Medicinal chemistry of aminoglycosides

Student thesis: Doctoral ThesisMPhil

Abstract

It is demonstrated that NMR spectroscopy is a powerful technique for separating and measuring each distinct pKa value of the amino groups located around aminoglycoside antibiotics. Unambiguous assignments were made for each individual amine and guanidine substituent on: 2-deoxystreptamine, neamine, neomycin C, paromomycin, tobramycin, kanamycin B, netilmicin, sisomicin, amikacin, and streptomycin using variations in the NMR spectroscopic chemical shift with 1H, 13C, and 15N HMBC as the reporter probes. These data were then compared with the literature data. Minor revisions to the assignment order were made for neomycin C and paromomycin. pKa values for kanamycin B have been reported using potentiometry, however no NMR derived pKa data have been reported, and for netilmicin no literature pKa values were found. Therefore, these data are reported for the first time herein.
Due to its sensitivity and natural abundance (99.98%), 1H NMR is less time consuming than 13C and 15N HMBC NMR spectroscopy. For this reason, 1H NMR is the most common and preferable method for measuring individual pKa values.
One of the ultimate objectives of this line of research is to be able to trace an aminoglycoside, e.g., tobramycin, in the body in a non-invasive way by tagging the aminoglycoside with a fluorescent probe. Taking both the pKa values of the individual amino functional groups of tobramycin and steric-hindrance factors into consideration, the investigation of the specific or selective reactions of the different amines located around tobramycin were carried out with amino acid protecting groups, e.g., Boc and Cbz, and with a fluorophore (FITC) that would generate a biologically relevant tagged product. Four out of five amines on tobramycin were protected with Boc protecting groups. However, the mono-protection of tobramycin with Boc or Cbz groups and labelling the unprotected (unreacted) N-3 amine on tetra-Boc protected tobramycin with FITC were not successful.
Date of Award13 Feb 2019
LanguageEnglish
Awarding Institution
  • University of Bath
SponsorsImam Abdulrahman Bin Faisal University
SupervisorIan Blagbrough (Supervisor) & Timothy Woodman (Supervisor)

Cite this

Medicinal chemistry of aminoglycosides
Al Khzem, A. (Author). 13 Feb 2019

Student thesis: Doctoral ThesisMPhil