Isolation, structure, and coccidiostat activity of coccidiostatin A.

Coccidiosis is one of the more common and costly diseases in poultry that is caused by various Eimeria species. In our quest to discover coccidiostats from natural products, we discovered a microbial fermentation extract that exhibited in vivo anticoccidial activity. Fractionation of this extract led to the discovery of two potent antiprotozoals, emecorrugatin A (1) and coccidiostatin A (2). The former compound exhibited only in vitro activity, whereas the latter new compound exhibited in vivo activity against Eimeria species in chickens at 150 ppm dosed in chicken feed. The isolation, structure elucidation, relative configuration, and activity of coccidiostatin A (2) are described.

Chemistry and Biology of Cylindrols: Novel Inhibitors of Ras Farnesyl-Protein Transferase from Cylindrocarpon lucidum.

Farnesyl-protein transferase (FPTase) is an enzyme responsible for the farnesylation of Ras protein. Farnesylation is required for cell-transforming activity in several tumor-types, and therefore, inhibition of FPTase activity may be a potential target for anticancer drugs. Our continued search for novel inhibitors led to the isolation of a number of bicyclic resorcinaldehyde cyclohexanone derivatives named here cylindrols A(1) to A(4), cylindrols B and B(1), and a number of known compounds, from Cylindrocarpon lucidum. The compounds were isolated by bioassay-guided separation using Sephadex LH-20, silica gel, and reverse phase HPLC. Structures were elucidated by extensive application of 2D NMR and X-ray crystallography. The determination of absolute stereochemistry was accomplished by CD measurements. Chemical transformations of the most abundant compound resulted in a number of key derivatives which were critical for the evaluation of structure activity relationship. These compounds are members of ascochlorin family and showed a wide range of inhibitory activity (0.7 &mgr;M to >140 &mgr;M) against FPTase. The FPTase activity was noncompetitive with respect to both substrates. Isolation, structures, chemical transformations, and FPTase activity are discussed in detail.