Bruceantin synthesis

Since the isolation and characterization of bruceantin (234) by Kupchan and associates over 30 years ago [104], synthetic organic chemists worldwide have been engaged in efforts to prepare (234) and closely related quassinoids via total synthesis. 

The synthesis of (234) described above for Grieco el al. commences with tricyclic ketone (342), which had been recognized over 20 years ago by number of synthetic groups as logical starting point for a synthesis of bruceantin (234) [142],... 

Bruceantin binds tightly to ribosomes and this is the major mechanism by which it inhibits protein synthesis (Blasko and Cordell, 1988). 

Liao LL, Kupchan SM, Horwitz SB (1976) Mode of action of the antitumor compound bruceantin, an inhibitor of protein synthesis. Mol Pharmacol 12 167... 

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). 

This reaction sequence could be applied to the synthesis of the quassinoid analogs 15-0-P-octanoylglaucarubolone (98) and 15-0-P-3, 4 -dimethyl-2 -pentenoylglaucarubolone (99) (5). The latter, which has the bruceantin (53) ester side chain, was obtained by esterification of the hydroxylactone (95) with 3,4-dimethyl-2-pentenoic anhydride prepared by treatment of the corresponding acid with chlorosulfonyl isocyanate (35). 

Liao, L. L., S. M. Kupchan, and S. B. Horwitz Mode of Action of the Antitumor Compound Bruceantin, an Inhibitor of Protein Synthesis. Mol. Pharmacol. 12, 167... 

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