Atkamine: A New Pyrroloiminoquinone Scaffold from the Cold Water Aleutian Islands <i>Latrunculia</i> Sponge

A new pyrroloiminoquinone alkaloid, named atkamine, with an unusual scaffold was discovered from a cold, deep water Alaskan sponge <i>Latrunculia</i> sp. collected from the Aleutian Islands. Olefin metathesis was utilized to determine the location of the double bond in the hydrocarbon chain. The absolute configuration was determined by using computational approaches combing with the ECD (electronic circular dichroism) spectroscopy

Reductive <i>N</i>-Alkylation of Nitroarenes: A Green Approach for the <i>N</i>‑Alkylation of Natural Products

A simple, mild, cost-effective, and green approach for the reductive mono-<i>N</i>-alkylation of nitroarenes has been developed. HOAc/Zn are utilized as the reducing system together with a carbonyl compound as an alkyl source in methanol. Excellent yields were obtained with stoichiometric control of mono- over dialkylated products. Application to five complex natural products demonstrated the practical utility of the method

Role of Marine Natural Products in the Genesis of Antiviral Agents

Role of Marine Natural Products in the Genesis of Antiviral Agent

An Iridoid Glucoside and the Related Aglycones from <i>Cornus florida</i>

A new iridoid glucoside, cornusoside A (<b>1</b>), and four new natural product iridoid aglycones, cornolactones A–D (<b>2</b>–<b>5</b>), together with 10 known compounds were isolated from the leaves of <i>Cornus florida</i>. The structures of compounds <b>1</b>–<b>5</b> were established by interpretation of their spectroscopic data. Cornolactone B (<b>3</b>) is the first natural <i>cis</i>-fused tricyclic dilactone iridoid containing both a five- and a six-membered lactone ring. A biosynthesis pathway is proposed for cornolactones C (<b>4</b>) and D (<b>5</b>), the C-6 epimers of compounds <b>1</b>–<b>3</b>

Solution Structure of a Sponge-Derived Cystine Knot Peptide and Its Notable Stability

A novel cystine knot peptide, asteropsin E (ASPE), was isolated from an <i>Asteropus</i> sp. marine sponge. The primary, secondary, and tertiary structures of ASPE were determined by high-resolution 2D NMR spectroscopy (900 MHz). With the exception of an <i>N</i>-terminal modification, ASPE shares properties with the previously reported asteropsins A–D, that is, the absence of basic residues, a highly acidic nature, conserved structurally important residues (including two <i>cis</i>-prolines), and a highly conserved tertiary structural framework. ASPE was found to be remarkably stable to gastrointestinal tract enzymes (chymotrypsin, elastase, pepsin, and trypsin) and to human plasma

SB-224289 Antagonizes the Antifungal Mechanism of the Marine Depsipeptide Papuamide A

<div><p>In order to expand the repertoire of antifungal compounds a novel, high-throughput phenotypic drug screen targeting fungal phosphatidylserine (PS) synthase (Cho1p) was developed based on antagonism of the toxin papuamide A (Pap-A). Pap-A is a cyclic depsipeptide that binds to PS in the membrane of wild-type <i>Candida albicans</i>, and permeabilizes its plasma membrane, ultimately causing cell death. Organisms with a homozygous deletion of the <i>CHO1</i> gene (<i>cho1ΔΔ</i>) do not produce PS and are able to survive in the presence of Pap-A. Using this phenotype (i.e. resistance to Pap-A) as an indicator of Cho1p inhibition, we screened over 5,600 small molecules for Pap-A resistance and identified SB-224289 as a positive hit. SB-224289, previously reported as a selective human 5-HT_1B receptor antagonist, also confers resistance to the similar toxin theopapuamide (TPap-A), but not to other cytotoxic depsipeptides tested. Structurally similar molecules and truncated variants of SB-224289 do not confer resistance to Pap-A, suggesting that the toxin-blocking ability of SB-224289 is very specific. Further biochemical characterization revealed that SB-224289 does not inhibit Cho1p, indicating that Pap-A resistance is conferred by another undetermined mechanism. Although the mode of resistance is unclear, interaction between SB-224289 and Pap-A or TPap-A suggests this screening assay could be adapted for discovering other compounds which could antagonize the effects of other environmentally- or medically-relevant depsipeptide toxins.</p></div

Compounds that conferred Pap-A resistance to <i>C</i>. <i>albicans</i> wild-type yeast.

<p>A) Structures of hits identified from the screen. B) Comparison of the ability of the hits to confer Pap-A resistance to wild type <i>C</i>. <i>albicans;</i> SB-224289, MG-624, and DMSO as a control.</p

Screen of FDA-approved bioactive compounds for those that confer Pap-A resistance.

<p>5,760 compounds were screened for their effects on the growth of wild-type <i>C</i>. <i>albicans</i> (open black circles) in the presence of 4 μg/ml Pap-A. Cell growth was measured by transformation of the dye Alamar Blue over approximately 3 hours at 37°C. The <i>cho1ΔΔ</i> positive control cells growth in the presence of Pap-A with no compounds from the library are represented by green circles. Compounds that allowed wild-type cells to display >90% (above the blue line) of the growth of <i>cho1ΔΔ</i> control were designated with filled-in blue circles. Around 95% of the tested compounds showed growth levels closer to the negative control, wells which contained no cells or drugs (open red circles). The horizontal lines show the 99th quantile (purple) where 99% of the compounds exhibited growth and the 95th quantile (yellow) 95% of the compounds lie. The vertical lines divide the compounds by the 384-well plate in which they were screened which correlate to plate numbers along the bottom. A full description of the screening method is found in Materials and Methods.</p

Resistance to Pap-A correlates with decreases in PS.

<p>The <i>cho1ΔΔ</i> mutant is resistant to all concentrations of papuamide A (Pap-A) indicating a total lack of PS. The <i>cho1ΔΔ</i>::<i>CHO1</i> reintegrant strain is more resistant to Pap-A than the wild-type (WT), but less resistant than the <i>cho1ΔΔ</i> mutant.</p

The full structure of SB-224289 is required to provide Pap-A resistance.

<p><b>(A)</b> and <b>(B)</b> show the structures of purchased or synthesized analogs of SB-224289, respectively. In <b>(C)</b> and <b>(D)</b> 1x10⁴ cells/ml were treated with a serial dilution of SB-224289, test compounds or DMSO control, and then allowed to incubate for 6 hours at 37°C. Pap-A was added at either 4 μg/ml or 5 μg/ml after 6 hours the plate was incubated at 37°C overnight. Alamar Blue was added and fluorescence signal measured at 590 nm indicating survival of cells.</p