Antony D. Buss

Benzylidene rhodanines as novel inhibitors of UDP-N-acetylmuramate/L-alanine ligase.

Benzylidene rhodanines are novel inhibitors of UDP N-acetylmuramate/L-alanine ligase. They showed selective whole-cell activity against the Gram-positive MRSA but not against the Gram-negative Escherichia coli. Their cytotoxic effect on mammalian CHO cells was also evaluated.

Spermine alkaloids from Albizia adinocephala with activity against Plasmodium falciparum plasmepsin II

Crude MeOH extracts from the stem bark and leaves of a Panamanian specimen of Albizia adinocephala (Leguminosae) were found to inhibit the malarial enzyme plasmepsin II. Bioassay guided fractionation led to the isolation of two new bioactive spermine alkaloids, budmunchiamines L4 and L5.

Interaction of kendomycin and semi-synthetic analogues with the anti-apoptotic protein Bcl-xl.

The cytotoxic macrolide kendomycin was identified as a ligand of Bcl-xl, an anti-apoptotic member of the Bcl-2 protein family. Hydrolysis-stable and protonable semi-synthetic analogues have been obtained that retain cytotoxicity and Bcl-xl binding.

Identification of a Naturally Occurring Quinazolin-4(3H)-one Firefly Luciferase Inhibitor

A prefractionated Streptomyces-derived extract was initially identified as being active using a luciferase-based AMP-activated protein kinase (AMPK) assay. Bioassay-guided fractionation led to the isolation of the new compound quinazolin-4(3H)-one (1) as the active component. However, 1 was shown to have potent firefly luciferase inhibitory activity with no effect on AMPK. This is the first report of a natural luciferase inhibitor.

Development of a Plasmepsin II Fluorescence Polarization Assay Suitable for High Throughput Antimalarial Drug Discovery

Despite decades of research, malaria remains the worlds most deadly parasitic disease. New treatments with novel mechanisms of action are urgently needed. Plasmepsin II is an aspartyl protease that has been validated as an antimalarial therapeutic target enzyme. Although natural products form the basis of most modern antimalarial drugs, no systematic high-throughput screening has been reported against this target. We have designed an effective strategy for carrying out high-throughput screening of an extensive library of natural products that uses a fluorescence resonance energy transfer primary screening assay in tandem with a fluorescence polarization assay. This strategy allows rapid screening of the library coupled with effective discrimination and elimination of false-positive samples and selection of true hits for chemical isolation of inhibitors of plasmepsin II.

Actephilol A and epiactephilol A: two novel aromatic terpenoids isolated from Actephila excelsa

An investigation into the chemical constituents of a crude MeOH extract from a specimen of Actephila excelsa (family Euphorbiaceae), led to the isolation of two new epimeric aromatic terpenoids, actephilol A 1 and epiactephilol A 2. The gross structures and relative stereochemistry of 1 and 2 were determined through extensive 2D NMR analysis

Phenolic derivatives from Wigandia urens with weak activity against the chemokine receptor CCR5

Three compounds, 2,3-dihydroxy-4-methoxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran (1), 8-methoxy-2-methyl-2-(4-methyl-3-pentenyl)-2H-1-benzopyran-6-ol (2) and 4-methoxy-3-(3-methyl-2-butenyl)-benzoic acid (3), have been isolated from Wigandia urens. The structures of compounds 1, 2 and 3 were determined from spectroscopic data and showed activity in a CCR5 assay with IC(50) values of 33, 46 and 26 muM respectively.

Isolation and synthesis of falcitidin, a novel myxobacterial-derived acyltetrapeptide with activity against the malaria target falcipain-2

A 384-well microtitre plate fluorescence cleavage assay was developed to identify inhibitors of the cysteine protease falcipain-2, an important antimalarial drug target. Bioassay-guided isolation of a MeOH extract from a myxobacterium Chitinophaga sp. Y23 isolated from soil collected in Singapore, led to the identification of a new acyltetrapeptide, falcitidin (1), which displayed an IC50 value of 6 μM against falcipain-2. The planar structure of 1 was secured by NMR and MS/MS analysis. Attempts to isolate further material for biological testing were hampered by inconsistent production and by a low yield (<100 μg l−1). The absolute configuration of 1 was determined by Marfey’s analysis and the structure was confirmed through total synthesis as isovaleric acid-D-His-L-Ile-L-Val-L-Pro-NH2. Falcitidin (1) is the first member of a new class of falcipain-2 inhibitors and, unlike other peptide-based inhibitors, does not contain reactive groups that irreversibly bind to active cysteine sites.

Flavonoids from Artocarpus Lanceifolius

One new compound, 14-hydroxyartonin E ( 1 ), together with the known compound, artonin E ( 2 ), was isolated from Artocarpus lanceifolius . Their structures were elucidated by spectroscopic methods.

Gargantulide A, a complex 52-membered macrolactone showing antibacterial activity from streptomyces sp.

Gargantulide A (1), an extremely complex 52-membered macrolactone, was isolated from Streptomyces sp. A42983 and displayed moderate activity against MRSA. The planar structure of 1 was determined using 2D NMR, and its stereochemistry was partially established on the basis of NOESY correlations, J-based configuration analysis, and Kishis universal NMR database.