Solid phase synthesis and biological evaluation of enantiomerically pure wasp toxin analogues PhTX-343 and PhTX-12

Research output: Contribution to journalJournal articleResearchpeer-review

K Strømgaard, I Bjørnsdottir, K Andersen, M J Brierley, S Rizoli, N Eldursi, I R Mellor, P N Usherwood, S H Hansen, P Krogsgaard-Larsen, J W Jaroszewski

PhTX-343 and PhTX-12, analogues of the natural polyamine wasp toxin PhTX-433, were synthesised in 40-60% yields as pure enantiomers using solid phase synthesis techniques. Capillary electrophoresis procedures were developed for chiral separation and determination of enantiomeric purity (ee) of the enantiomers of PhTX-343 and PhTX-12. The methods were optimised with respect to chiral selector, buffer pH, and temperature around the capillary. Thus, rac-PhTX-343 was resolved using a separation buffer containing 30 mM heptakis-(2, 6-di-O-methyl)-beta-cyclodextrin in 50 mM 6-aminocarproic acid (pH 4. 0) at 15 degrees C. rac-PhTX-12 was not resolvable in this system, but could be resolved using a separation buffer containing 10% w/v of dextrin 10, a linear maltodextrin, in 50 mM 6-aminocaproic acid (pH 4.0) at 15 degrees C. Using these methods, the optical purity of the synthetic enantiomers was determined to be ee > 99%. The enantiomers were also characterised by chiroptical methods. The antagonist potency of the enantiomers was tested on nicotinic acetylcholine receptors (human muscle-type nAChR) expressed in TE671 cells, ionotropic glutamate receptors in Xenopus laevis oocytes (expressing recombinant GluR1flop receptors), and locust muscle ionotropic glutamate receptors sensitive to quisqualate (qGluR). The potencies of each pair of enantiomers were similar (eudismic ratio close to 1).
Original languageEnglish
JournalChirality
Volume12
Issue number2
Pages (from-to)93-102
Number of pages10
ISSN0899-0042
DOIs
Publication statusPublished - Feb 2000

    Research areas

  • Animals, Circular Dichroism, Electrophoresis, Capillary, Evaluation Studies as Topic, Magnetic Resonance Spectroscopy, Mass Spectrometry, Membrane Potentials, Phenols, Polyamines, Stereoisomerism, Tyrosine, Wasp Venoms, Xenopus laevis

ID: 45824408