Malcolm Stewart Buchanan

Flinderoles A−C: Antimalarial Bis-indole Alkaloids from Flindersia Species

With the aim of finding new natural product antimalarials, the novel indole alkaloids flinderole A-C were found to have selective antimalarial activities with IC(50) values between 0.15-1.42 microM. Flinderole A was isolated from the Australian plant Flindersia acuminata and flinderoles B and C from the Papua New Guinean plant F. amboinensis. Flinderoles A-C contain an unprecedented rearranged skeleton compared to their related isomers of the borreverine class of compounds.

Clavatadine A, A Natural Product with Selective Recognition and Irreversible Inhibition of Factor XIa †

Bioassay-guided fractionation of a CH2Cl2/MeOH extract of the sponge Suberea clavata using the serine protease factor XIa to detect antithrombotic activity led to the isolation of the new marine natural products, clavatadines A and B. Clavatadines A and B inhibited factor XIa with IC50s of 1.3 and 27 microM, respectively. A crystal structure of protein-inhibitor (clavatadine A) complex was obtained and revealed interesting selective binding and irreversible inhibition of factor XIa. The cocrystal structure provides guidance for the design and synthesis of future factor XIa inhibitors as antithrombotic agents.

Antimalarial bromotyrosine derivatives from the Australian marine sponge Hyattella sp.

A drug discovery program aimed at identifying new antimalarial leads from a prefractionated natural product library has resulted in the identification of a new bromotyrosine alkaloid, psammaplysin G (1), along with the previously isolated compound, psammaplysin F (2). When tested against two different strains of the parasite Plasmodium falciparum (Dd2 and 3D7), 2 displayed IC(50) values of 1.4 and 0.87 microM, respectively, while 1 showed 98% inhibition at 40 microM against the chloroquine-resistant (Dd2) strain of P. falciparum.

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.

Antimalarial activity of pyrroloiminoquinones from the Australian marine sponge Zyzzya sp.

A new bispyrroloiminoquinone alkaloid, tsitsikammamine C (1), displayed potent in vitro antimalarial activity with IC(50) values of 13 and 18 nM against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum, respectively. Tsitsikammamine C (1) displayed selectivity indices of >200 against HEK293 cells and inhibited both ring and trophozoite stages of the malaria parasite life cycle. Previously reported compounds makaluvamines J (2), G (3), L (4), K (5) and damirones A (6) and B (7) were also isolated from the same marine sponge (Zyzzya sp.). Compounds 2-4 displayed potent growth inhibitory activity (IC(50) < 100 nM) against both P. falciparum lines and only moderate cytotoxicity against HEK293 cells (IC(50) = 1-4 μM). Makaluvamine G (3) was not toxic to mice and suppressed parasite growth in P. berghei infected mice following subcutaneous administration at 8 mg kg(-1) day(-1).

Antimalarial benzylisoquinoline alkaloid from the rainforest tree Doryphora sassafras.

Mass-directed isolation of the CH(2)Cl(2)/MeOH extract of Doryphora sassafras resulted in the purification of a new benzylisoquinoline alkaloid, 1-(4-hydroxybenzyl)-6,7-methylenedioxy-2-methylisoquinolinium trifluoroacetate (1), and the known aporphine alkaloid (S)-isocorydine (2). The structures of 1 and 2 were determined by 1D and 2D NMR and MS data analyses. The compounds were isolated during a drug discovery program aimed at identifying new antimalarial leads from a prefractionated natural product library. When tested against two different strains of the parasite Plasmodium falciparum (3D7 and Dd2), 1 displayed IC(50) values of 3.0 and 4.4 microM, respectively. Compound 1 was tested for cytotoxicity toward a human embryonic kidney cell line (HEK293) and displayed no activity at 120 microM.

Clavatadines C-E, Guanidine Alkaloids from the Australian Sponge Suberea clavata

Three new marine alkaloids, clavatadines C-E (1-3), together with the three known compounds aerophobin 1 (4), purealdin L (5), and aplysinamisine II (6) were isolated from extracts of the sponge Suberea clavata by bioassay-guided fractionation using a serine protease factor XIa assay. Their structures were determined by 1D and 2D NMR spectroscopy. Compounds 1-6 exhibited weak inhibition of factor XIa.

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.