Flavan-3-ols constitute a complex subclass of flavonoids, ranging from simple monomers to oligomeric and polymeric proanthocyanidins, which are also known as condensed tannins. The presence of these compounds in foods, whose epidemiology is associated with reduced incidences of cardiovascular and metabolic diseases, makes the investigation of their biological effects and mechanisms of action a topic of great interest.

These compounds undergo extensive metabolism in the gut to form products with a γ-valerolactone structure, which subsequently undergo hepatic phase II transformation yielding sulphate, methyl and glucuronide conjugates. γ-Valerolactone metabolites are generally not commercially available and, due to their low natural abundance in organic fluids, their isolation from natural sources in the amounts required for biological testing is not practical.

Hence, asymmetric synthesis is an attractive alternative considering that, being these metabolites chiral, the development of an efficient and versatile route that enables construction of the targeted compounds in an enantiopure form would be of great value.

The aim of the proposed research is to develop an efficient asymmetric synthetic route to obtain the physiologically relevant human g-valerolactone conjugates, in particular those from (-)-epicatechin and oligomeric procyanidins, the main flavan-3-ols in cocoa, red wine and nuts, and to rigorously evaluate their biological activity in vitro and in experimental animal models of cardiovascular disease and diabetes, at dosages coherent with dietary exposure.

Main publications about this subject:

1. Favari, C.; Mena, P.; Curti, C.; Istas, G.; Heiss, C.; Del Rio, D.; Rodriguez-Mateos, A. Kinetic profile and urinary excretion of phenyl-γ-valerolactones upon consumption of cranberry: a dose–response relationship. Food Funct. 2020,11, 3975-3985. doi.org/10.1039/D0FO00806K

2. Ruotolo, R.; Minato I.; La Vitola P.; Artioli L.; Curti C.; Franceschi V.; Brindani N.; Amidani D.; Colombo L.; Salmona M.; Forloni G.; Donofrio, G.; Balducci C.; Del Rio, D.; Ottonello S. Flavonoid‐Derived Human Phenyl‐γ‐Valerolactone Metabolites Selectively Detoxify Amyloid‐β Oligomers and Prevent Memory Impairment in a Mouse Model of Alzheimer's Disease. Mol. Nutr. Food Res. 2020, 64, 190890. DOI: 10.1002/mnfr.201900890

3. Angelino, D.; Carregosa, D.; Domenech-Coca, C.; Savi, M.; Figueira, M.; Brindani, N.; Jang, S.; Lakshman, S.; Molokin, A.; Urban Jr., J.; Davis, C.D.; Brito, M.A.; Kim, K.S.; Brighenti, F.; Curti, C.; Bladé, C.; del Bas, J.M; Stilli, D.; Solano-Aguilar, G.I.; dos Santos, G.N.; del Rio, D.; Mena, P.; 5-(Hydroxyphenyl)-γ-Valerolactone-Sulfate, a Key Microbial Metabolite of Flavan-3-ols, Is Able to Reach the Brain: Evidence from Different in Silico, In Vitro and In Vivo Experimental Models. Nutrients 2019, 11, 2678. DOI:10.3390/nu11112678

4. Mena, P.; Bresciani, L.; Brindani, N.; Ludwig, I.A.; Pereira-Caro, G.; Angelino, D.; Llorach, R.; Calani, L.; Brighenti, F.; Clifford, M.N; Gill, C.I.R.; Crozier, A.; Curti, C.; Del Rio, D. Phenyl-γ-valerolactones and phenylvaleric acids, the main colonic metabolites of flavan-3-ols: synthesis, analysis, bioavailability, and bioactivity. Nat. Prod. Rep. 2019, 36, 714-752. DOI: 10.1039/c8np00062j

5. Brindani, N.; Mena, P.; Calani, L.; Benzie, I.; Choi, S.W.; Brighenti, F.; Zanardi, F.; Curti C.; Del Rio D. Synthetic and analytical strategies for the quantificationof phenyl-γ-valerolactone conjugated metabolites inhuman urine. Mol. Nutr. Food Res. 2017, 61(9), 1700077. doi.org/10.1002/mnfr.201700077

6. Mena, P.; González de Llano, D.; Brindani, N.; Esteban-Fernández, A.; Curti, C.; Moreno-Arribas, M. V.; Del Rio, D.; Bartolomé, B. 5-(3′,4′-Dihydroxyphenyl)-g-valerolactone and its sulphate conjugates, representative circulating metabolites of flavan-3-ols, exhibit anti-adhesive activity against uropathogenic Escherichia coli in bladder epithelial cells. J. Funct. Foods 2017, 29, 275-280. DOI: 10.3390/nu11112678

7. Curti, C.; Brindani, N.; Battistini, L.; Sartori, A.; Pelosi, G.; Mena, P.; Brighenti, F.; Zanardi, F.; Del Rio, D. Catalytic, Enantioselective, Vinylogous Mukaiyama Aldol Reaction of Furan-Based Dienoxy Silanes: A Chemodivergent Approach to g-Valerolactone Flavan-3-ol Metabolites and d-Lactone Analogues. Adv. Synth. Catal. 2015, 357, 4082-4092. DOI: 10.1002/adsc.201500705.