Harringtonine, cephalotaxine esters

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. 

The slowly growing tree Cephalotaxus harringtonia is the source of cephalotaxine (12) and its esters harringtonine (13), deoxyharringtonine, isoharringtonine, and homoharringtonine. These compounds have shown significant antitumor activity. Production of these alkaloids by means of cell and tissue cultures has been patented (see Table XXI). 

Callus cultures of Cephalotaxus harringtonii produce cephalotaxine (35), and the antitumor esters harringtonine (33), isoharringtonine (37), and homoharringtonine (34) in both callus tissue and the medium. Deoxyharringtonine (36) was found in the medium but not in the callus (Delfel, 1980 Delfel and Rothfus, 1977 Spec. Per. Rep., 1975, 1979). 

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]. 

Harringtonine (9a), an anti-tumour alkaloid ester from Cephalotaxus harring-tonia, referred to above, has now been synthesized23 from cephalotaxine (9b)... 

Although cephalotaxine itself exhibits no significant antileukemic activity, a number of naturally occurring esters of the alkaloid, the harringtonines (107-110), are active against LI 210 and P388 leukemias in mice (89,100, 108), and so some attention has been devoted to the synthesis of the dicar-boxylic acid side chains (see also Section IV,A). 

Antitumor activity in P388 and L1210 experimental leukemia systems was detected in extracts from the seeds of C. harringtonia K. Koch var. harring-tonia (8, 95). It was soon discovered that the major component, cephalotaxine (105a), was inactive and that the activity resided in the esters 107-110 (the harringtonines) (184-187). 

Chinese workers have continued their pharmacological exploration of esters of cephalotaxine (3a) and have reported the transformation of this alkaloid into harringtonine (26a)12 and 0-(2-oxo-5-methylhexanoyl)cephalotaxine (26b).13 The latter compound is an intermediate in the synthesis of the antineoplastic alkaloid deoxyharringtonine (26c). The overall conversion of cephalotaxine into deoxyhar-ringtonine (26c) via (26b) has been patented.14 Of twenty-two esters of (-)-... 

Section VI deals with some of the unnatural ester derivatives of cephalotaxine, and Section VII reports analytical or spectroscopic studies. The last part of this chapter. Section VD, summarizes the clinical and pharmacological studies of harringtonine and homoharringtonine and provides a guide to the literature in this area. The literature is reviewed through May 1997. 

Cephalotaxine and its esters are of particular chemical and medical interest. Among these, 18 and harringtonine are most promising anticancer agents [89]. Homoharringtonine has been submitted to extensive phase 1/11 clinical studies in patients with different solid tumors, such as malignant melanoma, sarcoma, head and neck carcinoma, breast carcinoma, and colorectal carcinoma. Also, several clinical trials include studies efficacy in patients with acute leukemia, myelodysplastic syndrome (MDS), acute promyelocytic leukemia (APL), and chronic myeloid leukemia [90]. 

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