Efficient strategies for the one-step modification of aminoglycoside antibiotics

PhD ceremony: Mr. A.A. Bastian, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Efficient strategies for the one-step modification of aminoglycoside antibiotics

Promotor(s): prof. A. Herrmann

Faculty: Mathematics and Natural Sciences

Emerging trends in drug discovery are prompting a renewed interest in natural products as source of chemical diversity and lead structures. However, owing structural complexity of many natural compounds the synthesis of derivatives is not easily realized. Therefore, in this thesis two strategies are presented which enable regioselective modification of compounds carrying several functionalities of similar reactivity in a single synthetic step. First, a conceptually new approach is demonstrated using supramolecular protective groups based on RNA aptamers, so called aptameric protective groups (APGs), for the modification of complex natural products. It is shown that APGs block several functionalities by non-covalent interactions in a molecule while functional groups not in contact with the APG can be transformed chemo- and regioselectively. Using this technique aminoglycoside antibiotics neomycin B and paromomycin were modified at different positions employing different APGs and chemical transformations. According to these results APGs merit consideration as a new synthetic method in organic synthesis as they can be evolved for a large variety of target molecules and their generation relies on a well-established process. The second strategy is based on a regioselective azide introduction in a particular position of neamine antibiotics without the use of protective group chemistry. Here, an azide-transfer reagent was employed for the selective modification of diverse neamine antibiotics in C3 position of the 2 deoxystreptamine ring. Since this position is one target of the bacterial resistance mechanism, this facile azide introduction will accelerate the development of new promising antibiotics overcoming antibacterial resistance.