Cephalotaxus species

Esters of cephalotaxine (85) that are found in Cephalotaxus species are exemplified by deoxyharringtonine (89), isoharringtonine (90), and harring-tonine (91). The acyl portion (92) of deoxyharringtonine (89) derives from the amino-acid leucine. The results published previously in preliminary form (cf. Vol. 8, p. 13) are now available in full.25 Additional information is that (92) serves as a specific precursor for the acyl portions of (91) and (90) and that (93) is not involved in the biosynthesis of the latter. Results of an examination of (89) as a possibly intact precursor for (91) were inconclusive.25... 

The Homoerythrina alkaloids have not been reviewed before, except briefly in conjunction with Cephalotaxus alkaloids, with which they occur in Cephalotaxus species (9). 

Recently, a GC-MS method for the separation and quantitative identification of extracts from Cephalotaxus species (97) has been described. Most of the alkaloids were resolved, particularly the biologically active esters. The seven Homoerythrina alkaloids were only resolved into two groups of five and two components, respectively, under the conditions described. Acetylcephalotaxine (106), 11-hydroxycephalotaxine (114), and desmethyl-cephalotaxinone (113) were not resolved by retention time, but could be identified within the mixture by their MS fragmentation patterns. Cepha-lotaxinone (112) gave two GC peaks after silylation, presumably due to a contribution from the enol component. The artifact peak overlaps partly with the peak for drupacine (115) and hence introduces a slight error for this component and makes it difficult to quantify cephalotaxinone. 

El has been investigated in anticancer clinical trials at the U.S. National Cancer Institute (NCI), particularly for the treatment of myeloid leukemia (66, 67). However, its side effects still remain an issue. Thus, the authors have continued to study new natural constituents of Cephalotaxus species and to develop new analogs on the basis of SAR studies, as presented in a review by Itokawa et al. (68). 

Homoharringtonine (HHT) (19) is an ester derivative of the parent alkaloid cephalotaxine (20), which has an unusual tetracyclic ring system. Cephalotaxine was isolated from two Cephalotaxus species" and its final structure was assigned by X-ray crystallography." HHT was isolated in 1970 by workers at the USDA laboratories in Peoria" but its anticancer activity was first recognized by Chinese investigators. 

Cephalotaxine.—Cephalotaxine (122) is an abundant alkaloid of Cephalotaxus species. The natural co-occurrence of cephalotaxine and alkaloids of the homo-erythrina type, e.g. 3-epischelhammericine (123), suggested that these two alkaloid... 

Oppenauer oxidation gave the hemiketal (16). Furthermore, hydrolysis of the diacetate (14 R = R = Ac) in aqueous dioxan at ambient temperatures resulted in epimerization at C-11. All these reactions are best accommodated by the proposed stereochemical formulation (14 R = R = H) for 11-hydroxy-cephalotaxine. Interestingly, this formulation represents the most hindered of four possible geometric isomers. The alkaloids (14 R = R = H) and (15) are unique to C. harringtonia var. drupacea. It is not yet clear if drupacine (15) is identical with Alkaloid IV obtained by Asada during an extensive reinvestigation of Cephalotaxus species. ... 

The alkaloid cephalomannine (43) has been isolated from Taxus wallichiana (the compound name reflects the fact that plant source was originally considered to be a Cephalotaxus species) (Miller et al., 1981 Powell et al., 1979). This alkaloid has antitumor activity in KB cell lines. 

Cephalotaxus is a genus of plum yew natural to Eastern Asia, although it is now cultivated in many parts of the world (94). There are about seven species and most have been examined for alkaloids, which have been obtained from all parts of the plants. Since the alkaloidal extracts were reported in 1969 to exhibit antitumor activity (95), an intense investigation of the Cephalotaxus alkaloids has followed (8, 9). Most of the isolation work, structural elucidation, and pharmacological assay has come from the Northern Regional Research Laboratory in Illinois (5). 

The alkaloids were best isolated from the ethanol extract of the plant material, partially fractionated by counter-current distribution, and subsequently purified by preparative chromatography. Of the 11 known Cephalotaxus alkaloids (105-115 in Figs. 8 and 9), cephalotaxine (105a) is ubiquitous and the most abundant (up to 64% of the total alkaloid extract) in all species examined. C. wilsoniana Hay., which yields only minor quantities of cephalotaxine, is the exception, however it is rich in Homoerythrina alkaloids,... 

Work which culminated in two total syntheses of cephalotaxine (34 R = H), the major antitumour alkaloid of several species of Cephalotaxus (plum-yews), and... 

Incidentally, a yew-related species from China named Cephalotaxus fortunei yields a toxic anticancer substance known as harringtonine (Griggs, 1991, p. 318). A similar species in the United States is known as Cephalotaxus harringtonia, from which is derived the bioactive substance homoharringtonine. 

There are about eight species in the only genus of the family, Cephalotaxus (Huang and Xue, 1984), Some workers have considered the family to be closely related to the Taxaceae, whereas others have even placed the family in its own order, the order Cephalotaxales. 

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