TOTAL SYNTHESIS OF CYCLOISODITYROSINE, RA-VII, DEOXYBOUVARDIN, AND N29-DESMETHYL-RA-VII - IDENTIFICATION OF THE PHARMACOPHORE AND REVERSAL OF THE SUBUNIT FUNCTIONAL ROLES

Full details of a concise total synthesis of RA-VII (1) and deoxybouva rdin (2) are described based on the implementation of an effective int ramolecular Ullmann reaction as the key macrocyclization reaction in t he preparation of the elusive 14-membered cycloisodityrosine subunit ( 33) of the bicyclic hexapeptides. Subsequent coupling of 34 to tetrape ptide 17 and macrocyclization with C2-N3 amide bond formation provided 1 and 2. In efforts that address the key structural and conformationa l features of the agents that contribute to their antitumor activity, N29-desmethyl-RA-VII was prepared and its chemical, conformational, an d preliminary biological properties are detailed. The comparable confo rmational features of N29-desmethyl-RA-VII and RA-VII including a char acteristic cis C30-N29 amide bond suggest that the tetrapeptide housed within the 18-membered ring induces the 14-membered cycloisodityrosin e to adopt a conformation possessing an inherently disfavored cis seco ndary or tertiary amide. Moreover, in contrast to prior suppositions i n which the rigid 14-membered ring of N-methylcycloisodityrosine has b een suggested to serve the functional role of inducing a rigid, normal ly inaccessible conformation within the biologically relevant D-Ala-Al a-N-Me-Tyr-(OMe)-Ala tetrapeptide, experimental studies demonstrating that the intrinsic activity of the agents resides within the cycloisod ityrosine subunit are presented. Thus, the results of the experimental studies require a reversal of the functional roles of the subunits of the agents in which it is the tetrapeptide housed within the 18-membe red ring that potentiates the inherent biological properties and alter s the conformation of cycloisodityrosine.