SYNTHESIS OF ANTITUMOR AGENTS

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We propose to continue our efforts directed towards to==the synthesis of polyketide marine natural products which exhibit notable anticancer activities. The specific synthetic target molecules selected for the proposed grant period are tedanolide (1), C32H52O11, isolated from Caribbean sponge Tedania ignis, aplyronine (2), C54H92N2)12, from sea hare Aplysia kurodai, and discodermolide (3), C33H55NO8, from the marine sponge Discodermia dissoluta. Each of these marine products is a potent anticancer agent possessing a unique structure. Tedanolide contains as many as three acid-and base-sensitive beta-hydroxy moieties embedded in the carbon framework, a feature rarely seen in other macrolide natural products. Aplyronine exhibits striking biological activity as illustrated by a 200-550% extension of the average lifetime of leukemic mice. Aplyronine is a representative of structurally related compounds including scytophycins, halichondramides, kabiramide and swinholides. Discodermolide (3) not only inhibits the in vitro proliferation of murine P388 leukemia cells, but has also been found to be an immunosuppressive agent ten times as potent as cyclosporine. The relative simplicity of its structure is another attractive feature and its synthesis may constitute a means of providing substantial quantities of this compound for further biological studies. The proposed syntheses of 1-3 extensively use aldol reactions, the stereochemical courses of which are governed by the rule of double asymmetric synthesis. Thus, fragments of a target molecule are constructed by single or multiple use of acetate or propionate additions to a selected aldehyde with several chiral reagents now available. The coupling of fragments involves a chiral aldehyde and a chiral ketone (both of which are fragments) and is executed either (i) by the use of a third chiral component which plays a stereochemically dominant role in the aldol reaction or (ii) by exploiting certain types of structural features existing in the reactants. The selection of chiral reagents to be used in both the synthesis and coupling of fragments is a central theme of this proposal.