Cephalotaxine esters

Alkaloid distribution in C. harringtonia in relation to age has been noted. Physiological stress (pruning) was found to cause hydrolysis of cephalotaxine esters. Environmental factors also caused hydrolysis and, in addition, oxidation of cephalotaxine (85) to 11-hydroxycephalotaxine and of two other alkaloids to epoxy-derivatives.24... 

Spencer GF, Plattner RD, Powell RG. Quantitative gas chromatography and gas chromatography-mass spectrometry of Cephalotaxus alkaloids. J. Chromatogr. 1976 120 335-341. Grem JL, Cheson BD, King SA, Leyland-Jones B, Suffness M. Cephalotaxine esters antileukemic advance or therapeutic failure J. Natl. Cancer Inst. 1988 80 1095-1103. 

Interest has been expressed by the People s Republic of China in the preparation of cephalotaxine ester alkaloids and analogues, no doubt for the purpose of evaluation of antitumour activity. Thus a number of esters, e.g. (34), (R = Me2CHCH2CH2COCO or PhCOCO), were subjected to Reformatsky reaction with methyl bromoacetate to give, e.g., [34 R = Me2CHCH2CH2C(OH)-(CH2C02Me)C0] (deoxyharringtonine) and [34 R = PhC(0H)(CH2C02Me)C0]. 

III. The syntheses of cephalotaxine esters are discussed in Section IV approaches to the ring system and model studies follow in Section V. The syntheses are presented as described in the original literature with a minimum of analysis of either the strategies employed or the methods used, although some editorial comments and comparisons of various synthetic strategies have been made. At the end of Section III, a brief analysis is provided of the types of connectivities actually used to attain the various syntheses of cephalotaxine, with the hope that its inclusion may stimulate further ideas for innovative construction of these exciting and challenging molecules. 

The synthesis of cephalotaxine esters has been motivated by the recognition of the antitumor properties associated with some of these compounds, most notably homoharringtonine. Most, if not all, of their syntheses focus on the efficient preparation of the side chains and methods of esterification of the intact cephalotaxine nucleus, usually obtained from natural sources, where it is far more abundant than any of the corresponding esters. Because of the hindered nature of the cephalotaxyl alcohol, many approaches rely on partial esterification and further functionalization of the side chains. 

Two new cephalotaxine esters having significant antileukemic activity, neoharringtonine (11) and anhydroharringtonine (12), were isolated in 1992 by Wang and co-workers (9) from C. fortunei Hook f. These authors also reported their semisynthesis from cephalotaxine and harringtonine, respectively (Scheme 31). On treatment with phenyl pyruvyl chloride in the presence of pyridine, cephalotaxine (1) produced an intermediate a-keto ester. Reformatsky reaction of this cephalotaxyl phenyl pyruvate with methyl bromoacetate yielded a mixture of neoharringtonine (11) and its epimer. 

Effects of Cephalotaxine Esters on HL-60 Leukemia Cell Differentiation and Inhibition of L-1210 In Vrntd ... 

Wei and co-workers 96) have reported the preparation and cytotoxic activities of the unsaturated cephalotaxine esters 325-328. Ester 325 showed significant cytotoxic activity, as shown in Table V. The activity of homohar-ringtonine (3) is shown for comparison. 

Wang et al. (97) have synthesized the cephalotaxine esters 329-342. Their cytotoxic activities against P-388 leukemia cells are shown in Table VI. Note that the antileukemic activities of compounds 329,2 /I-330,2 /f-330 -t- 2 5-330,2 li-332, and 333 are comparable to that of homoharringtonine (3), and four others TR-231,2 S-331,340, and 341) show moderate activity. The activity of homoharringtonine (3) is shown for comparison. 

Growth Inhibition (%) of Cephalotaxine Esters against P-388 Leukemia Cells In Vitro... 

Clinical research on homoharringtonine and other cephalotaxine esters has been extensive, as clinical trials in the treatment of myeloid and lymphoblastic leukemia continue in both China and the United States. This re-... 

Syntheses of hcanoharringtonine and cephalotaxine esters have been 20 21... 

Homoharringtonine (18) is an alkaloid of unusual structure and belongs to harringtonine class, which is structurally characterized as cephalotaxine esters. These compounds have been exclusively isolated from Cephalotaxus plants, including C. fortunei Hook F and C. harringtonia K. Koch var. harringtorda [88]. 

A study of the constituents of Cephalotaxus plants was made by using a young plant grown in a controlled environment (33). The concentration of free alkaloids (homoerythrinan-type alkaloids and cephalotaxine) did not increase with age, but that of cephalotaxine esters did. Total alkaloid concentrations increased in the older leaves and decreased in the older stems. Hydrolytic cleavage... 

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