Using 'biased-privileged' scaffolds to identify lysine methyltransferase inhibitors.

Methylation of histones by lysine methyltransferases (KMTases) plays important roles in regulating chromatin function. It is also now clear that improper KMTases activity is linked to human diseases, such as cancer. We report an approach that employs drug-like 'privileged' scaffolds biased with motifs present in S-adenosyl methionine, the cofactor used by KMTases, to efficiently generate inhibitors for Set7, a biochemically well-characterized KMTase. Setin-1, the most potent inhibitor of Set7 we have developed also inhibits the KMTase G9a. Together these data suggest that these inhibitors should provide good starting points to generate useful probes for KMTase biology and guide the design of KMTase inhibitors with drug-like properties.

Cytotoxic macrolides from a new species of the deep-water marine sponge Leiodermatium.

Chemical investigation of a new species of the deep-water marine sponge Leiodermatium, collected by manned submersible at a depth of 740 feet in Palau, resulted in the isolation of two cytotoxic macrolides, leiodolides A (1) and B (2). The leiodolides represent the first members of a new class of 19-membered ring macrolides, incorporating several unique functional groups including a conjugated oxazole ring, a bromine substituent, and an alpha-hydroxy-alpha-methyl carboxylic acid side-chain terminus. The structures of these new metabolites were established by spectroscopic analysis, chemical modification, and degradation. The relative and absolute stereochemistries at most chiral centers were assigned on detailed interpretation of spectroscopic data, coupled with chemical degradation and application of the modified Mosher ester method. Leiodolide A showed significant cytotoxicity (average GI(50) = 2.0 microM) in the National Cancer Institute's 60 cell line panel with enhanced activity against HL-60 leukemia and OVCAR-3 ovarian cancer cell lines.

Fluorescent profiling of natural product producers.

The identification of natural product producer organisms remains a problem for both isolation and natural product classification. A concise screen is developed through fluorescent modification of a set of natural products that offer a common activity. Through real-time multicolor microscopy, the processing, storage, and effects of a natural product are rapidly screened at the level of the strain and individual organism.

Cytotoxic beta-carbolines and cyclic peroxides from the Palauan sponge Plakortis nigra.

Four beta-carbolines, plakortamines A-D, two cyclic peroxides, epiplakinic acids G and H, and two related gamma-lactones, (2S,4R)- and (2R,4R)-2,4-dimethyl-4-hydroxy-16-phenylhexadecanoic acid 1,4-lactones, were isolated from the deep-water sponge Plakortis nigra from Palau. The structures of the eight new metabolites were elucidated by interpretation of spectroscopic data. Most of the metabolites inhibited the HCT-116 human colon tumor cell line.