Synthesis of natural urolithin M6, a galloflavin mimetic, as a potential inhibitor of lactate dehydrogenase A.
Glycolysis is the main route for energy production in tumors. LDH-A is a key enzyme of this process and its inhibition represents an attractive strategy to hamper cancer cell metabolism. Galloflavin is a reliable LDH-A inhibitor as previously identified by us; however, its poor physicochemical properties and chemical tractability render it unsuitable for further development. Therefore, a rational design was undertaken with the aim to reproduce the pharmacophore of galloflavin on simpler, potentially more soluble and synthetic accessible scaffolds. Following a process of structural simplification, natural urolithin M6 (UM6), which is an ellagitannin metabolite produced by gut microbiota, was identified as a putative galloflavin mimetic. In the present study, the synthesis of UM6 is described for the first time. An efficient synthetic pathway has been developed, which involved five steps from readily accessible starting materials. The key reaction steps, a Suzuki coupling and an intramolecular C-H oxygenation, have been optimized to improve the synthetic feasibility and provide the best conditions in terms of reaction time and yield. Moreover, this route would be suitable to obtain other analogs for SAR studies. Preliminary biological tests revealed that UM6 was able to smoothly reproduce the behavior of galloflavin, confirming that our approach was successful in providing a new and accessible structure in the search for new LDH-A inhibitors.
Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy. marinella.roberti@unibo.it.
Sebastiano
0000-0002-0993-8455
S
Rupiani
Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy. marinella.roberti@unibo.it.
Laura
L
Guidotti
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via S. Giacomo 14, 40126 Bologna, Italy.
Marcella
M
Manerba
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via S. Giacomo 14, 40126 Bologna, Italy.
Lorenza
L
Di Ianni
CompuNet, Istituto Italiano di Tecnologia, via Morego 30, 16163, Genova, Italy.
Elisa
E
Giacomini
CompuNet, Istituto Italiano di Tecnologia, via Morego 30, 16163, Genova, Italy.
Federico
0000-0001-7385-649X
F
Falchi
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via S. Giacomo 14, 40126 Bologna, Italy.
Giuseppina
G
Di Stefano
Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy. marinella.roberti@unibo.it.
Marinella
0000-0001-9807-2886
M
Roberti
Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy. marinella.roberti@unibo.it.
Maurizio
M
Recanatini
D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D049934:Isocoumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors*; D000080864:Lactate Dehydrogenase 5; D019344:Lactic Acid / Q000096:biosynthesis
D004791:Enzyme Inhibitors; D049934:Isocoumarins; D007527:Isoenzymes; C572336:galloflavin; D019344:Lactic Acid; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5