Synthesis of four novel natural product inspired scaffolds for drug discovery.

Inspired by the novel spiro structures of a number of bioactive natural products such as the histrionicotoxins, a series of novel spiro scaffolds have been designed and robust syntheses developed. The scaffolds are ready-to-use building blocks and can be easily prepared on a 5-20 g scale. They contain two amino groups (one Boc-protected) and have been designed for ease of conversion to a lead generation library, using either amide formation or reductive amination procedures. The synthesis of the 1,9-diazaspiro[5.5]undecane and 3,7-diazaspiro[5.6]dodecane ring systems was achieved using RCM as the key step. A simple workup procedure is reported for the removal of highly colored ruthenium residues. The synthesis of the 1,8-diazaspiro[4.5]decane scaffold has been achieved using a bromine-mediated 5-endo cyclization of the corresponding 4-aminobutene intermediate under acidic conditions. This is the first example of this type of cyclization to be reported. A novel mechanism involving a bromine transfer reaction from an initially formed bromonium ion to a neighboring nitrogen atom is suggested as the reason for the failure of this type of reaction under "normal" bromination conditions. An unusual rearrangement of a 1-acyl-1,9-diazaspiro[5.5]undecane to the corresponding 9-acyl-1,9-diazaspiro[5.5]undecane is reported.

Exiguaquinol: a novel pentacyclic hydroquinone from Neopetrosia exigua that inhibits Helicobacter pylori MurI.

Bioassay-guided fractionation of the methanol extract of the Australian sponge Neopetrosia exigua led to the isolation of exiguaquinol (2), a new pentacyclic hydroquinone that inhibited Helicobacter pylori glutamate racemase (MurI) with an IC(50) of 4.4 microM. Its structure and relative configuration were assigned on the basis of spectroscopic data. Exiguaquinol (2), bearing a novel pentacyclic ring skeleton, is the first natural product to show inhibition of H. pylori MurI. Its protein-ligand modeling is also discussed.

Dysinosin A: a novel inhibitor of Factor VIIa and thrombin from a new genus and species of Australian sponge of the family Dysideidae.

A new marine natural product dysinosin A 1 has been isolated from a new genus and species of sponge of the family Dysideidae found near Lizard Island, North Queensland, Australia. Dysinosin A is a potent inhibitor of the blood coagulation cascade factor VIIa and an inhibitor of the serine protease thrombin. Among the distinctive features of dysinosin A are the presence of a 5,6-dihydroxy-octahydroindole-2-carboxylic acid, 3-amino-ethyl 1-N-amidino-Delta-3-pyrroline, a sulfated glyceric acid, and d-leucine, assembled through three peptidic linkages. Dysinosin A inhibited factor VIIa at a Ki of 108 nM and thrombin at a Ki of 452 nM. The identification of the 1-N-amidino-Delta-3-pyrroline and 5,6-dihydroxy-octahydroindole-2-carboxylic acid as P1 and P2 moieties respectively, should pave the way for the design and synthesis of new structure-based inhibitors.

Axinellamines A-D, Novel Imidazo-Azolo-Imidazole Alkaloids from the Australian Marine Sponge Axinella sp.

Four imidazo-azolo-imidazole alkaloids, axinellamines A-D, have been isolated from an Australian marine sponge, Axinella sp. (order: Halichondrida: family: Axinellidae). These compounds contain a unique perhydrocyclopenta-imidazo-azolo-imidazole carbon skeleton. Three of these compounds had bactericidal activity against Helicobacter pylori at 1000 &mgr;M.

Adociasulfates 1, 7, and 8: New Bioactive Hexaprenoid Hydroquinones from the Marine Sponge Adocia sp.

Adociasulfate 1 (1), adociasulfate 7 (2), and adociasulfate 8 (3), which are inhibitors of proton pump activity in hen bone-derived membrane vesicles, were isolated from an extract of the sponge Adocia sp. (Chalinidae). Structure elucidation by 2D-NMR spectroscopy revealed that they are novel hexaprenoid hydroquinone sulfates.