Bruceantin antileukemic compound

Various quassinoids with antileukemic activity have been isolated from the Ethiopian tree Brucea antitfysenterica Mill, including the antileukemic compound bruceantin (234) by kupchan and associates... 

An earlier investigation of the antileukemic constituents of the Ethiopian Brucea aniidysenterica by Kupchan and associates [2] led to the isolation of quassinoids such as bruceantin (1), bruceantarin (2), dehydrobruceantin (3), dehydrobruceantarin (4), and isobrucein-B (5). Among these quassinoids, bruceantin (1) demonstrated potent antileukemic activity, including the P-388 and L-1210 lymphocytic leukemias, the Lewis lung carcinoma, and the B-16 melanoma. This compound was in Phase II clinical trial as an anticancer drug by the US National Cancer Institute (NCI). 

A series of new bisbrusatolyl and brusatolyl esters and related compounds were synthesized and tested for in vivo antileukemic activity against a quassinoid sensitive strain of P-388 lymphocytic leukemia in BDFi mice as shown in Table 8. Bisbrusatolylmalonate (81), bisbrusatolylsuccinate (82), bisbrusatolylglutarate (83), bisbrusatolyladipate (84), and bisbrusatolyl sebacate (85) were as active as, or more active than, brusatol (8). The C-3 esters of brusatol (8) or bruceantin (1) were also as active as, or more active than, the original brusatol (8) and bruceantin (1) in general. 

Several quassinoids are known to have antileukemic activity (Blasko and Cordell, 1988 Cordell, 1978 Polonsky, 1983). Only compounds with a C20 skeleton have antileukemic activity. Quassimarin (51) from Quassia amara and bruceoside A (52) from Brucea javanica and a series of other quassinoids from Brucea antidysenterica (all Simarou-baceae) (Fig. 25.12) are active in this regard. Bruceantin (53) has a high degree of antitumor activity in P-388, LE, LL and B16 tissue culture systems (Cordell, 1978). Six quassinoids from Simaba multiflora and Soulamea soulameoides were shown to be active against several mmor systems (Klocke et al., 1985). 

As to the mode of action of these compounds, Liao etal. 54), using HeLa cells, have shown that the antitumor activity of bruceolide (48) esters at the molecular level is due to irreversible inhibition of protein synthesis. The antileukemic activity of a series of esters of brusatol (55 a), bis-brusatol (55b) and bruceantin (53) has been correlated with the ability of these compounds to suppress DNA and protein synthesis in P-388 lymphocytic leukemia cells. The active compounds were also shown to inhibit DNA polymerase activity and purine synthesis (27). 

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