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Titolo:
N-DESMETHYL DERIVATIVES OF DEOXYBOUVARDIN AND RA-VII - SYNTHESIS AND EVALUATION
Autore:
BOGER DL; ZHOU JC;
Indirizzi:
SCRIPPS CLIN & RES INST,DEPT CHEM,10666 N TORREY PINES RD LA JOLLA CA92037
Titolo Testata:
Journal of the American Chemical Society
fascicolo: 28, volume: 117, anno: 1995,
pagine: 7364 - 7378
SICI:
0002-7863(1995)117:28<7364:NDODAR>2.0.ZU;2-7
Fonte:
ISI
Lingua:
ENG
Soggetto:
ANTITUMOR CYCLIC HEXAPEPTIDES; ULLMANN MACROCYCLIZATION REACTION; SUBUNIT FUNCTIONAL ROLES; KEY PARTIAL STRUCTURES; RUBIAE RADIX; AMINOPEPTIDASE-B; CONFORMATIONAL-ANALYSIS; BICYCLIC HEXAPEPTIDES; CHEMICAL SYNTHESIS; SOLUTION FORMS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
86
Recensione:
Indirizzi per estratti:
Citazione:
D.L. Boger e J.C. Zhou, "N-DESMETHYL DERIVATIVES OF DEOXYBOUVARDIN AND RA-VII - SYNTHESIS AND EVALUATION", Journal of the American Chemical Society, 117(28), 1995, pp. 7364-7378

Abstract

The synthesis of the complete set of seven N-desmethyl derivatives ofRA-VII (8) are described. Thus, the synthesis of the four 14-memberedcycloisodityrosine 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 propertiesof 8 and 14-20 were examined by 1D and 2D H-1 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 C-30-N-29 tertiary amide central to the 14-membered cycloisodityrosine subunit. Moreover, this cis amide is the predominant conformation (85-95%) observed with N-29-desmethyl RA-VII (14) indicating that even a secondary C-30-N-29 amide adopts this inherently disfavored cis amide stereochemistry. Theminor conformation of 8 observed in solution (12-17%) is shown to be derived from a minor cis C-8-N-9 tertiary amide which was not observedwith its conversion to a secondary amide. Both N-9-desmethyl RA-VII (15) and N-9,N-29-desmethyl RA-VII (18) adopt exclusively a single solution conformation that corresponds to the major solution conformationsof 8 and 14. This conformation contains a characteristic cis C-30-N-29 amide central to a type VI beta-turn and the cycloisodityrosine subunit, a trans C-8-N-9 amide central to a typical type II beta-turn capped with a tight Ala(4)-NH-O=C-Ala(1) hydrogen bond, and a trans C-14-N-15 N-methyl amide. In sharp contrast, removal of the N-15 methyl group within 16, 17, 19, and 20 results in the adoption of solution conformations possessing the inherently favored trans C-30-N-29 amide central to the cycloisodityrosine (14)-membered subunit. Thus, the N-15-methyl group within 8 is responsible for the agents adoption of the disfavored cis C-30-N-29 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 C-30-N-29 amide conformation within the 14-membered cycloisodityrosine subunit. The studies detailed herein reveal that it is the N-15-methyl group that induces this conformational preference for the disfavored cis C-30-N-29 amide and that its removal results in a major conformational change with adoption of the trans C-30-N-29 amide and a loss of biological activity. Thus, the N-15-methyl group is essential for maintenance of the conformational and biological properties of 8; the N-9-methyl group is not essential, and its removal leads to exclusive population of a single biologically active conformation; and the N-29-methyl group once thought essential td the adoption of the C-30-N-29 cis amide is not essential, and its removal does not alter the conformational or biological properties of 8.

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Documento generato il 23/09/20 alle ore 16:09:19