Synthesis, structure-activity analysis, and biological evaluation of sanguinamide B analogues.
We report the first synthesis of sanguinamide B analogues. Substituting N-methylated (N-Me) amino acids, glycine (Gly), and L- or D-phenylalanine (Phe) into the backbone of sanguinamide B showed that only l- and d-Phe residues controlled the macrocycle conformation. The N-methylated and glycine analogues all had multiple conformations, whereas the L- and D-Phe derivatives only had a single conformation. Testing of all conformer analogues showed that inclusion of an L- or D-Phe was a superior design element than incorporating the N-Me moiety that is often utilized to control macrocyclic conformation. Finally, we show that there is an ideal Phe residue (in this case L-Phe) for generating compounds that have the greatest inhibitory effect on bacterial motility. Our data support the hypothesis that the macrocyclic conformation is dictated by the benzyl moiety requiring a "pseudoequatorial" position, and all other energy considerations are secondary.
School of Chemistry, Gate 2 High Street, Dalton 219, University of New South Wales, Sydney, NSW 2052, Australia.
Hendra
H
Wahyudi
Worawan
W
Tantisantisom
Xuechao
X
Liu
Deborah M
DM
Ramsey
Erinprit K
EK
Singh
Shelli R
SR
McAlpine
D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry*
D000596:Amino Acids; D010080:Oxazoles; D010456:Peptides, Cyclic; D013844:Thiazoles; C572270:sanguinamide B