Pharmaceutical Chemistry

Biography

Biography: Piotr Przybylski

Abstract

Macrolide antibiotics are large group of natural products of attractive biological properties and produced by Streptomyces strains. Macrolides can be classified via inter-alia the type and the size of the macrolide ring¹ as for e.g. lactone macrolides 14-membered erythromycins, 15-membered azithromycins, and 16-membered spiramycins and leucomycins, or lactam 26-membered rifamycins as e.g. rifampicine. Macrolide antibiotics, especially lactone ones, can be divided also by the type of saccharide moiety attached at the aglycone.² Mechanism of action of macrolide lactone antibiotics’ is based on the inhibition of bacterial protein biosynthesis at different stages by reversible binding at bacterial 50S subunit of ribosomes³ whereas macrolide lactam antibiotics mechanism of action as rifamycins depends on inhibition of bacterial RNA polymerases⁴. Our modifications were performed using cascade and ‘click’ approaches in aim to construct novel semisynthetic antibiotics of well-balanced physico-chemical parameters (lipophilicity, water solubility) and of improved docking mode at the biological target. For example, modifications at aglycone ring via complete reconstruction of saccharides parts using regio- and diastereoselective cascade combination of  intramolecular esterifications, tandem E1cB eliminations and subsequent 1,2-addition to carbonyl followed by 1,6-conjugate addition at α,β,γ,δ – unsaturated aglycone yielded novel lactone macrolides of enhanced antibacterial and anticancer activities.^5,6 We use also analogous combined cascade and ‘click’ approaches to modification of other group of natural macrolide antibiotics like lactone erythromycins to obtain alternatives to the currently used antibiotics in clinical therapy. The project is financially supported by Polish National Science Centre (NCN), decision number UMO-2015/19/B/ST5/00231.