138571-40-1Relevant academic research and scientific papers
BOUVARDIN DERIVATIVES AND THERAPEUTIC USES THEREOF
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, (2013/09/12)
The present invention is directed at bouvardin analogs arid related compounds for the treatment of disorders including cancer. Provided herein are bouvardin analogs and related compounds, pharmaceutical compositions and kits comprising at least one bouvar
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.
