Zeinab Khalil

Heronapyrroles A−C: Farnesylated 2-Nitropyrroles from an Australian Marine-Derived Streptomyces sp.

Chemical analysis of a marine-derived Streptomyces sp. (CMB-M0423) isolated from beach sand off Heron Island, Australia, yielded three new members of the rare pyrroloterpene biosynthetic structure class. Identified by detailed spectroscopic analysis as the first reported examples of naturally occurring 2-nitropyrroles, heronapyrroles A-C (1-3) displayed promising biological activity-with low to submicromolar IC(50) activity against Gram-positive bacteria but no cytotoxicity toward mammalian cell lines.

A search for BACE inhibitors reveals new biosynthetically related pyrrolidones, furanones and pyrroles from a southern Australian marine sponge, Ianthella sp.

Fractionation of a southern Australian marine sponge, Ianthella sp., yielded sixteen metabolites including a new class of pyrrolidone, ianthellidones A-F (1-6), a new class of furanone, ianthellidones G-H (7-8), new and known lamellarins, lamellarins O1 (9), O2 (10), O (11) and Q (12), plus the known 4-hydroxybenzaldehyde (13), 4-hydroxybenzoic acid (14), 4-methoxybenzoic acid (15) and ethyl 4-hydroxybenzoate (16). Structures for all Ianthella metabolites were determined by detailed spectroscopic analysis, supported by a plausible biosynthetic relationship. The ianthellidones were non-cytotoxic towards two human colon cancer cell lines (SW620 and SW620 Ad300), as well as Gram +ve and Gram -ve bacteria, and a fungus. Ianthellidone F (6) and lamellarins O2 (10) and O (11) displayed modest BACE inhibitory properties (IC(50) > 10 μM), while lamellarin O1 (9) was more potent (IC(50) < 10 μM). Lamellarin O (11) exhibited modest cytotoxicity towards SW620 and SW620 Ad300 cell lines (IC(50) > 22 μM), was an inhibitor of the multi-drug resistance efflux pump P-glycoprotein, and displayed selective growth inhibitory activity against the Gram +ve bacterium Bacillus subtilis (ATCC 6633) (IC(50) 2.5 μM).

Lamellarins as Inhibitors of P‐Glycoprotein‐Mediated Multidrug Resistance in a Human Colon Cancer Cell Line

Chemical analysis of a Didemnum sp. (CMB-01656) collected during scientific Scuba operations off Wasp Island, New South Wales, yielded five new lamellarins A1 (1), A2 (2), A3 (3), A4 (4) and A5 (5) and eight known lamellarins C (6), E (7), K (8), M (9), S (10), T (11), X (12) and χ (13). Analysis of a second Didemnum sp. (CMB-02127) collected during scientific trawling operations along the Northern Rottnest Shelf, Western Australia, yielded the new lamellarin A6 (14) and two known lamellarins G (15) and Z (16). Structures were assigned to 1-16 on the basis of detailed spectroscopic analysis with comparison to literature data and authentic samples. Access to this unique library of natural lamellarins (1-16) provided a rare opportunity for structure-activity relationship (SAR) investigations, probing interactions between lamellarins and the ABC transporter efflux pump P-glycoprotein (P-gp) with a view to reversing multidrug resistance in a human colon cancer cell line (SW620 Ad300). These SAR studies, which were expanded to include the permethylated lamellarin derivative (17) and a series of lamellarin-inspired synthetic coumarins (19-24) and isoquinolines (25-26), successfully revealed 17 as a promising new non-cytotoxic P-gp inhibitor pharmacophore.

Wollamides: Antimycobacterial Cyclic Hexapeptides from an Australian Soil Streptomyces

A soil Streptomyces nov. sp. (MST-115088) isolated from semiarid terrain near Wollogorang Station, Queensland, returned two known and two new examples of a rare class of cyclic hexapeptide, desotamides A and B (1 and 2) and E and F (3 and 4), respectively, together with two new d-Orn homologues, wollamides A and B (5 and 6). Structures were assigned by detailed spectroscopic and C3 Marfeys analysis. The desotamides/wollamides exhibit growth inhibitory activity against Gram-positive bacteria (IC50 0.6-7 μM) and are noncytotoxic to mammalian cells (IC50 >30 μM). The wollamides exhibit antimycobacterial activity (IC50 2.8 and 3.1 μM), including reduction in the intracellular mycobacterial survival in murine bone marrow-derived macrophages.

Heronapyrrole D: a case of co-inspiration of natural product biosynthesis, total synthesis and biodiscovery

Summary The heronapyrroles A–C have first been isolated from a marine-derived Streptomyces sp. (CMB-0423) in 2010. Structurally, these natural products feature an unusual nitropyrrole system to which a partially oxidized farnesyl chain is attached. The varying degree of oxidation of the sesquiterpenyl subunit in heronapyrroles A–C provoked the hypothesis that there might exist other hitherto unidentified metabolites. On biosynthetic grounds a mono-tetrahydrofuran-diol named heronapyrrole D appeared a possible candidate. We here describe a short asymmetric synthesis of heronapyrrole D, its detection in cultivations of CMB-0423 and finally the evaluation of its antibacterial activity. We thus demonstrate that biosynthetic considerations and the joint effort of synthetic and natural product chemists can result in the identification of new members of a rare class of natural products.

C3 and 2D C3 Marfey’s methods for amino acid analysis in natural products

We validate the improved resolution and sensitivity of the C3 Marfeys method, including an ability to resolve all Ile isomers, against an array of amino acids commonly encountered in natural products and by comparison to an existing Marfeys method. We also describe an innovative 2D C3 Marfeys method as an analytical approach for determining the regiochemistry of enantiomeric amino acid residues in natural products. The C3 and 2D C3 Marfeys methods represent valuable tools for probing and defining the stereocomplexity of hydrolytically accessible amino acid residues in natural products.

New dictyodendrins as BACE inhibitors from a southern Australian marine sponge, Ianthella sp.

Chemical analysis of a southern Australian marine sponge, an Ianthella sp., yielded dictyodendrins F–J (1–5) as new examples of a rare class of marine alkaloid. Structures were assigned on the basis of detailed spectroscopic analysis, while biosynthetic considerations suggested a relationship between the dictyodendrins and co-metabolites belonging to the lamellarin and ianthellidone structure classes. The dictyodendrins 1 and 3–5 exhibited significant BACE inhibitory activity (IC50 1–2 μM), with the differential cytotoxicity displayed by 1–4 towards two human colon cancer cell lines (IC50 2–16 μM) marking them as both cytotoxins and probable substrates for the multi-drug resistance efflux pump P-glycoprotein. The dictyodendrins 1–5 did not inhibit growth of Gram −ve bacteria or fungi, but 1, 3, and 4 were selective Gram +ve antibacterials (IC50 1–3 μM). Dictyodendrin J (5), with its unique seco-carbon skeleton and unusual 1,2-diketone functionality, exhibited a promising non-cytotoxic biological activity profile, inclusive of significant BACE inhibitory activity (IC50 2 μM), supportive of further investigation.

Shornephine A: structure, chemical stability, and P-Glycoprotein inhibitory properties of a rare Diketomorpholine from an Australian marine-derived Aspergillus sp.

Chemical analysis of an Australian marine sediment-derived Aspergillus sp. (CMB-M081F) yielded the new diketomorpholine (DKM) shornephine A (1) together with two known and one new diketopiperazine (DKP), 15b-β-hydroxy-5-N-acetyladreemin (2), 5-N-acetyladreemin (3), and 15b-β-methoxy-5-N-acetyladreemin (4), respectively. Structure elucidation of 1–4 was achieved by detailed spectroscopic analysis, supported by chemical degradation and derivatization, and biosynthetic considerations. The DKM (1) underwent a facile (auto) acid-mediated methanolysis to yield seco-shornephine A methyl ester (1a). Our mechanistic explanation of this transformation prompted us to demonstrate that the acid-labile and solvolytically unstable DKM scaffold can be stabilized by N-alkylation. Furthermore, we demonstrate that at 20 μM shornephine A (1) is a noncytotoxic inhibitor of P-glycoprotein-mediated drug efflux in multidrug-resistant human colon cancer cells.

Kinase Inhibitor Scaffolds against Neurodegenerative Diseases from a Southern Australian Ascidian, Didemnum sp.

Screening a library of Southern Australian and Antarctic marine invertebrates and algae for inhibitors of neurodegenerative disease kinase targets casein kinase 1 (CK1δ), cyclin‐dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β) identified a Western Australian Didemnum species (CMB‐02127) as a high‐priority specimen. Chemical fractionation returned the known aromatic alkaloids ningalins B–D as the major metabolites, together with six minor metabolites, the new ningalins E–G and the known hexacyclic pyrrole alkaloids lamellarins Z, G and A6. All structures were assigned by detailed spectroscopic analysis and literature comparisons, and the structural assignments were supported by biosynthetic considerations. The ningalins showed potent and broad inhibition across the three kinases, while the lamellarins were generally more selective for CDK5. Docking studies using published X‐ray crystal structures of CDK5 revealed both scaffolds target the ATP binding pocket.

Aranciamycins I and J, Antimycobacterial Anthracyclines from an Australian Marine-Derived Streptomyces sp.

Chemical analysis of an Australian marine-derived Streptomyces sp. (CMB-M0150) yielded two new anthracycline antibiotics, aranciamycins I (1) and J (2), as well as the previously reported aranciamycin A (3) and aranciamycin (4). The aranciamycins 1-4, identified by detailed spectroscopic analysis, were noncytotoxic when tested against selected Gram-negative bacteria and fungi (IC50 >30 μM) and exhibited moderate and selective cytotoxicity against Gram-positive bacteria (IC50 >1.1 μM) and a panel of human cancer cell lines (IC50 > 7.5 μM). Significantly, 1-4 were cytotoxic (IC50 0.7-1.7 μM) against the Mycobacterium tuberculosis surrogate M. bovis bacille Calmette-Guérin.