Deoxyharringtonine, cephalotaxine esters

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]. 

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... 

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 (-)-... 

Five Homoerythrina alkaloids (3 R = Me, = H), (3 R + R = OCH2O), (3 R - R = Me), (4 R R = H, Me), and (4 R = R = Me) have been shown to co-occur with cephalotaxine (5 R = H) and its ester derivatives in Cephalotaxus harringtonia var. harringtoniaf The structures of the minor Homoerythrina alkaloids were established by spectroscopic studies and comparison with the known alkaloids (3 R = Me, R — H) and (3 R + R = OCHjO) which had been previously isolated from Schelhammera pedunculata and whose structures and absolute chemistry had been established. The co-occurrence of Homoerythrina and Cephalotaxus alkaloids makes it most attractive to propose that both types are derived from a common dienone (Scheme 1). An alternative biogenetic scheme for the formation of cephalotaxine (5 R = H) from an Erythrina precursor has been previously offered as speculation. Deoxyharringtonine (6), a new alkaloid with antileukemic activity of the same order of magnitude as the other known cephalotaxine alkaloids, has been... 

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). 

Delfel and Rothfus (402) found also that callus cultures of this plant did produce the alkaloids, although at much lower levels (1-3% of levels found in the mature tree). About 60% of the alkaloids formed was cephalotaxine, and the esters represented 40%. Deoxyharringtonine could only be found... 

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). 

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