Gregory Allen Fechner

Aplysamine 6, an Alkaloidal Inhibitor of Isoprenylcysteine Carboxyl Methyltransferase from the Sponge Pseudoceratina sp.

The anticancer target isoprenylcysteine carboxyl methyltransferase (Icmt) was the focus of a natural product high-throughput screening campaign. The Australian marine sponge Pseudoceratina sp. yielded aplysamine 6, a new bromotyrosine derivative with an alpha,beta-unsaturated amide linkage, as the bioactive constituent. Its structure was determined by 1D and 2D NMR spectroscopy.

Cytotoxic Cyclic Depsipeptides from the Australian Marine Sponge Neamphius huxleyi

Three new cyclic depsipeptides, neamphamides B (2), C (3), and D (4), were isolated from the Australian sponge Neamphius huxleyi. The planar structural characterization of these molecules was elucidated using 2D NMR experiments and ESI-FTICR-MS(n). Their configurations were determined by Marfeys method and J-based NMR analysis. These new metabolites inhibited the growth of human cell lines (A549, HeLa, LNCaP, PC3, and NFF) with IC(50) values ranging from 88 to 370 nM. However, neamphamide D causes A549 cell proliferation at subcytotoxic doses and should be treated cautiously as a cytotoxic compound.

Bromotyrosine alkaloids from the Australian marine sponge Pseudoceratina verrucosa.

Two new bromotyrosine alkaloids, pseudoceralidinone A (1) and aplysamine 7 (2), along with three known compounds were isolated from the Australian sponge Pseudoceratina verrucosa. Their structures were characterized by NMR and MS data and the synthetic route. Their cytotoxicity was evaluated against cancer cell lines (HeLa and PC3) and a noncancer cell line (NFF).

Alkaloids from the Australian Rainforest Tree Ochrosia moorei

High-throughput screening of a plant and marine invertebrate extract library to find natural products that down-regulate expression of pro-inflammatory genes associated with the glucocorticoid receptor ligand complex led to the identification of bioactive CH2Cl 2 extracts from stems and leaves of the Queensland tree Ochrosia moorei. Bioassay-guided purification of the stem extract enabled the isolation of four alkaloids including two new compounds, ochrosamines A (1) and B (2), and the known compounds ellipticine (3) and 9-methoxyellipticine (4). The leaf extract also afforded 3 and 4 as well as apparicine (5) and desoxycordifoline (6). The structures of the two new compounds were assigned from interpretation of 2D NMR and high-resolution ESIMS data. Ellipticine and 9-methoxyellipticine were the most active components, and both displayed IC 50 values of 90 microM. Apparicine and desoxycordifoline were only very weakly active, and ochrosamines A and B were inactive.

(-)-Dibromophakellin : An α2B adrenoceptor agonist isolated from the Australian marine sponge, Acanthella costata

Bioassay-guided fractionation of the organic extract from the marine sponge Acanthella costata resulted in the isolation of the known natural product, (-)-dibromophakellin (1). Using a fluorescence imaging plate reader (FLIPR) based assay, compound 1 was identified as displaying agonist activity against the alpha(2B) adrenoceptor, with an EC(50) of 4.2muM. Debromination and Suzuki-Miyaura coupling reactions were undertaken in order to provide structure activity data about the pyrrole ring of this marine metabolite. These synthetic studies generated the known natural product analogues, (-)-phakellin (2), and (-)-monobromophakellin (3), along with the new synthetic derivatives (-)-4-bromo-5-phenylphakellin (5) and (-)-4,5-diphenylphakellin (6). Substitution of the C-5 Br of 1 with H (2 and 3) or phenyl (5 and 6) resulted in loss of activity indicating that Br at C-5 is required for agonist activity.

Prenylated dihydrochalcones from Boronia bipinnata that inhibit the malarial parasite enzyme target hemoglobinase II.

High-throughput screening of a plant and marine invertebrate extract library to find natural products that inhibit the malarial parasite enzyme target hemoglobinase II led to the isolation of two new active prenylated chalcones, bipinnatones A (1) and B (2), from aerial parts of the Queensland shrub Boronia bipinnata. Their structures were assigned from interpretation of 2D NMR and high-resolution ESIMS data. Compounds 1 and 2 inhibited hemoglobinase II with IC 50 values of 64 and 52 microM, respectively.

The functional antagonist Met-RANTES: A modified agonist that induces differential CCR5 trafficking

CC chemokine receptor 5 (CCR5) is a pro-inflammatory chemokine receptor that is expressed on cells of the immune system, and specializes in cell migration in response to inflammation and tissue damage. Due to its key role in cell communication and migration, this receptor is involved in various inflammatory and autoimmune diseases, in addition to HIV infection. Met-RANTES is a modified CCR5 ligand that has previously been shown to antagonize CCR5 activation and function in response to its natural ligands in vitro. In vivo, Met-RANTES is able to reduce inflammation in models of induced inflammatory and autoimmune diseases. However, due to the fact that Met-RANTES is also capable of partial agonist activity regarding receptor signaling and internalization, it is clear that Met-RANTES does not function as a conventional receptor antagonist. To further elucidate the effect of Met-RANTES on CCR5, receptor trafficking was investigated in a CHO-CCR5-GFP cell line using the Opera confocal plate reader. The internalization response of CCR5 was quantified, and showed that Met-RANTES internalized CCR5 in a slower, less potent manner than the agonists CCL3 and CCL5. Fluorescent organelle labeling and live cell imaging showed CCL3 and CCL5 caused CCR5 to traffic through sorting endosomes, recycling endosomes and the Golgi apparatus. In contrast, Met-RANTES caused CCR5 to traffic through sorting endosomes and the Golgi apparatus in a manner that was independent of recycling endosomes. As receptor trafficking impacts on cell surface expression and the ability of the receptor to respond to more ligand, this information may indicate an alternative regulation of CCR5 by Met-RANTES that allows the modified ligand to reduce inflammation through stimulation of a pro-inflammatory receptor.

Potent cytotoxic peptides from the Australian marine sponge Pipestela candelabra

Two consecutive prefractionated fractions of the Australian marine sponge extract, Pipestela candelabra, were identified to be selectively active on the human prostate cancer cells (PC3) compared to the human neonatal foreskin fibroblast non-cancer cells (NFF). Twelve secondary metabolites were isolated in which four compounds are new small peptides. Their structures were characterized by spectroscopic and chemical analysis. These compounds inhibited selectively the growth of prostate cancer cells with IC50 values in the picomolar to sub-micromolar range. Structure-activity relationship of these compounds is discussed.

Lysianadioic acid, a carboxypeptidase B inhibitor from Lysiana subfalcata

A new natural product, lysianadioic acid, was isolated from the plant Lysiana subfalcata as a carboxypeptidase B (CPB) inhibitor. It is a potent inhibitor of CPB with an IC(50) of 0.36 microM. This is the first known example of a small molecule CPB inhibitor isolated from plant origin. Its structure was determined by NMR spectroscopy.

Corrigendum to “Solid-phase synthesis of Biotin-S-Farnesyl- l -Cysteine, a surrogate substrate for isoprenylcysteine Carboxylmethyltransferase (ICMT)” [Bioorg. Med. Chem. Lett. 23 (2013) [5671–5673]

The authors would like to apologise and point out that the following corrections are required to Fig. 1, Fig. 2, Scheme 1 and Scheme 2. Hydrogens are missing from the structure of the Biotin ring system: