138605-23-9Relevant academic research and scientific papers
N-Desmethyl derivatives of deoxybouvardin and RA-VII: Synthesis and evaluation
Boger, Dale L.,Zhou, Jiacheng
, p. 7364 - 7378 (2007/10/02)
The synthesis of the complete set of seven N-desmethyl derivatives of RA-VII (8) are described. Thus, the synthesis of the four 14-membered cycloisodityrosine derivatives 21-24 and their coupling with the two tetrapeptides 32 and 33 followed by formation of the 18-membered ring with macrocyclization provided the full set of seven desmethyl derivatives 14-20 of RA-VII (8). The solution phase conformational properties of 8 and 14-20 were examined by 1D and 2D 1H NMR to reveal the role of N-methylation on the key conformational aspects of the natural agents. In contrast to each of the simple cycloisodityrosine derivatives 21-24 which adopt a single, rigid solution conformation possessing a secondary or tertiary trans amide central to the 14-membered ring, the natural agents including 8 adopt a single predominant solution conformation (83-88%) that corresponds closely to the X-ray structure conformation which possesses an inherently disfavored cis C30-N29 tertiary amide central to the 14-membered cycloisodityrosine subunit. Moreover, this cis amide is the predominant conformation (85-95%) observed with N29-desmethyl RA-VII (14) indicating that even a secondary C30-N29 amide adopts this inherently disfavored cis amide stereochemistry. The minor conformation of 8 observed in solution (12-17%) is shown to be derived from a minor cis C8-N9 tertiary amide which was not observed with its conversion to a secondary amide. Both N9-desmethyl RA-VII (15) and N9,N29-desmethyl RA-VII (18) adopt exclusively a single solution conformation that corresponds to the major solution conformations of 8 and 14. This conformation contains a characteristic cis C30-N29 amide central to a type VI β-turn and the cycloisodityrosine subunit, a trans C8-N9 amide central to a typical type II β-turn capped with a tight Ala4-NH-O=C-Ala1 hydrogen bond, and a trans C14-N15 N-methyl amide. In sharp contrast, removal of the N15 methyl group within 16, 17, 19, and 20 results in the adoption of solution conformations possessing the inherently favored trans C30-N29 amide central to the cycloisodityrosine 14-membered subunit. Thus, the N15-methyl group within 8 is responsible for the agents adoption of the disfavored cis C30-N29 amide central to the cycloisodityrosine subunit. Importantly, preceding studies have defined the cycloisodityrosine subunit of 8 as the pharmacophore and, in a reversal of the initially assigned roles, revealed that it is the tetrapeptide housed in the 18-membered ring that induces and maintains the rigid, normally inaccessible cis C30-N29 amide conformation within the 14-membered cycloisodityrosine subunit. The studies detailed herein reveal that it is the N15-methyl group that induces this conformational preference for the disfavored cis C30-N29 amide and that its removal results in a major conformational change with adoption of the trans C30-N29 amide and a loss of biological activity. Thus, the N15-methyl group is essential for maintenance of the conformational and biological properties of 8; the N9-methyl group is not essential, and its removal leads to exclusive population of a single biologically active conformation; and the N29-methyl group once thought essential to the adoption of the C30-N29 cis amide is not essential, and its removal does not alter the conformational or biological properties of 8.
Total synthesis of cycloisodityrosine, RA-VII, deoxybouvardin, and N29-desmethyl-RA-VII: Identification of the pharmacophore and reversal of the subunit functional roles
Boger, Dale L.,Yohannes, Daniel,Zbou, Jiacheng,Patane, Michael A.
, p. 3420 - 3430 (2007/10/02)
Full details of a concise total synthesis of RA-VII (1) and deoxybouvardin (2) are described based on the implementation of an effective intramolecular Ullmann reaction as the key macrocyclization reaction in the preparation of the elusive 14-membered cycloisodityrosine subunit (33) of the bicyclic hexapeptides. Subsequent coupling of 34 to tetrapeptide 17 and macrocyclization with C2-N3 amide bond formation provided 1 and 2. In efforts that address the key structural and conformational features of the agents that contribute to their antitumor activity, N29-desmethyl-RA-VII was prepared and its chemical, conformational, and preliminary biological properties are detailed. The comparable conformational features of N29-desmethyl-RA-VII and RA-VII including a characteristic cis C30-N29 amide bond suggest that the tetrapeptide housed within the 18-membered ring induces the 14-membered cycloisodityrosine to adopt a conformation possessing an inherently disfavored cis secondary or tertiary amide. Moreover, in contrast to prior suppositions in which the rigid 14-membered ring of N-methylcycloisodityrosine has been suggested to serve the functional role of inducing a rigid, normally inaccessible conformation within the biologically relevant D-Ala-Ala-N-Me-Tyr-(OMe)-Ala tetrapeptide, experimental studies demonstrating that the intrinsic activity of the agents resides within the cycloisodityrosine 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-membered ring that potentiates the inherent biological properties and alters the conformation of cycloisodityrosine.
