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Three analogs of harringtonine (II), an ester alkaloid which is active in the P-388 experimental leukemia system, were prepared by acylating cephalotaxine (I). They were the 2-hydroxy-2-methylbutyryl (III), 2-carbomethoxymethyl-5-methylhexanoyl (IXc, and 2-carbomethoxymethylene-5-methylhexanoyl VIId) esters of I. A special sequence was developed for the synthesis of III. All of these harringtonine analogs, with the possible exception of III, are inactive in the P-388 system. In addition, data are presented which show that a rearranged harringtonine isomer (X) also is inactive. These results emphasize some highly specific structural requirements for antitumor activity of Cephalotaxusalkaloids.

Cephalotaxine and several of its esters were isolated from Cephalotaxus harringtoniaK. Koch var. harringtonia.Although cephalotaxine is inactive, harringtonine, isoharringtonine, homoharringtonine, and deoxyharringtonine have shown significant activity against experimental P388 leukemia and against L-1210 leukemia in mice.