Harringtonines

Harmonic light generation, 14 678-680 Harmonic spectroscopy, 23 139 Harringtonine, 2 90 Harrison Narcotic Act, 13 683 Harris slag refining process, 16 150 Harris softening process, 14 750, 754 Hartree-Fock SCF techniques, 16 736 Harvest aids, economic aspects of,... 

Cephalotaxus fortunei Hook. C. oliveri Mast. C. qinensis (Rehd. et Wils.) Li San Jian Shan (Plum yew) (branch) Cephalotaxine, harringtonine, epicephalotaxine, epiwilsonine, demethylcephalotaxine, wilsonine, cephalotaxinone.33 This herb is toxic. Treat malignant tumors. 

Harringtonine Cephalotaxus fortunei, C. qinensis, C. oliveri, C. wilsoniana, Stephania japonica... 

Powell described as early as 1970 the antitumor activity of the related harringtonins 2 5 with respect to the mouse leukemias P-388 and L-1210.6 Activity in terms of human cancers has also been established.7 and is currently the subject of clinical studies. 

Cephalomannine is cytotoxic in KB cell culture (LD50 = 3.8 x 1CT3 p.g ml-1) and it shows potent inhibition of PS leukaemia in mice.10 The compounds (8b) and (8c) have previously been reported only in the genus Tax us,11,12 but neither they, nor cephalomannine, are structurally related to the harringtonine series of alkaloids (9). 

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

The synthesis of a mixture of two diastereoisomers of harringtonine has also been reported24 by esterifying cephalotaxine (9b) with the acid chloride (33) of racemic 4-benzyloxy-7,7-dimethyl-2-oxo-l-oxacycloheptane-4-carboxylic acid and converting the functionality of the acyl moiety into that of harringtonine. Isomerically pure harringtonine (9a) was made formally accessible by optical resolution of a hydroxy-acid precursor. 

When the alkaloidal extracts of C. harringtonia var. harringtonia were found to possess antileukemia properties, a search for the responsible alkaloids was initiated, since the major component, cephalotaxine, was inactive. Four alkaloids (the harringtonines) that exhibited anticancer properties were isolated. The structures of harringtonine, isoharringtonine, and homo-harringtonine were reported in 1970 (107), and that of deoxyharringtonine was reported in 1972 (108). 

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). 

Harringtonine (107) has been synthesized 170) by the method shown in Scheme 59. Claisen condensation between 283 and ethyl oxalate in the presence of NaH gave 284 which, when heated under reflux with aqueous HC1, was converted to a mixture from which the oxide (285) was isolated. Without purification, 285 was treated with HCl/MeOH to yield 286, saponification of which yielded the unsaturated acid as its sodium salt 287. After conversion to the acid chloride, reaction with cephalotaxine yielded 288. 

Hydration of the double bond of 288 gave 289, on which a Reformatski reaction was performed to yield harringtonine (107) together with epiharring-tonine (because of the two modes of hydration of the double bond in 288) (Scheme 59). The required ester (283) was prepared by first condensing iso-butyraldehyde with malonic acid to form 290, followed by isomerizing with... 

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). 

Harringtonine (107) and homoharringtonine (108) had about the same activity in the P388 system and both were more active than deoxyharring-tonine (110) and isoharringtonine (109). The latter two were only marginally active in the LI 210 system (S). The optimum dose (for mice) was in the range 2-12 mg/kg by intraperitoneal injection over a period of 9 days (186, 187). 

Harringtonine appears to be the most effective agent and recent studies in the People s Republic of China have shown that it is effective against L615 leukemia, L7212 leukemia, sarcoma 180, and Walker carcinosarcoma 256 (188). Harringtonine also appeared to be effective in the treatment of acute and chronic myelocytic leukemia in humans (189). 

The mode of action of the harringtonines has been investigated. All inhibit protein synthesis in eukaryotic cells (190-192). The principal effect of harringtonine was inhibition of protein biosynthesis in HeLa cells (193). Homoharringtonine, a potential antineoplastic alkaloid (191), was cytotoxic in HeLa, KB, and L cells growing in monolayer cell cultures (194). 

The spirocyclic CD-ring of 197, the precursor of the harringtonine family of alkaloid 198, is constructed efficiently (33% yield) by allyliminium salt 196 photo-cyclizations [88], as shown in Scheme 8.54. 

F P. S. (1984) Model studies examining the application of allyliminium salt photospirocyclization methodologies in synthetic approaches to the harringtonine alkaloids. Journal of Organic Chemistry, 49, 228-236. 

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 (-)-... 

Inhibition of protein synthesis in eukaryotic cells by the Cephalotaxus alkaloids harringtonine, homoharringtonine, and isoharringtonine has been studied.16 In model systems, these alkaloids were found not to inhibit any of the initiation steps but to block certain parts of the elongation phase of translation. 

Cepahalotaxine alkaloids are based on cephalotaxine which has a pentacyclic system including a seven-membered ring and a five-membered ring sharing an N atom (MD-Phe C6N C4 N G5 ). Cephalotaxine alkaloids include the cytotoxic, anticancer protein synthesis inhibitors cephalotaxine, harringtonine and homoharringtonine. 

Additional oxidative coupling processes among the various methylated derivatives of laudanosoline yield many other families of bases, including the pavine argemonine (88) from Argemone mexicana E berberine (89) from Hydrastis canadensis E which, despite its toxicity, has been used as an antimalarial protopine (90) and chelidonine (91) from Chelidonium majus E rhoeadine (92) and the cephalotaxus ester harringtonine (93) from Japanese plum yews ( Cephalotaxus spp.), which is a compound of some significance because it possesses potent antileukemic activity (see Fig. 3). 

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