Michael T. Davies-Coleman

Pyrroloiminoquinone and related metabolites from marine sponges

This review presents the structure, biological activity, biosynthetic studies and, where applicable, references to syntheses of 81 marine alkaloids containing either tetra-, hexa- or octa-hydrogenated variants of pyrrolo[4,3,2-de]quinoline, pyrrolo[4,3,2-de]pyrrolo[2,3-h]quinoline and pyrido[2,3-h]pyrrolo[4,3,2-de]quinoline core skeletons. The literature describing the isolation of pyrroloiminoquinones, and related metabolites, from marine sponges is littered with taxonomic inconsistencies and recent efforts to clarify the taxonomy of the sponges that produce this group of metabolites are discussed.

Anti-inflammatory metabolites from marine sponges

Marine sponges are a rich source of biologically active secondary metabolites with novel chemical structures. Eighty four anti-inflammatory compounds have been isolated from marine sponges. This is the first comprehensive review presenting the structures and anti-inflammatory activities of marine sponge metabolites. (100 references).

Cytotoxic and antioxidant marine prenylated quinones and hydroquinones.

Covering: 1972 to 2011. This review covers the literature of prenylated quinone, hydroquinone and naphthoquinone marine natural products with reported cytotoxic and/or antioxidant properties. The structures, biological activity and, where applicable, the syntheses of 159 cytotoxic/antioxidant compounds, isolated from various marine organisms, are presented, while trends in the distribution of these cytotoxic metabolites, across the different marine phyla, are highlighted. Marine prenylated quinones, hydroquinones and naphthoquinones are of mixed polyketide and terpenoid biogenesis and recent biosynthetic studies of selected compounds are discussed.

Methicillin-resistant Staphylococcus aureus (MRSA) Pyruvate Kinase as a Target for Bis-indole Alkaloids with Antibacterial Activities

Background: Methicillin-resistant Staphylococcus aureus (MRSA) PK has been recently identified as a potential novel antimicrobial drug target. Results: Screening of a marine extract library led to the identification of several bis-indole alkaloids as novel potent and selective MRSA PK inhibitors. Conclusion: These results help to understand the mechanism of the antibacterial activities of marine bis-indole alkaloids. Significance: This study provides the basis for development of potential novel antimicrobials. Novel classes of antimicrobials are needed to address the emergence of multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). We have recently identified pyruvate kinase (PK) as a potential novel drug target based upon it being an essential hub in the MRSA interactome (Cherkasov, A., Hsing, M., Zoraghi, R., Foster, L. J., See, R. H., Stoynov, N., Jiang, J., Kaur, S., Lian, T., Jackson, L., Gong, H., Swayze, R., Amandoron, E., Hormozdiari, F., Dao, P., Sahinalp, C., Santos-Filho, O., Axerio-Cilies, P., Byler, K., McMaster, W. R., Brunham, R. C., Finlay, B. B., and Reiner, N. E. (2011) J. Proteome Res. 10, 1139–1150; Zoraghi, R., See, R. H., Axerio-Cilies, P., Kumar, N. S., Gong, H., Moreau, A., Hsing, M., Kaur, S., Swayze, R. D., Worrall, L., Amandoron, E., Lian, T., Jackson, L., Jiang, J., Thorson, L., Labriere, C., Foster, L., Brunham, R. C., McMaster, W. R., Finlay, B. B., Strynadka, N. C., Cherkasov, A., Young, R. N., and Reiner, N. E. (2011) Antimicrob. Agents Chemother. 55, 2042–2053). Screening of an extract library of marine invertebrates against MRSA PK resulted in the identification of bis-indole alkaloids of the spongotine (A), topsentin (B, D), and hamacanthin (C) classes isolated from the Topsentia pachastrelloides as novel bacterial PK inhibitors. These compounds potently and selectively inhibited both MRSA PK enzymatic activity and S. aureus growth in vitro. The most active compounds, cis-3,4-dihyrohyrohamacanthin B (C) and bromodeoxytopsentin (D), were identified as highly potent MRSA PK inhibitors (IC50 values of 16–60 nm) with at least 166-fold selectivity over human PK isoforms. These novel anti-PK natural compounds exhibited significant antibacterial activities against S. aureus, including MRSA (minimal inhibitory concentrations (MIC) of 12.5 and 6.25 μg/ml, respectively) with selectivity indices (CC50/MIC) >4. We also report the discrete structural features of the MRSA PK tetramer as determined by x-ray crystallography, which is suitable for selective targeting of the bacterial enzyme. The co-crystal structure of compound C with MRSA PK confirms that the latter is a target for bis-indole alkaloids. It elucidates the essential structural requirements for PK inhibitors in “small” interfaces that provide for tetramer rigidity and efficient catalytic activity. Our results identified a series of natural products as novel MRSA PK inhibitors, providing the basis for further development of potential novel antimicrobials.

Spongian diterpenoids from marine sponges

This review presents the structure, biological activity and, where applicable, references to the syntheses of 154 spongian and rearranged spongian diterpenoids isolated from marine sponges of the orders Dictyoceratida and Dendroceratida. There have been no studies of the biosynthesis of either spongian diterpenoids or their rearranged derivatives reported in the literature. The potential chemotaxonomic significance of spongian and rearranged spongian ditepenoids is discussed.

New alkaloids from a South African latrunculid sponge

The structures of two new bispyrroloiminoquinone alkaloids, tsitsikammamine A (1) and tsitsikammamine B (2) and two new pyrroloiminoquinone alkaloids 14-bromodiscorhabdin C (3) and 14-bromodihydrodiscorhabdin C (4) were determined spectroscopically. Compounds 1 and 2 are the first bispyrroloiminoquinone alkaloids to be isolated from a marine sponge while compounds 3 and 4 are the first reported discorhabdin metabolites with a C-14 substituent. All four compounds exhibit antimicrobial activity.

The Structure and Synthesis of Tsitsikammafuran: A New Furanosesquiterpene from a South African Dysidea Sponge

Abstract Three furanosesquiterpenes, the new tsitsikammafuran (1) and the known nakafurans-8 (2) and -9 (3) were isolated from a South African Dysidea sponge. The structure of tsitsikammafuran, initially proposed as 3-[(furan-3-yl)methyl]-p-cymene, from a combination of biosynthetic arguments and the available spectroscopic data, was unequivocally confirmed by the synthesis of 1 from thymol. The synthesis of two regioisomers of tsitsikammafuran, 4-[(furan-3-yl)methyl]-m-cymene (4) and 2-[(furan-3-yl)methyl]-p-cymene (22), from p-cresol and 2-bromo-2-nitrocamphane respectively, further supported the structural assignment of 1.

5,6-Dihydro-α-pyrones from Syncolostemon argenteus

Abstract The chemical structures of five new α-pyrones, synargentolides A-E, isolated from Syncolostemon argenteus , have been established as 6 R -[4 R ,5 R ,6 S -triacetyloxy-1 E -heptenyl]-5,6-dihydro-2H-pyran-2-one, 6 R -[5,6 S -diacetyloxy-1,2-dihydroxy-3 E -heptenyl]-5,6-dihydro-2H-pyran-2-one, 6 R -[5,6 S -diacetyloxy-1,2-dihydroxy-3 E -heptenyl]-5 S -acetyloxy-5,6-dihydro-2H-pyran-2-one, 6 R -[5,6 S -diacetyloxy-1,2-dihydroxy-3 E -heptenyl]-5-hydroxy-5,6-dihydro-2H-pyran-2-one and 6 S -[4,6 S -diacetyloxy-1,5-dihydroxy-2 E -heptenyl]-5 S -acetyloxy-5,6-dihydro-2H-pyran-2-one, respectively, based on spectral chiroptical and chemical evidence.

Stereochemical studies on boronolide, an α-pyrone from Tetradenia barberae

Abstract The structure of boronolide isolated from Tetradenia barberae has been confirmed as 6 R -[1 R ,2 R ,3 S -(trisacetyloxy)-heptyl]-5,6-dihydr

Screening for small molecule modulators of Hsp70 chaperone activity using protein aggregation suppression assays: inhibition of the plasmodial chaperone PfHsp70-1

Abstract Plasmodium falciparum heat shock protein 70 (PfHsp70-1) is thought to play an essential role in parasite survival and virulence in the human host, making it a potential antimalarial drug target. A malate dehydrogenase based aggregation suppression assay was adapted for the screening of small molecule modulators of Hsp70. A number of small molecules of natural (marine prenylated alkaloids and terrestrial plant naphthoquinones) and related synthetic origin were screened for their effects on the protein aggregation suppression activity of purified recombinant PfHsp70-1. Five compounds (malonganenone A-C, lapachol and bromo-β-lapachona) were found to inhibit the chaperone activity of PfHsp70-1 in a concentration dependent manner, with lapachol preferentially inhibiting PfHsp70-1 compared to another control Hsp70. Using growth inhibition assays on P. falciparum infected erythrocytes, all of the compounds, except for malonganenone B, were found to inhibit parasite growth with IC50 values in the low micromolar range. Overall, this study has identified two novel classes of small molecule inhibitors of PfHsp70-1, one representing a new class of antiplasmodial compounds (malonganenones). In addition to demonstrating the validity of PfHsp70-1 as a possible drug target, the compounds reported in this study will be potentially useful as molecular probes for fundamental studies on Hsp70 chaperone function.