: conformational and biological aspects
Knijnenburg, A.D.
Citation
Knijnenburg, A. D. (2011, September 29). Synthetic modifications of the antibiotic peptide gramicidin S : conformational and biological aspects.
Retrieved from https://hdl.handle.net/1887/17882
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Synthetic Modifications of the Antibiotic Peptide
Gramicidin S
Conformational and Biological Aspects
P ROEFSCHRIFT
ter verkrijging van
de graad van Doctor aan de Universiteit Leiden
op gezag van Rector Magnificus prof. mr. P. F. van der Heijden, volgens besluit van het College voor Promoties
te verdedigen op donderdag 29 september 2011 klokke 11.15 uur
door
Annemiek Dorien Knijnenburg
Geboren te Rotterdam in 1984
Promotiecommissie
Promotor: Prof. dr. H. S. Overkleeft
Copromotor: Dr. ing. M. Overhand
Overige leden: Prof. dr. G. A. van der Marel Prof. dr. J. Brouwer
Prof. dr. J. Lugtenburg
Dr. M. D. P. Risseeuw
The printing of this thesis was financially supported by the J. E. Jurriaanse
stichting.
Contents
List of abbreviations 6
General introduction 9
Exploring the conformational and biological versatility of β-turn modified gramicidin S derivatives by using sugar amino acid homologs that vary in ring-size
25
Ring-extended derivatives of gramicidin S with
furanoid sugar amino acids in the turn region 53
Synthesis and evaluation of strand and turn
modified ring-extended gramicidin S derivatives 67
Ring-extended gramicidin S analogs with strand modification and sugar amino acids that vary in ring-size in the turn region
85
“Inverted” gramicidin S derivatives with combined adamantane amino acids and sugar amino acids with varying ring-size
105
Tuning hydrophobicity of highly cationic tetradecameric gramicidin S analogs using
adamantyl amino acids 117
Summary and future prospects 131
Samenvatting 142
List of publications 146
Curriculum vitae 148
Dankwoord 150
List of abbreviations
Å Ångstrom AA amino acid
Ac acetyl
ACN acetonitrile Ada adamantyl aq. aqueous Ar aromatic B. cereus Bacillus cereus B. brevis Bacillus brevis B. subtilis Bacillus subtilis BHA benzylhydrylamine
Bn benzyl
Boc tert-butyloxycarbonyl br broad
Bu butyl
calcd. calculated cat. catalytic
CAP cationic antimicrobial peptide CD circular dichroism
COSY correlation spectroscopy Cq quaternary carbon atom cROESY compensated rotational nuclear
Overhauser effect spectroscopy CSA camphorsulfonic acid CVFF Consistent Valence Force Field d doublet
δ chemical shift Δ change DCE 1,2-dichloroethane DCM dichloromethane dd doublet of doublet ddd double double doublet ddt double double triplet DEAD diethyl azodicarboxylate DG distance geometry DiPEA N,N-diisopropyl-N-ethylamine DNA deoxyribonucleic acid DMAP N,N-dimethylaminopyridine DMF N,N-dimethylformamide
DQF Double-Quantum Filtered DMSO dimethylsulfoxide
dt double triplet E.coli Escherichia coli E. faecalis Enterococcus faecalis
ESI electron spray ionization Et ethyl
et al. et alii (and others) EtOAc ethyl acetate
Fmoc 9H-fluoren-9-ylmethoxycarbonyl g gram(s)
GC gas chromatography GS gramicidin S h hour(s)
HATU 2-(1H-7-azabenzotriazol-1-yl)- 1,1,3,3-tetramethyl uranium hexafluorophosphate methanaminium
HBTU O-Benzotriazole-N,N,N’,N’- tetramethyl-uronium-hexafluoro- phosphate
HCTU 2-(6-chloro-1H-benzotriazole-1- yl-1,1,3,3-tetramethyl-aminium hexafluorophosphate
HOBt 1-hydroxy-benzotriazole HMPB 4-(4-hydroxymethyl-3-methoxy-
phenoxy)- butyric acid
HPLC high performance liquid chromatography
HRMS high resolution mass spectroscopy HSQC heteronuclear single quantum
coherence spectroscopy
Hz hertz
HC50 hemolytic concentration at which 50% of human red blood cells are lysed
i. e. id est. (in other words) IR infrared isoprop isopropyl
J coupling constant L liter(s)
Leu (L) leucine (one letter abbreviation) LC/MS liquid chromatography mass
spectroscopy
LPS lipopolysaccharide Lys (K) lysine (one letter abbreviation) m multiplet
MAA morpholino amino acid m/z mass/charge ratio
rt room temperature RT retention time s singlet sat. saturated
S.aureus Staphylococcus aureus S. epidermidis Staphylococcus epidermidis SAA sugar amino acid
sext sextet
SPPS solid-phase peptide synthesis t triplet
TBAF tetra n–butylammonium fluoride TBDPS t-butyldiphenylsilyl
THF tetrahydrofuran Tf triflate TFA trifluoroacetic acid TFE trifluoroethanol TIS triisoproylsilane TMS trimethylsilyl Ts tosyl
TLC thin-layer chromatography TOCSY totally correlated spectroscopy Tyr (Y) tyrosine (one letter abbreviation)
UV ultraviolet v/v volume ratio
Valine (V) valine (one letter abbreviation) MeOH methanol
MIC minimal inhibitory concentration MS mass spectrometry MRSA methicilin resistant Staphylococcus
aureus
MW molecular weight NMP N-methyl-2-pyrolidone
NMR nuclear magnetic resonance NOE nuclear Overhauser effect
Orn (O) ornithine (one letter abbreviation) ORD optical rotary dispersion
P. aeruginosa Pseudonomas aeruginosa PE light petroleum ether Phe (F) phenylalanine (one letter
abbreviation)
Ph phenyl
ppb parts per billion ppm parts per million
Pro (P) proline (one letter abbreviation) pyBOP benzotriazol-1-yl-oxy-tris-
pyrrolidinophosphonium hexafluorophosphate q quartet
ROE rotational nuclear Overhauser effect
r.o.s. recovery of starting material
