Homoharringtonine, cephalotaxine esters

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. 

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. 

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-... 

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]. 

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. 

Another synthesis of homoharringtonine was reported by Wang et al. 49-51) in 1980 (Scheme 21). Treatment of the sodium salt 154 of the protected keto acid with oxalyl chloride, followed by cephalotaxine, gave the cephalotaxyl ester 155, which, under Reformatsky conditions, reacted with methyl bromoacetate to furnish the expected diastereomeric mixture of ketals 156. Hydrolysis of 156 yielded an equilibrium mixture of ketone 157 and its cychc hemiketal 158. Treatment of this mixture with methyl-magnesium iodide yielded homoharringtonine (3) and its epimer. 

In the follow-up detailed report, Hudlicky s group (53) also described the synthesis of homoharringtonine from the unsaturated keto acid 151 (Scheme 23). Acid 151 was treated with formic acid in the presence of perchloric acid to provide the intermediate formylated derivative 163, which, on treatment with aqueous sodium hydroxide, produced hydroxy acid 164. Esterification of 164 with cephalotaxine yielded the cephalotaxyl ester 165, which underwent the Reformatsky reaction with methyl bro-... 

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. 

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). 

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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