Summary:
This thesis refers to the development of strategies concerning the synthesis of
novel aminoglycoside analogues that are expected to exhibit improved antibiotic
activity and binding selectivity towards the decoding site of the bacterial
ribosomal RNA (A-site). After quoting representative examples from the
literature, we focused on synthetic strategies of properly substituted
2-deoxystreptamine (2-DOS) analogues, since 2-DOS consists the
diaminocycloexitol core of most natural aminoglycosides. Great emphasis was
given to the orthogonal protection of all these analogues, in order to achieve
higher flexibility in their functionalization. Particularly, we used as
starting material the aminoglycoside neomycin B, which demonstrates
considerable antibiotic activity, and we examined in detail several suitable
combinations of protecting groups regarding the 2-DOS scaffold, in order to
accomplish further variability in the ring’s substitution. Furthermore, we
applied these orthogonal strategies on the syntheses of novel representative
mono-, di-, tri and tetra-substituted 2-DOS analogues. During these syntheses,
we utilized oxazolidinones as drug-carrier groups, as well as triazole rings
resulting from 1,3-dipolar cycloadditions. To evaluate the antibiotic activity
of selected examples of the newly synthesized 2-DOS analogues we employed in
vitro assays, concerning both the whole bacterial ribosome and the A-site. The
furnished biological results were promising and provided the first useful
information for further investigation of the prospective SAR studies
(Structure-Activity Relationship).
Keywords:
Antibiotics, Aminoglycosides, RNA, 2-Deoxystreptamine (2-DOS), 2-Deoxystreptamine analogues (2-DOS)
