Synthesis of natural urolithin M6, a galloflavin mimetic, as a potential inhibitor of lactate dehydrogenase A

Abstract

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.

Mitochondria-Centric Review of Polyphenol Bioactivity in Cancer Models

“…The reliance on LDH makes it a potential target for starving tumor cells, especially in combination with cancer therapeutics that target other pathways to overcome resistance. Galloflavin and the gut microbial metabolite of ellagitannin, urolithin M6, inhibited human LDH-A with IC 50 values of 70 and 77 lM in a biochemical assay (165). They inhibited proliferation of Raji cells (IC 50 33 and 25 lM) and inhibited lactate production in these cells with IC 50 values of 62 and 36 lM.…”

“…A large number of studies have often observed antioxidant and antiproliferative activities of products of polyphenol metabolism (135), such as hydroxyphenyl-c-valerolactones (58), protocatechuic acid (115,224), and urolithins (165).…”

Ellagic Acid-Derived Urolithins as Modulators of Oxidative Stress

“… Strategies in urolithin synthesis: (a) from References [ 16 , 17 ], (b) from Reference [ 18 ], (c) from Reference [ 19 ], (d) from Reference [ 20 ], and (e) from Reference [ 21 ]. …”

Predicting protein–ligand binding affinity and correcting crystal structures with quantum mechanical calculations: lactate dehydrogenase A

“…As such, inhibitors of this enzyme have been sought as potential therapeutics. Several classes of inhibitors of LDHA have been described and a wealth of structural information and binding affinity data are available 62–77. The set of compounds ( 1–11 ) studied include seven from high-throughput screening (HTS) of the Genentech/Roche corporate compound collection;66,68,69,71,72,78 two small, negatively charged compounds;73 and three compounds sharing malonate as a common substructure originating from AstraZeneca's fragment screening approach (Table 2, Fig.…”