Gabriele Carullo

Quercetin and derivatives: useful tools in inflammation and pain management

Inflammation represents a very frequent condition in humans; it is often underestimated, making the problem an increasingly alarming phenomenon. For these reasons, conventional therapies are losing their effectiveness, leaving room for innovative therapies. In this field, natural products showed their efficacy in various diseases; and flavonoids, in particular quercetin, is known for its broad range of activities. In this review, we have highlighted its efficacy in various models of inflammation, focusing also on the activity of its semisynthetic derivatives, and those naturally present in plant extracts. Finally, the analgesic property of quercetin, intrinsically linked to its anti-inflammatory action, has been also evaluated, to investigate about an innovative approach to this interesting natural compound, such as analgesic remedial.

From Vegetable Waste to New Agents for Potential Health Applications: Antioxidant Properties and Effects of Extracts, Fractions and Pinocembrin from Glycyrrhiza glabra L. Aerial Parts on Viability of Five Human Cancer Cell Lines

Glycyrrhiza glabra cultivation and harvesting produces substantial quantities of aerial parts as waste. With the aim to prospect an innovative valorization of these byproducts, the aerial parts were harvested in May and October and analyzed for their chemical profile, antioxidant properties, and effects on viability of five cancer cell lines. Pinocembrin was the main constituent. A significant protection of lipid peroxidation was observed with the May total extract (IC50 of 4.2 ± 0.4 μg/mL at 30 min of incubation). The effects on viability of HeLa, MCF-7, MDA-MB-231, Caco-2, and PC3 human cancer cells were investigated. All samples shown a remarkable activity with IC50 values below 25 μg/mL. Samples from plants harvested in May exhibited greater activity than those harvested in October. MCF-7 and HeLa were the most sensitive cells with IC50 in the range 2.73-3.01 and 3.28-5.53 μg/mL, respectively. G. glabra aerial parts represent a good source of valuable products.

TRPV1–FAAH–COX: The Couples Game in Pain Treatment

Pain is a complex sensation involving the perception and transduction of diverse environmental pain stimuli with cognitive and emotional processing by the central nervous system. It can manifest as acute or chronic pain. Pain is controlled by a series of enzymes and receptors, implicated in a variety of interconnected mechanisms and pathways. In fact, several studies have shown the cannabinoid receptor 1 and the transient receptor potential vanilloid channel 1 to be new players in modulating the sophisticated pain transduction system at the central level. At the peripheral level, the perception of pain involves cyclooxygenases and fatty acid amide hydrolase, as recent studies demonstrate. This Minireview describes the physiological aspects of the receptors and enzymes mentioned above and focuses on the consideration of dual mechanisms as a new therapeutic approach in the treatment of pain.

An ancient remedial repurposing: synthesis of new pinocembrin fatty acid acyl derivatives as potential antimicrobial/anti-inflammatory agents

Abstract Five new pinocembrin derivatives (MC1-MC5) were synthesized by Steglich reaction, and investigated for their antimicrobial, antioxidant, and anti-inflammatory activity. MC2 (oleoyl derivative) and MC3 (linoleoyl derivative) have shown the highest inhibitory effects on bacterial proliferation, with MIC values of 32 μg/mL against Staphylococcus aureus. The docosahexaenoyl derivative MC5 displayed the highest anti-inflammatory activity, decreasing NO production in LPS-stimulated macrophages with an IC50 value of 15.51 μg/mL higher than the positive control diclofenac (IC50 of 39.71 μg/mL). All new synthesized compounds showed no anti-proliferative effects on RAW 264.7 cells. Results demonstrated as the introduction of fatty acid substituents improved the biological profile of pinocembrin. Moreover, the chemical nature of substituents significantly affects the bioactivity. These preliminary results outline the importance to investigate the synthesis of pinocembrin fatty acids derivatives as new and safe anti-microbial/anti-inflammatory agents.

Towards the Identification of Novel Breast Cancer Inhibitors Specific for GPER-Expressing Cells

Together with estrogen receptors ERα and ERβ, the G protein‐coupled estrogen receptor (GPER) mediates important pathophysiological signaling pathways induced by estrogens and is currently regarded as a promising target for ER‐negative (ER−) and triple‐negative (TN) breast cancer. Only a few selective GPER modulators have been reported to date, and their use in cancer cell lines has often led to contradictory results. Herein we report the application of virtual screening and cell‐based studies for the identification of new chemical scaffolds with a specific antiproliferative effect against GPER‐expressing breast cancer cell lines. Out of the four different scaffolds identified, 8‐chloro‐4‐(4‐chlorophenyl)pyrrolo[1,2‐a]quinoxaline 14 c was found to be the most promising compound able to induce: 1) antiproliferative activity in GPER‐expressing cell lines (MCF7 and SKBR3), similarly to G15; 2) no effect on cells that do not express GPER (HEK293); 3) a decrease in cyclin D1 expression; and 4) a sustained induction of cell‐cycle negative regulators p53 and p21.

Bio-Catalytic Synthesis of Quercetin-3-Oleate

Polyphenols are well-known health promoting agents, but they have some limitations due to their spontaneous oxidation. This evidence has limited their use as drugs in the last years. In this field, several chemical modifications have been proposed to overcome these restrictions; among these, the esterification seems to be the preferred. Ester derivatives could be able to reduce the bioavailability problems connected to polyphenols. On the other hand, the presence of the esterase enzymes in the body guarantees the ester hydrolysis, which in turn frees the two molecules that make it up. Lipase-catalyzed esterifications afforded several derivatives of flavonoids glycosides, in green conditions. In this short note, pancreatic porcine lipase was firstly used as a cheap bio-catalyst, to synthesize oleoyl derivatives of quercetin in aglycone form. Results demonstrated how the enzyme acyl regioselective in position C-3, with high yields and easy purification processes.

Quercetin-3-oleate

Polyphenols are well-known health promoting agents, but they have some limitations due to their spontaneous oxidation. This evidence has limited their use as drugs in recent years. In this field, several chemical modifications have been proposed to overcome these restrictions; among these, esterification seems to be the preferred modification. Ester derivatives may be able to reduce the bioavailability problems connected to polyphenols. On the other hand, the presence of esterase enzymes in the body guarantees ester hydrolysis, which in turn frees the two molecules that make it up. Lipase-catalyzed esterifications gave birth to several derivatives of flavonoids glycosides, in green conditions. In this short paper, pancreatic porcine lipase was firstly used as a cheap bio-catalyst, to synthesize oleoyl derivatives of quercetin in aglycone form. The results demonstrated how the enzyme is able to promote a regioselective acylation on C-3 position, with high yields and easy purification processes.

Synthesis and Experimental Validation of New PDI Inhibitors with Antiproliferative Activity

Protein disulfide isomerase (PDI) is a member of the thioredoxin superfamily of redox enzymes. PDI is a multifunctional protein that catalyzes disulfide bond formation, cleavage, and rearrangement in unfolded or misfolded proteins and functions as a chaperone in the endoplasmic reticulum. Besides acting as a protein folding catalyst, several evidences have suggested that PDI can bind small molecules containing, for example, a phenolic structure, which includes the estrogenic one. Increasing studies indicate that PDI is involved in both physiology and pathophysiology of cells and tissues and is involved in the survival and proliferation of different cancers. Propionic acid carbamoyl methyl amides (PACMAs) showed anticancer activity in human ovarian cancer, both in vitro and in vivo, by inhibiting PDI. The inhibition of PDI’s activity may have a therapeutic role, in various diseases, including cancer. In the present study, we designed and synthesized a diversified small library of compounds with the aim of identifying a new class of PDI inhibitors. Most of synthesized compounds showed a good inhibitory potency against PDI and particularly 4-methyl substituted 2,6-di-tert-butylphenol derivatives (8–10) presented an antiproliferative activity in a wide panel of human cancer cell lines, including ovarian ones.