Unique Polybrominated Hydrocarbons from the Australian Endemic Red Alga <i>Ptilonia australasica</i>

The red alga <i>Ptilonia australasica</i> is endemic to Australian temperate waters. Chemical investigation of <i>P. australasica</i> led to the identification of four new polybrominated compounds, ptilones A–C (<b>1</b>–<b>3</b>) and australasol A (<b>4</b>). 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 <b>1</b>, <b>2</b>, and <b>4</b> were determined by quantum chemical ECD calculations employing time-dependent density functional theory. Ptilones A–C (<b>1</b>–<b>3</b>) show unique 4-ethyl-5-methylenecyclopent-2-enone (<b>1</b> and <b>2</b>) and 2-methyl-6-vinyl-4<i>H</i>-pyran-4-one (<b>3</b>) 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

Actinomycete Metabolome Induction/Suppression with <i>N</i>‑Acetylglucosamine

The metabolite profiles of three sponge-derived actinomycetes, namely, <i>Micromonospora</i> sp. RV43, <i>Rhodococcus</i> sp. RV157, and <i>Actinokineospora</i> sp. EG49 were investigated after elicitation with <i>N</i>-acetyl-d-glucosamine. ¹H NMR fingerprint methodology was utilized to study the differences in the metabolic profiles of the bacterial extracts before and after elicitation. Our study found that the addition of <i>N</i>-acetyl-d-glucosamine modified the secondary metabolite profiles of the three investigated actinomycete isolates. <i>N</i>-Acetyl-d-glucosamine induced the production of 3-formylindole (<b>11</b>) and guaymasol (<b>12</b>) in <i>Micromonospora</i> sp. RV43, the siderophore bacillibactin <b>16</b>, and surfactin antibiotic <b>17</b> in <i>Rhodococcus</i> sp. RV157 and increased the production of minor metabolites actinosporins E–H (<b>21</b>–<b>24</b>) in <i>Actinokineospora</i> sp. EG49. These results highlight the use of NMR fingerprinting to detect changes in metabolism following addition of <i>N</i>-acetyl-d-glucosamine. <i>N</i>-Acetyl-d-glucosamine was shown to have multiple effects including suppression of metabolites, induction of new metabolites, and increased production of minor compounds

Dereplication of cytotoxic compounds from different parts of <i>Sophora pachycarpa</i> using an integrated method of HPLC, LC-MS and ¹H-NMR techniques

<p><i>Sophora pachycarpa</i> Schrenk ex C.A.Mey. is an annual plant belonging to the family Fabaceae. The cytotoxic activities of methanol-dichloromethane extracts (1:1) of different parts of <i>S. pachycarpa</i> were investigated on DU145 (prostate cancer cell line) and MCF-7 (breast cancer cell line) cell lines. The root extract of <i>S. pachycarpa</i> was the only extract that showed significant cytotoxic activity with IC₅₀ values of 39.88 and 16.49 μg/mL on DU145 and MCF-7 cell lines, respectively. The root extract was then subjected to RP-HPLC for further fractionations. Among the isolated fractions from root extract, only one of them had remarkable cytotoxic effects with IC₅₀ value of 26.43 on MCF-7 and 7.54 μg/mL on DU145 cell lines. Further purification led to isolation of a compound with IC₅₀ values of 5.44 and 2.44 μg/mL on MCF-7 and DU145 cell lines, respectively. Based on ¹H NMR and ¹³C NMR spectra, together with LC-MS, the structure of the purified compound was assigned as the flavonostilbene alopecurone A.</p

Structural Insights into the Molecular Basis of the Ligand Promiscuity

Selectivity is a key factor in drug development. In this paper, we questioned the Protein Data Bank to better understand the reasons for the promiscuity of bioactive compounds. We assembled a data set of >1000 pairs of three-dimensional structures of complexes between a “drug-like” ligand (as its physicochemical properties overlap that of approved drugs) and two distinct “druggable” protein targets (as their binding sites are likely to accommodate “drug-like” ligands). Studying the similarity between the ligand-binding sites in the different targets revealed that the lack of selectivity of a ligand can be due (i) to the fact that Nature has created the same binding pocket in different proteins, which do not necessarily have otherwise sequence or fold similarity, or (ii) to specific characteristics of the ligand itself. In particular, we demonstrated that many ligands can adapt to different protein environments by changing their conformation, by using different chemical moieties to anchor to different targets, or by adopting unusual extreme binding modes (e.g., only apolar contact between the ligand and the protein, even though polar groups are present on the ligand or at the protein surface). Lastly, we provided new elements in support to the recent studies which suggest that the promiscuity of a ligand might be inferred from its molecular complexity

Drug-like Properties: Guiding Principles for the Design of Natural Product Libraries

While natural products or their derivatives and mimics have contributed around 50% of current drugs, there has been no approach allowing front-loading of chemical space compliant with lead- and drug-like properties. The importance of physicochemical properties of molecules in the development of orally bioavailable drugs has been recognized. Classical natural product drug discovery has only been able to undertake this analysis retrospectively after compounds are isolated and structures elucidated. The present approach addresses front-loading of both extracts and subsequent fractions with desired physicochemical properties prior to screening for drug discovery. The physicochemical profiles of natural products active against two neglected disease targets, malaria and African trypanosomiasis, are presented based on this strategy. This approach can ensure timely development of natural product leads at a hitherto unachievable rate

Thiaplakortones A–D: Antimalarial Thiazine Alkaloids from the Australian Marine Sponge Plakortis lita

A high-throughput screening campaign using a prefractionated natural product library and an in vitro antimalarial assay identified active fractions derived from the Australian marine sponge Plakortis lita. Bioassay-guided fractionation of the CH₂Cl₂/CH₃OH extract from P. lita resulted in the purification of four novel thiazine-derived alkaloids, thiaplakortones A–D (<b>1</b>–<b>4</b>). The chemical structures of <b>1</b>–<b>4</b> were determined following analysis of 1D/2D NMR and MS data. Comparison of the chiro-optical data for <b>3</b> and <b>4</b> with literature values of related <i>N</i>-methyltryptophan natural products was used to determine the absolute configuration for both thiaplakortones C and D as 11<i>S</i>. Compounds <b>1</b>–<b>4</b> displayed significant growth inhibition against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum (IC₅₀ values <651 nM) and only moderate cytotoxicity against HEK293 cells (IC₅₀ values >3.9 μM). Thiaplakortone A (<b>1</b>) was the most active natural product, with IC₅₀ values of 51 and 6.6 nM against 3D7 and Dd2 lines, respectively

Structural diversity analysis of 7365 non-flat fragment-sized natural products based on pharmacophore (orange) and radial (red) fingerprints.

<p>Using SOMs (generated by training non-flat structures subset) we analyzed the distribution and therefore the coverage of the total diversity of non-flat fragments by the subsets clustered on the number of rings present in the structure.</p

Distribution of 2-ring fragments dataset within the non-flat fragment-sized natural products SOM.

<p>For a few selected cells are, the most representative structures (green circle) is shown. In the black square box is reported one example of the molecular similarity within the same cell. The entire list of seed compounds can be found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120942#pone.0120942.s003" target="_blank">S3 Table</a>.</p

Distribution of compounds within the SOMs trained using ECPF_4 fingerprints of 20185 fragment-sized natural products (Fig 3A and 3B) and 7365 non-flat fragment-sized natural products (Fig 3C–3H).

<p><b>(a)</b> 20185 fragment-sized natural products. <b>(b)</b> 7365 non-flat fragment sized natural products (F<i>sp</i>³* > 0.45). <b>(c)</b> 7365 non-flat fragment-sized natural products. <b>(d)</b> 1-ring molecules; 37% coverage of non-flat fragments. <b>(e)</b> 2-ring molecules; 68% coverage of non-flat fragments. <b>(f)</b> 3-ring molecules; 56% coverage of non-flat fragments. <b>(g)</b> 4-ring molecules; 21% coverage of non-flat fragments. <b>(h)</b> 5-ring molecules; 2% coverage of non-flat fragments. Each cell represents a cluster of fragments and the distance between cells (i.e. nearby cell are structurally related compounds) is indicated by the shading of the cell borders; darker borders indicate larger distance. Cells are coloured by population, with white for empty cells, and red for cell containing more than 5 compounds. The trained SOM is characterized by a toroidal architecture, which means that the top edge is connected to the lower edge and the left edge with the right edge.</p

Pharmacophore analysis of natural products.

<p>Based on the number of unique pharmacophore triplets (1–6 bonds), generated using eight features, we identified that fragment-sized natural products cover ~66% of the unique pharmacophore of the whole DNP.</p