Selective Modification of Streptozotocin at the C3 Position to Improve Its Bioactivity as Antibiotic and Reduce Its Cytotoxicity towards Insulin-Producing β Cells
Ji Zhang,
Liubov Yakovlieva,
Bart J. de Haan,
Paul de Vos,
Adriaan J. Minnaard,
Martin D. Witte,
Marthe T. C. Walvoort
Affiliations
Ji Zhang
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands
Liubov Yakovlieva
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands
Bart J. de Haan
Department of Pathology and Medical Biology, University of Groningen Medical Center, Hanzeplein 1, 9700 RB Groningen, The Netherlands
Paul de Vos
Department of Pathology and Medical Biology, University of Groningen Medical Center, Hanzeplein 1, 9700 RB Groningen, The Netherlands
Adriaan J. Minnaard
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands
Martin D. Witte
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands
Marthe T. C. Walvoort
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands
With the increasing resistance of bacteria to current antibiotics, novel compounds are urgently needed to treat bacterial infections. Streptozotocin (STZ) is a natural product that has broad-spectrum antibiotic activity, albeit with limited use because of its toxicity to pancreatic β cells. In an attempt to derivatize STZ through structural modification at the C3 position, we performed the synthesis of three novel STZ analogues by making use of our recently developed regioselective oxidation protocol. Keto-STZ (2) shows the highest inhibition of bacterial growth (minimum inhibitory concentration (MIC) and viability assays), but is also the most cytotoxic compound. Pre-sensitizing the bacteria with GlcNAc increased the antimicrobial effect, but did not result in complete killing. Interestingly, allo-STZ (3) revealed moderate concentration-dependent antimicrobial activity and no cytotoxicity towards β cells, and deoxy-STZ (4) showed no activity at all.
