Cephalotaxus alkaloids are a family of cytotoxic heterocyclic natural products elaborated by trees of the genus Cephalotaxus (Cephalotaxaceae), some of which showed potent antileukemic activity. Although a number of Cephalotaxus alkaloids with various side chains have been isolated so far, there are very few reports on backbone skeletons other than that of cephalotaxine. Recently, we have isolated six new cytotoxic alkaloids, cephalezomines A〜F, from the leaves of Cephalotaxus harringtonia var. nana. Our continuing search for structurally unique and biogenetically interesting Cephalotaxus alkaloids resulted in the isolation of cephalocyclidin A (1), a novel alkaloid with an unprecedented fused-pentacyclic ring system from the fruits of Cephalotaxus harringtonia var. nana. The structure of 1 was elucidated on the basis of spectroscopic data. The relative and absolute stereochemistry of 1 was determined by combination of NOESY correlations, X-ray crystallographic data, and exciton chirality method. These unusual ring systems have attracted great interest as challenging targets for total synthesis or biosynthetic studies. Five new cephalotaxine-type alkaloids, cephalezomines G, H, J, K, and L, and a new homoerythrina-type alkaloid, cephalezomine M, have been isolated from the leaves of Cephalotaxus harringtonia var. nana. The relative and absolute stereochemistry was elucidated by NOESY data, CD analysis applying exciton chirality methods, and chemical means. Alkaloidal materials were subjected to LH-20 column chromatography followed by silica gel column chromatography to afford bis-cephalezomines A〜E. The structures and stereochemistry were elucidated on the basis of spectroscopic data including 2D NMR and FABMS/MS spectra, and chemical means. Cephalocyclidin A, cephalezomines, bis-cephaloezomines, and known related alkaloids showed cytotoxicities against murine lymphoma L1210 cells and human epidermoid carcinoma KB cells.
