Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface.

The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a therapeutic modality that dramatically expands the currently accepted limits of druggability. WDB002, in complex with the FK506-binding protein (FKBP12), potently and selectively binds the human centrosomal protein 250 (CEP250), resulting in disruption of CEP250 function in cells.

Structure Elucidation of Nigricanoside A Through Enantioselective Total Synthesis.

Nigricanoside A was isolated from green alga, and its dimethyl ester was found to display potent cytotoxicity. Its scarcity prevented a full structure elucidation, leaving total synthesis as the only means to determine its relative and absolute stereochemistry and to explore its biological activity. Here we assign the stereochemistry of the natural product through enantioselective total synthesis and provide initial studies of its cytotoxicity.

Precursor-Directed Generation of Amidine Containing Ammosamide Analogs: Ammosamides E-P.

Ammosamides E-F (1-2), are amidine analogs of the ammosamide family of alkaloids isolated from a marine-derived Streptomyces variabilis. Further studies with S. variabilis revealed a variety of aryl and alkyl amines added into the fermentation media could be efficiently incorporated into the ammosamide framework to generate a library of precursor-directed amidine analogs, ammosamides G-P (9 - 18).

Ammosamide D, an oxidatively ring opened ammosamide analog from a marine-derived Streptomyces variabilis.

Ammosamide D (1), an oxidized analog of the ammosamide family, was isolated from a marine-derived Streptomyces variabilis. Pyrroloquinoline containing alkaloids are a growing class of natural products, with 1 being the first example of an oxidized analog resulting in a 5,6-dioxo-5,6-dihydroquinoline ring system. Attempts at chemical conversion of ammosamide B to ammosamide D revealed that a strong chemical oxidant is required.

Antiplasmodial and antiproliferative pseudoguaianolides of Athroisma proteiforme from the Madagascar Dry Forest.

Investigation of extracts from the plant Athroisma proteiforme (Humbert) Mattf. (Asteraceae) for antimalarial activity led to the isolation of the five new sesquiterpene lactones 1-5 together with centaureidin (6). The structures of the new compounds were deduced from analyses of physical and spectroscopic data, and the absolute configuration of compound 1 was confirmed by an X-ray crystallographic study.

Isolation and synthesis of antiproliferative eupolauridine alkaloids of Ambavia gerrardii from the Madagascar Dry Forest.

Investigation of the Madagascan endemic plant Ambavia gerrardii for antiproliferative activity against the A2780 ovarian cancer cell line led to the isolation of the three new alkaloids 8-hydroxyeupolauridine (1), 9-methoxyeupolauridine 1-oxide (2), and 11-methoxysampangine (3) and the three known alkaloids 4-6. The structures of 1 and 2 were confirmed by synthesis. Compounds 3, 4, and 6 showed moderate to good antiproliferative activities, with IC50 values of 10.

Cardenolides of Leptadenia madagascariensis from the Madagascar dry forest.

Investigation of the endemic Madagascar plant Leptadenia madagascariensis Decne. (Apocynaceae) for antiproliferative activity against the A2780 ovarian cancer cell line led to the isolation of the four new cardenolides 1-4. The structure elucidations of these compounds were based on analyzes of their 1D and 2D NMR spectra and mass spectrometric data.

Four diphenylpropanes and a cycloheptadibenzofuran from Bussea sakalava from the Madagascar dry forest.

Investigation of the endemic Malagasy plant Bussea sakalava for antiproliferative activity against the A2780 ovarian cancer cell line led to the isolation of the four new diphenylpropanes 1-4 and the new cycloheptadibenzofuran 5; compound 5 has a previously unreported natural product skeleton. The structure elucidation of these compounds was based on the analysis of their 1D and 2D NMR and mass spectroscopic data. Compounds 1-5 were tested for antiproliferative activity against the A2780 human ovarian cancer cell line.

A new labdane diterpene from Vitex cauliflora Moldenke from the Madagascar rainforest.

Fractionation of an antiplasmodial ethanolic extract from the aerial parts of Vitex cauliflora led to the isolation of the new labdane diterpene 1 together with the known triterpene uvaol. The structure of the new compound 1 was established as 3-oxo,15,17,18-triacetoxy-labda-7,13E-diene on the basis of spectroscopic data (1D and 2D NMR, MS).