateaued, and unique populations of endemic, biologically diverse sessile marine organisms represent increasingly critical opportunities to discover new chemistry. Discovery of the mandelalides [1] as potent inhibitors of cancer cell growth from the new South African tunicate Lissoclinum mandelai is an example of the diverse suites of metabolites with potent biological activities that have been isolated from tunicates and other filter-feeding sessile marine organisms that house complex microbial consortia. Further investigation of archived and new tunicate collections from Algoa Bay, South Africa, has revealed a group of didemnid tunicates with an unusual gelatinous morphology similar to Lissoclinum mandelai. Using a bioassay-guided isolation approach, a new “gelatinous” species of the genus Didemnum has yielded a cytotoxic pentadecapeptide with a molecular mass of 1603.7688 Da, comprising fifteen residues including both proteinogenic and non-proteinogenic amino acids. The pure compound inhibited both HeLa cervical cancer and NCI-H460 non-small cell lung cancer cell lines when tested at 30 nM in preliminary assays against cells seeded at low densities. Inhibition of cancer cells at low starting density may be indicative of an anti-proliferative mechanism of action. The compound did not show antibacterial activity against Vibrio cholera. Didemnin B and its clinically approved analogue dehydrodidemnin B (plitidepsin, Aplidin®) [2, 3] are important macrocyclic depsipeptides from a didemnid tunicate. The pentadecapeptide reported here provides justification for our continued investigation of unique, endemic didemnid tunicates from South Africa as a source of new macrocyclic natural products with cytotoxic, anti-viral or antimicrobial activity. , We acknowledge the South African government for permission to collect the subject tunicate (Collection Permit No. 278 RES2013/43)
- Full Text: false
- Date Issued: 2016
- Authors: Gallegos, D , Serrill, J , Parker-Nance, Shirley , Dorrington, Rosemary A , Ishmael, J , McPhail, Kerry L
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/65935 , vital:28863 , https://doi.org/10.1055/s-0036-1596683
- Description: publisher version , The rate of discovery of new natural product chemical entities has plateaued, and unique populations of endemic, biologically diverse sessile marine organisms represent increasingly critical opportunities to discover new chemistry. Discovery of the mandelalides [1] as potent inhibitors of cancer cell growth from the new South African tunicate Lissoclinum mandelai is an example of the diverse suites of metabolites with potent biological activities that have been isolated from tunicates and other filter-feeding sessile marine organisms that house complex microbial consortia. Further investigation of archived and new tunicate collections from Algoa Bay, South Africa, has revealed a group of didemnid tunicates with an unusual gelatinous morphology similar to Lissoclinum mandelai. Using a bioassay-guided isolation approach, a new “gelatinous” species of the genus Didemnum has yielded a cytotoxic pentadecapeptide with a molecular mass of 1603.7688 Da, comprising fifteen residues including both proteinogenic and non-proteinogenic amino acids. The pure compound inhibited both HeLa cervical cancer and NCI-H460 non-small cell lung cancer cell lines when tested at 30 nM in preliminary assays against cells seeded at low densities. Inhibition of cancer cells at low starting density may be indicative of an anti-proliferative mechanism of action. The compound did not show antibacterial activity against Vibrio cholera. Didemnin B and its clinically approved analogue dehydrodidemnin B (plitidepsin, Aplidin®) [2, 3] are important macrocyclic depsipeptides from a didemnid tunicate. The pentadecapeptide reported here provides justification for our continued investigation of unique, endemic didemnid tunicates from South Africa as a source of new macrocyclic natural products with cytotoxic, anti-viral or antimicrobial activity. , We acknowledge the South African government for permission to collect the subject tunicate (Collection Permit No. 278 RES2013/43)
- Full Text: false
- Date Issued: 2016
Latrunculid sponges, their microbial communities and secondary metabolites: connecting conserved bacterial symbionts to pyrroloiminoquinone production
- Dorrington, Rosemary A, Hilliar, Storm Hannah, Kalinski, Jarmo-Charles J, Krause, Rui W M, McPhail, Kerry L, Parker-Nance, Shirley, Wlalmsley, Tara A, Waterworth, Samantha C
- Authors: Dorrington, Rosemary A , Hilliar, Storm Hannah , Kalinski, Jarmo-Charles J , Krause, Rui W M , McPhail, Kerry L , Parker-Nance, Shirley , Wlalmsley, Tara A , Waterworth, Samantha C
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/65915 , vital:28858 , https://doi.org/10.1055/s-0036-1596655
- Description: publisher version , The Latrunculiidae are cold water sponges known for their production of bioactive pyrroloiminoquinone alkaloids (e.g. makaluvamines, discorhabdins and tsitsikammamines). Since pyrroloiminoquinones have also been isolated from sponges belonging to other families, ascidians and microorganisms, the biosynthetic origin of these alkaloids in latrunculid sponges is likely microbial. This study focuses on the secondary metabolites produced by closely-related Tsitsikamma species and Cyclacanthia bellae, all latrunculid sponges endemic to Algoa Bay on the South African southeast coast. The sponges produced suites of related pyrroloiminoquinones, including tsitsikammine A and B, and discohabdin C and V, the combination and relative abundance of which is species-specific. Characterisation of the diversity of sponge-associated bacterial communities revealed the unprecedented conservation of two dominant bacterial species. The first, a Betaproteobacterium, is also found in other latrunculids and related sponge families, representing a novel clade of sponge endosymbionts that have co-evolved with their hosts. The second conserved bacterial symbiont is a spirochaete found only in Cyclacanthia and Tsitsikamma species that is likely to have been recruited from free-living spirochaetes in the environment. This study sheds new light on the interactions between latrunculid sponges, their dominant bacterial symbionts, and the potential involvement of these bacteria in pyrroloiminoquinone biosynthesis.
- Full Text: false
- Date Issued: 2016
- Authors: Dorrington, Rosemary A , Hilliar, Storm Hannah , Kalinski, Jarmo-Charles J , Krause, Rui W M , McPhail, Kerry L , Parker-Nance, Shirley , Wlalmsley, Tara A , Waterworth, Samantha C
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/65915 , vital:28858 , https://doi.org/10.1055/s-0036-1596655
- Description: publisher version , The Latrunculiidae are cold water sponges known for their production of bioactive pyrroloiminoquinone alkaloids (e.g. makaluvamines, discorhabdins and tsitsikammamines). Since pyrroloiminoquinones have also been isolated from sponges belonging to other families, ascidians and microorganisms, the biosynthetic origin of these alkaloids in latrunculid sponges is likely microbial. This study focuses on the secondary metabolites produced by closely-related Tsitsikamma species and Cyclacanthia bellae, all latrunculid sponges endemic to Algoa Bay on the South African southeast coast. The sponges produced suites of related pyrroloiminoquinones, including tsitsikammine A and B, and discohabdin C and V, the combination and relative abundance of which is species-specific. Characterisation of the diversity of sponge-associated bacterial communities revealed the unprecedented conservation of two dominant bacterial species. The first, a Betaproteobacterium, is also found in other latrunculids and related sponge families, representing a novel clade of sponge endosymbionts that have co-evolved with their hosts. The second conserved bacterial symbiont is a spirochaete found only in Cyclacanthia and Tsitsikamma species that is likely to have been recruited from free-living spirochaetes in the environment. This study sheds new light on the interactions between latrunculid sponges, their dominant bacterial symbionts, and the potential involvement of these bacteria in pyrroloiminoquinone biosynthesis.
- Full Text: false
- Date Issued: 2016
Sarqaquinoic acid and related synthetic naphthoquinones inhibit the function of Hsp90
- Chiwakata, M, de la Mare, Jo-Anne, Edkins, Adrienne L, Beukes, Denzil R
- Authors: Chiwakata, M , de la Mare, Jo-Anne , Edkins, Adrienne L , Beukes, Denzil R
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66324 , vital:28933 , https://doi.org/10.1055/s-0036-1596751
- Description: publisher version , Heat shock protein 90 (Hsp90) is of critical importance in the proper folding of numerous proteins, including those involved in cancer. Consequently, there is significant interest in the discovery and development of Hsp90 inhibitors as anticancer drugs. In this study, we investigated the ability of sargaquinoic acid (SQA) and selected naphthoquinone derivatives to inhibit Hsp90 function. SQA was isolated and purified from Sargassum incisifolium while the naphthoquinones were synthesised via a straightforward sequence incorporating a Diels-Alder reaction between benzoquinone derivatives and myrcene followed by coupling with substituted alkyl or arylamines. Hsp90 inhibition was assessed by a client protein degradation assay. At a concentration of 1µM, SQA showed almost complete inhibition of Hsp90 but only moderate antiproliferative effects (IC50 658µM) against a Hs578T breast cancer carcinoma cell line. Interestingly, the most potent synthetic aminonaphthoquinone inhibited Hsp90 function by 50% at a concentration of 1µM but showed much improved activity against the Hs578T cell line (IC50 0.32µM). Furthermore, unlike geldanamycin, none of the compounds tested upregulates Hsp70 suggesting that these compounds may bind to the C-terminal end of Hsp90.
- Full Text: false
- Date Issued: 2016
- Authors: Chiwakata, M , de la Mare, Jo-Anne , Edkins, Adrienne L , Beukes, Denzil R
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66324 , vital:28933 , https://doi.org/10.1055/s-0036-1596751
- Description: publisher version , Heat shock protein 90 (Hsp90) is of critical importance in the proper folding of numerous proteins, including those involved in cancer. Consequently, there is significant interest in the discovery and development of Hsp90 inhibitors as anticancer drugs. In this study, we investigated the ability of sargaquinoic acid (SQA) and selected naphthoquinone derivatives to inhibit Hsp90 function. SQA was isolated and purified from Sargassum incisifolium while the naphthoquinones were synthesised via a straightforward sequence incorporating a Diels-Alder reaction between benzoquinone derivatives and myrcene followed by coupling with substituted alkyl or arylamines. Hsp90 inhibition was assessed by a client protein degradation assay. At a concentration of 1µM, SQA showed almost complete inhibition of Hsp90 but only moderate antiproliferative effects (IC50 658µM) against a Hs578T breast cancer carcinoma cell line. Interestingly, the most potent synthetic aminonaphthoquinone inhibited Hsp90 function by 50% at a concentration of 1µM but showed much improved activity against the Hs578T cell line (IC50 0.32µM). Furthermore, unlike geldanamycin, none of the compounds tested upregulates Hsp70 suggesting that these compounds may bind to the C-terminal end of Hsp90.
- Full Text: false
- Date Issued: 2016
Stromatolite microbial communities as a source of new bioactive secondary metabolites
- Flatt, P M, Damarjanan, C, Isamonger, E, Kalinski, Jarmo-Charles J, Dorrington, Rosemary A, McPhail, Kerry L
- Authors: Flatt, P M , Damarjanan, C , Isamonger, E , Kalinski, Jarmo-Charles J , Dorrington, Rosemary A , McPhail, Kerry L
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/65871 , vital:28851 , https://doi.org/10.1055/s-0036-1596638
- Description: publisher version , Stromatolites represent some of the earliest microbial communities on Earth. They are formed by accretion and precipitation of layered calcium carbonate structures that result from the metabolic activity of complex microbial communities and the geochemical conditions of their environment. Modern stromatolite communities include aerobic heterotrophs, sulphide-oxidizing bacteria, sulphate-reducing bacteria, fermentative bacteria and cyanobacteria. Phylogenetic analyses revealed the presence of new and known cyanobacterial taxa related to known producers of biologically active secondary metabolites in tufa stromatolites along the South African southeast coast [1]. Prompted us to investigate their potential for producing novel bioactive secondary metabolites. A series of three tide pools provided the opportunity to collect stromatolites along a vertical transect from pool A (highest elevation, low nitrogen input, fresh water), pool B (within high tide zone, brackish water) and pool C (within tidal zone). The microbial community in pool A is particularly distinct. Chemical extracts of stromatolites from different pools have been profiled by LC-MS/MS and the data subjected to molecular spectral networking using the GnPS platform [2] in order to establish the diversity and biological potential of the microbial metabolome that is being expressed within each of these microhabitats. Correlation of the phylogenetic and secondary metabolomic data is expected to guide the isolation of new natural products with biomedical relevance.
- Full Text: false
- Date Issued: 2016
- Authors: Flatt, P M , Damarjanan, C , Isamonger, E , Kalinski, Jarmo-Charles J , Dorrington, Rosemary A , McPhail, Kerry L
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/65871 , vital:28851 , https://doi.org/10.1055/s-0036-1596638
- Description: publisher version , Stromatolites represent some of the earliest microbial communities on Earth. They are formed by accretion and precipitation of layered calcium carbonate structures that result from the metabolic activity of complex microbial communities and the geochemical conditions of their environment. Modern stromatolite communities include aerobic heterotrophs, sulphide-oxidizing bacteria, sulphate-reducing bacteria, fermentative bacteria and cyanobacteria. Phylogenetic analyses revealed the presence of new and known cyanobacterial taxa related to known producers of biologically active secondary metabolites in tufa stromatolites along the South African southeast coast [1]. Prompted us to investigate their potential for producing novel bioactive secondary metabolites. A series of three tide pools provided the opportunity to collect stromatolites along a vertical transect from pool A (highest elevation, low nitrogen input, fresh water), pool B (within high tide zone, brackish water) and pool C (within tidal zone). The microbial community in pool A is particularly distinct. Chemical extracts of stromatolites from different pools have been profiled by LC-MS/MS and the data subjected to molecular spectral networking using the GnPS platform [2] in order to establish the diversity and biological potential of the microbial metabolome that is being expressed within each of these microhabitats. Correlation of the phylogenetic and secondary metabolomic data is expected to guide the isolation of new natural products with biomedical relevance.
- Full Text: false
- Date Issued: 2016
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