Marine Drugs

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1774 KiB

Open AccessArticle

Salternamide A Suppresses Hypoxia-Induced Accumulation of HIF-1α and Induces Apoptosis in Human Colorectal Cancer Cells

by Duc-Hiep Bach, Seong-Hwan Kim, Ji-Young Hong, Hyen Joo Park, Dong-Chan Oh and Sang Kook Lee

Mar. Drugs 2015, 13(11), 6962-6976; https://doi.org/10.3390/md13116962 - 19 Nov 2015

Cited by 34 | Viewed by 8837

Abstract

Hypoxia inducible factor-1α (HIF-1α) is an essential regulator of the cellular response to low oxygen concentrations, activating a broad range of genes that provide adaptive responses to oxygen deprivation. HIF-1α is overexpressed in various cancers and therefore represents a considerable chemotherapeutic target. Salternamide [...] Read more.

Hypoxia inducible factor-1α (HIF-1α) is an essential regulator of the cellular response to low oxygen concentrations, activating a broad range of genes that provide adaptive responses to oxygen deprivation. HIF-1α is overexpressed in various cancers and therefore represents a considerable chemotherapeutic target. Salternamide A (SA), a novel small molecule that is isolated from a halophilic Streptomyces sp., is a potent cytotoxic agent against a variety of human cancer cell lines. However, the mechanisms by which SA inhibits tumor growth remain to be elucidated. In the present study, we demonstrate that SA efficiently inhibits the hypoxia-induced accumulation of HIF-1α in a time- and concentration-dependent manner in various human cancer cells. In addition, SA suppresses the upstream signaling of HIF-1α, such as PI3K/Akt/mTOR, p42/p44 MAPK, and STAT3 signaling under hypoxic conditions. Furthermore, we found that SA induces cell death by stimulating G2/M cell cycle arrest and apoptosis in human colorectal cancer cells. Taken together, SA was identified as a novel small molecule HIF-1α inhibitor from marine natural products and is potentially a leading candidate in the development of anticancer agents. Full article

(This article belongs to the Special Issue Marine Bioactive Natural Product Studies—A Southern Hemisphere Perspective)

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271 KiB

Open AccessArticle

Synthesis and Antiplasmodial Evaluation of Analogues Based on the Tricyclic Core of Thiaplakortones A–D

by Brett D. Schwartz, Mark J. Coster, Tina S. Skinner-Adams, Katherine T. Andrews, Jonathan M. White and Rohan A. Davis

Mar. Drugs 2015, 13(9), 5784-5795; https://doi.org/10.3390/md13095784 - 15 Sep 2015

Cited by 5 | Viewed by 5249

Abstract

Six regioisomers associated with the tricyclic core of thiaplakortones A–D have been synthesized. Reaction of 1H-indole-4,7-dione and 1-tosyl-1H-indole-4,7-dione with 2-aminoethanesulfinic acid afforded a regioisomeric series, which was subsequently deprotected and oxidized to yield the tricyclic core scaffolds present in [...] Read more.

Six regioisomers associated with the tricyclic core of thiaplakortones A–D have been synthesized. Reaction of 1H-indole-4,7-dione and 1-tosyl-1H-indole-4,7-dione with 2-aminoethanesulfinic acid afforded a regioisomeric series, which was subsequently deprotected and oxidized to yield the tricyclic core scaffolds present in the thiaplakortones. All compounds were fully characterized using NMR and MS data. A single crystal X-ray structure was obtained on one of the N-tosyl derivatives. All compounds were screened for in vitro antiplasmodial activity against chloroquine-sensitive (3D7) and multidrug-resistant (Dd2) Plasmodium falciparum parasite lines. Several analogues displayed potent inhibition of P. falciparum growth (IC₅₀ < 500 nM) but only moderate selectivity for P. falciparum versus human neonatal foreskin fibroblast cells. Full article

(This article belongs to the Special Issue Marine Bioactive Natural Product Studies—A Southern Hemisphere Perspective)

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640 KiB

Open AccessArticle

Structure-Activity Relationships of the Bioactive Thiazinoquinone Marine Natural Products Thiaplidiaquinones A and B

by Jacquie L. Harper, Iman M. Khalil, Lisa Shaw, Marie-Lise Bourguet-Kondracki, Joëlle Dubois, Alexis Valentin, David Barker and Brent R. Copp

Mar. Drugs 2015, 13(8), 5102-5110; https://doi.org/10.3390/md13085102 - 10 Aug 2015

Cited by 15 | Viewed by 6324

Abstract

In an effort to more accurately define the mechanism of cell death and to establish structure-activity relationship requirements for the marine meroterpenoid alkaloids thiaplidiaquinones A and B, we have evaluated not only the natural products but also dioxothiazine regioisomers and two precursor quinones [...] Read more.

In an effort to more accurately define the mechanism of cell death and to establish structure-activity relationship requirements for the marine meroterpenoid alkaloids thiaplidiaquinones A and B, we have evaluated not only the natural products but also dioxothiazine regioisomers and two precursor quinones in a range of bioassays. While the natural products were found to be weak inducers of ROS in Jurkat cells, the dioxothiazine regioisomer of thiaplidiaquinone A and a synthetic precursor to thiaplidiaquinone B were found to be moderately potent inducers. Intriguingly, and in contrast to previous reports, the mechanism of Jurkat cell death (necrosis vs. apoptosis) was found to be dependent upon the positioning of one of the geranyl sidechains in the compounds with thiaplidiaquinone A and its dioxothiazine regioisomer causing death dominantly by necrosis, while thiaplidiaquinone B and its dioxothiazine isomer caused cell death via apoptosis. The dioxothiazine regioisomer of thiaplidiaquinone A exhibited more potent in vitro antiproliferative activity against human tumor cells, with NCI sub-panel selectivity towards melanoma cell lines. The non-natural dioxothiazine regioisomers were also more active in antiplasmodial and anti-farnesyltransferase assays than their natural product counterparts. The results highlight the important role that natural product total synthesis can play in not only helping understand the structural basis of biological activity of natural products, but also the discovery of new bioactive scaffolds. Full article

(This article belongs to the Special Issue Marine Bioactive Natural Product Studies—A Southern Hemisphere Perspective)

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3059 KiB

Open AccessArticle

Isolation and Total Synthesis of Stolonines A–C, Unique Taurine Amides from the Australian Marine Tunicate Cnemidocarpa stolonifera

by Trong D. Tran, Ngoc B. Pham, Merrick Ekins, John N. A. Hooper and Ronald J. Quinn

Mar. Drugs 2015, 13(7), 4556-4575; https://doi.org/10.3390/md13074556 - 22 Jul 2015

Cited by 28 | Viewed by 9026

Abstract

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 [...] Read 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. Full article

(This article belongs to the Special Issue Marine Bioactive Natural Product Studies—A Southern Hemisphere Perspective)

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1473 KiB

Open AccessArticle

Structure Elucidation of New Acetylated Saponins, Lessoniosides A, B, C, D, and E, and Non-Acetylated Saponins, Lessoniosides F and G, from the Viscera of the Sea Cucumber Holothuria lessoni

by Yadollah Bahrami and Christopher M. M. Franco

Mar. Drugs 2015, 13(1), 597-617; https://doi.org/10.3390/md13010597 - 16 Jan 2015

Cited by 30 | Viewed by 9072

Abstract

Sea cucumbers produce numerous compounds with a wide range of chemical structural diversity. Among these, saponins are the most diverse and include sulfated, non-sulfated, acetylated and methylated congeners with different aglycone and sugar moieties. In this study, MALDI and ESI tandem mass spectrometry, [...] Read more.

Sea cucumbers produce numerous compounds with a wide range of chemical structural diversity. Among these, saponins are the most diverse and include sulfated, non-sulfated, acetylated and methylated congeners with different aglycone and sugar moieties. In this study, MALDI and ESI tandem mass spectrometry, in the positive ion mode, were used to elucidate the structure of new saponins extracted from the viscera of H. lessoni. Fragmentation of the aglycone provided structural information on the presence of the acetyl group. The presence of the O-acetyl group was confirmed by observing the mass transition of 60 u corresponding to the loss of a molecule of acetic acid. Ion fingerprints from the glycosidic cleavage provided information on the mass of the aglycone (core), and the sequence and type of monosaccharides that constitute the sugar moiety. The tandem mass spectra of the saponin precursor ions [M + Na]⁺ provided a wealth of detailed structural information on the glycosidic bond cleavages. As a result, and in conjunction with existing literature, we characterized the structure of five new acetylated saponins, Lessoniosides A–E, along with two non-acetylated saponins Lessoniosides F and G at m/z 1477.7, which are promising candidates for future drug development. The presented strategy allows a rapid, reliable and complete analysis of native saponins. Full article

(This article belongs to the Special Issue Marine Bioactive Natural Product Studies—A Southern Hemisphere Perspective)

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327 KiB

Open AccessArticle

A Great Barrier Reef Sinularia sp. Yields Two New Cytotoxic Diterpenes

by Anthony D. Wright, Jonathan L. Nielson, Dianne M. Tapiolas, Catherine H. Liptrot and Cherie A. Motti

Mar. Drugs 2012, 10(8), 1619-1630; https://doi.org/10.3390/md10081619 - 31 Jul 2012

Cited by 21 | Viewed by 7029

Abstract

The methanol extract of a Sinularia sp., collected from Bowden Reef, Queensland, Australia, yielded ten natural products. These included the new nitrogenous diterpene (4R*,5R*,9S*,10R*,11Z)-4-methoxy-9-((dimethylamino)-methyl)-12,15-epoxy-11(13)-en-decahydronaphthalen-16-ol (1), and the new lobane, (1R* [...] Read more.

The methanol extract of a Sinularia sp., collected from Bowden Reef, Queensland, Australia, yielded ten natural products. These included the new nitrogenous diterpene (4R*,5R*,9S*,10R*,11Z)-4-methoxy-9-((dimethylamino)-methyl)-12,15-epoxy-11(13)-en-decahydronaphthalen-16-ol (1), and the new lobane, (1R*,2R*,4S*,15E)-loba-8,10,13(14),15(16)-tetraen-17,18-diol-17-acetate (2). Also isolated were two known cembranes, sarcophytol-B and (1E,3E,7E)-11,12-epoxycembratrien-15-ol, and six known lobanes, loba-8,10,13(15)-triene-16,17,18-triol, 14,18-epoxyloba-8,10,13(15)-trien-17-ol, lobatrientriol, lobatrienolide, 14,17-epoxyloba-8,10,13(15)-trien-18-ol-18-acetate and (17R)-loba-8,10,13(15)-trien-17,18-diol. Structures of the new compounds were elucidated through interpretation of spectra obtained after extensive NMR and MS investigations and comparison with literature values. The tumour cell growth inhibition potential of 1 and 2 along with loba-8,10,13(15)-triene-16,17,18-triol, 14,17-epoxyloba-8,10,13(15)-trien-18-ol-18-acetate, lobatrienolide, (1E,3E,7E)-11,12-epoxycembratrien-15-ol and sarcophytol-B were assessed against three human tumour cell lines (SF-268, MCF-7 and H460). The lobanes and cembranes tested demonstrated 50% growth inhibition in the range 6.8–18.5 µM, with no selectivity, whilst 1 was less active (GI₅₀ 70–175 µM). Full article

(This article belongs to the Special Issue Marine Bioactive Natural Product Studies—A Southern Hemisphere Perspective)

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Review

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2273 KiB

Open AccessReview

Recent Advances in Drug Discovery from South African Marine Invertebrates

by Michael T. Davies-Coleman and Clinton G. L. Veale

Mar. Drugs 2015, 13(10), 6366-6383; https://doi.org/10.3390/md13106366 - 14 Oct 2015

Cited by 15 | Viewed by 6755

Abstract

Recent developments in marine drug discovery from three South African marine invertebrates, the tube worm Cephalodiscus gilchristi, the ascidian Lissoclinum sp. and the sponge Topsentia pachastrelloides, are presented. Recent reports of the bioactivity and synthesis of the anti-cancer secondary metabolites cephalostatin [...] Read more.

Recent developments in marine drug discovery from three South African marine invertebrates, the tube worm Cephalodiscus gilchristi, the ascidian Lissoclinum sp. and the sponge Topsentia pachastrelloides, are presented. Recent reports of the bioactivity and synthesis of the anti-cancer secondary metabolites cephalostatin and mandelalides (from C. gilchristi and Lissoclinum sp., respectively) and various analogues are presented. The threat of drug-resistant pathogens, e.g., methicillin-resistant Staphylococcus aureus (MRSA), is assuming greater global significance, and medicinal chemistry strategies to exploit the potent MRSA PK inhibition, first revealed by two marine secondary metabolites, cis-3,4-dihydrohamacanthin B and bromodeoxytopsentin from T. pachastrelloides, are compared. Full article

(This article belongs to the Special Issue Marine Bioactive Natural Product Studies—A Southern Hemisphere Perspective)

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777 KiB

Open AccessReview

Natural Product Research in the Australian Marine Invertebrate Dicathais orbita

by Kirsten Benkendorff

Mar. Drugs 2013, 11(4), 1370-1398; https://doi.org/10.3390/md11041370 - 23 Apr 2013

Cited by 46 | Viewed by 9650

Abstract

The predatory marine gastropod Dicathais orbita has been the subject of a significant amount of biological and chemical research over the past five decades. Natural products research on D. orbita includes the isolation and identification of brominated indoles and choline esters as precursors [...] Read more.

The predatory marine gastropod Dicathais orbita has been the subject of a significant amount of biological and chemical research over the past five decades. Natural products research on D. orbita includes the isolation and identification of brominated indoles and choline esters as precursors of Tyrian purple, as well as the synthesis of structural analogues, bioactivity testing, biodistributional and biosynthetic studies. Here I also report on how well these compounds conform to Lipinski’s rule of five for druglikeness and their predicted receptor binding and enzyme inhibitor activity. The composition of mycosporine-like amino acids, fatty acids and sterols has also been described in the egg masses of D. orbita. The combination of bioactive compounds produced by D. orbita is of interest for further studies in chemical ecology, as well as for future nutraceutical development. Biological insights into the life history of this species, as well as ongoing research on the gene expression, microbial symbionts and biosynthetic capabilities, should facilitate sustainable production of the bioactive compounds. Knowledge of the phylogeny of D. orbita provides an excellent platform for novel research into the evolution of brominated secondary metabolites in marine molluscs. The range of polarities in the brominated indoles produced by D. orbita has also provided an effective model system used to develop a new method for biodistributional studies. The well characterized suite of chemical reactions that generate Tyrian purple, coupled with an in depth knowledge of the ecology, anatomy and genetics of D. orbita provide a good foundation for ongoing natural products research. Full article

(This article belongs to the Special Issue Marine Bioactive Natural Product Studies—A Southern Hemisphere Perspective)

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1632 KiB

Open AccessReview

Computational Studies of Marine Toxins Targeting Ion Channels

by M. Harunur Rashid, Somayeh Mahdavi and Serdar Kuyucak

Mar. Drugs 2013, 11(3), 848-869; https://doi.org/10.3390/md11030848 - 13 Mar 2013

Cited by 27 | Viewed by 7000

Abstract

Toxins from marine animals offer novel drug leads for treatment of diseases involving ion channels. Computational methods could be very helpful in this endeavour in several ways, e.g., (i) constructing accurate models of the channel-toxin complexes using docking and molecular dynamics (MD) simulations; [...] Read more.

Toxins from marine animals offer novel drug leads for treatment of diseases involving ion channels. Computational methods could be very helpful in this endeavour in several ways, e.g., (i) constructing accurate models of the channel-toxin complexes using docking and molecular dynamics (MD) simulations; (ii) determining the binding free energies of toxins from umbrella sampling MD simulations; (iii) predicting the effect of mutations from free energy MD simulations. Using these methods, one can design new analogs of toxins with improved affinity and selectivity properties. Here we present a review of the computational methods and discuss their applications to marine toxins targeting potassium and sodium channels. Detailed examples from the potassium channel toxins—ShK from sea anemone and κ-conotoxin PVIIA—are provided to demonstrate capabilities of the computational methods to give accurate descriptions of the channel-toxin complexes and the energetics of their binding. An example is also given from sodium channel toxins (μ-conotoxin GIIIA) to illustrate the differences between the toxin binding modes in potassium and sodium channels. Full article

(This article belongs to the Special Issue Marine Bioactive Natural Product Studies—A Southern Hemisphere Perspective)

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