Flavonoids with lipase inhibitory activity from lemon squeezing waste: isolation, multispectroscopic and in silico studies.

BACKGROUND: Obesity is recognized as a lifestyle-related disease and the main risk factor for a series of pathological conditions, including cardiovascular diseases, hypertension and type 2 diabetes. Citrus limon is an important medicinal plant, and its fruits are rich in flavonoids investigated for their potential in managing obesity. In the present work, a green extraction applied to lemon squeezing waste (LSW) was optimized to recover pancreatic lipase (PL) inhibitors. RESULTS: The microwave-assisted procedure yielded an extract with higher lipase inhibitory activity than those obtained by maceration and ultrasound. The main compounds present in the extract were identified by high-performance liquid chromatographic-mass spectrometric analysis, and hesperidin, eriocitrin and 4'-methyllucenin II were isolated. The three compounds were evaluated for in vitro PL inhibitory activity, and 4'-methyllucenin II resulted in the most promising inhibitor (IC50 = 12.1 µmol L-1; Ki = 62.2 µmol L-1). Multispectroscopic approaches suggested the three flavonoids act as competitive inhibitors and the binding studies indicated a greater interaction between PL and 4'-methyllucenin II. Docking analysis indicated the significant interactions of the three flavonoids with the PL catalytic site. CONCLUSION: The present work highlights flavonoid glycosides as promising PL inhibitors and proposes LSW as a safe ingredient for the preparation of food supplements for managing obesity. © 2024 Society of Chemical Industry.

Synthesis of obovatol and related neolignan analogues as α-glucosidase and α-amylase inhibitors.

Diabetes mellitus is a metabolic disease characterized by hyperglycemia, which can be counteracted by the inhibition of α-glucosidase (α-Glu) and α-amylase (α-Amy), enzymes responsible for the hydrolysis of carbohydrates. In recent decades, many natural compounds and their bioinspired analogues have been studied as α-Glu and α-Amy inhibitors. However, no studies have been devoted to the evaluation of α-Glu and α-Amy inhibition by the neolignan obovatol (1). In this work, we report the synthesis of 1 and a library of new analogues. The synthesis of these compounds was achieved by implementing methodologies based on: phenol allylation, Claisen/Cope rearrangements, methylation, Ullmann coupling, demethylation, phenol oxidation and Michael-type addition. Obovatol (1) and ten analogues were evaluated for their in vitro inhibitory activity towards α-Glu and α-Amy. Our investigation highlighted that the naturally occurring 1 and four neolignan analogues (11, 22, 26 and 27) were more effective inhibitors than the hypoglycemic drug acarbose (α-Amy: 34.6 µM; α-Glu: 248.3 µM) with IC5O value of 6.2-23.6 µM toward α-Amy and 39.8-124.6 µM toward α-Glu. Docking investigations validated the inhibition outcomes, highlighting optimal compatibility between synthesized neolignans and both the enzymes. Concurrently circular dichroism spectroscopy detected the conformational changes in α-Glu induced by its interaction with the studied neolignans. Detailed studies through fluorescence measurements and kinetics of α-Glu and α-Amy inhibition also indicated that 1, 11, 22, 26 and 27 have the greatest affinity for α-Glu and 1, 11 and 27 for α-Amy. Surface plasmon resonance imaging (SPRI) measurements confirmed that among the compounds studied, the neolignan 27 has the greater affinity for both enzymes, thus corroborating the results obtained by kinetics and fluorescence quenching. Finally, in vitro cytotoxicity of the investigated compounds was tested on human colon cancer cell line (HCT-116). All these results demonstrate that these obovatol-based neolignan analogues constitute promising candidates in the pursuit of developing novel hypoglycemic drugs.

Evaluation of honokiol, magnolol and of a library of new nitrogenated neolignans as pancreatic lipase inhibitors.

Obesity is a complex disease defined as an excessive amount of body fat. It is considered a risk factor for several pathologies; therefore, there is an increasing interest in its treatment. Pancreatic lipase (PL) plays a key role in fat digestion, and its inhibition is a preliminary step in the search for anti-obesity agents. For this reason, many natural compounds and their derivatives are studied as new PL inhibitors. This study reports the synthesis of a library of new compounds inspired by two natural neolignans, honokiol (1) and magnolol (2) and bearing amino or nitro groups linked to a biphenyl core. The synthesis of unsymmetrically substituted biphenyls was achieved through an optimisation of the Suzuki-Miyaura cross-coupling reaction followed by the insertion of allyl chains, thus furnishing the O- and/or N-allyl derivatives, and finally, a sigmatropic rearrangement yielding in some cases, the C-allyl analogues. Magnolol, honokiol and the twenty-one synthesised biphenyls were evaluated for their in vitro inhibitory activity toward PL. Three compounds (15b, 16 and 17b) were more effective inhibitors than the natural neolignans (magnolol IC50 = 158.7 µM and honokiol IC50 = 115.5 µM) with IC50 of 41-44 µM. Detailed studies through kinetics suggested better inhibitory activity of the synthetic analogues compared with the natural 1 and 2. Magnolol (Ki = 614.3 µM; K'i of 140.9 µM) and the synthetic biphenyls 15b (Ki = 286.4 µM; K'i = 36.6 µM) and 16 (Ki = 176.2 µM; K'i = 6.4 µM) are mixed-type inhibitors, whereas honokiol (Ki = 674.8 µM) and 17b (Ki = 249 µM) are competitive inhibitors. Docking studies corroborated these findings, showing the best fitting for intermolecular interaction between biphenyl neolignans and PL. The above outcomes highlighted how the proposed structures could be considered interesting candidates for future studies for the development of more effective PL inhibitors.

Transient left ventricular apical ballooning syndrome: a 4-year experience.

BACKGROUND: Transient left ventricular apical ballooning syndrome, primarily described in Japanese patients, has been recently recognized outside Japan also. Aim of this study is to elucidate incidence and clinical features of left ventricular apical ballooning syndrome in a tertiary-care hospital in northeastern Italy. METHODS AND RESULTS: From January 2002 to August 2006, 29 patients admitted for suspected acute coronary syndrome (25 women, mean age 64+/-12 years) fulfilled the Mayo Clinic Criteria of left ventricular apical ballooning syndrome. Twenty patients (69%) had an episode of emotional or physiologic stress preceding left ventricular apical ballooning syndrome. Fourteen patients (48%) had at least one risk factor for coronary artery disease. Chest pain was present at admission in 24 patients (83%). Twenty-five patients (86%) had ST-T segment abnormalities at ECG on admission. Four patients were treated with fibrinolytic therapy and one with glycoprotein IIb/IIIa inhibitors. At coronary angiography, 23 patients (79%) had no coronary lesions, 2 (7%) had small vessel occlusion and 4 (14%) had nonsignificant coronary stenosis. ECG changes and echocardiographic wall motion abnormalities completely regressed in all patients within 10 weeks. Neither death nor major complications occurred during in-hospital stay and after discharge. Two patients (7%) experienced a recurrence during follow-up. CONCLUSION: Left ventricular apical ballooning syndrome is a novel syndrome with a nonnegligible incidence, a clinical presentation mimicking acute myocardial infarction and a favorable outcome. The present data confirm a higher prevalence in women and the frequent association with emotional stress. The differential diagnosis with acute myocardial infarction at presentation is still puzzling, and only ECG findings in conjunction with echocardiography and coronary angiography are so far diagnostics.