Artificial intelligence-driven identification of morin analogues acting as CaV1.2 channel blockers: Synthesis and biological evaluation

Carullo, Gabriele; Falbo, Federica; Ahmed, Amer; Trezza, Alfonso; Gianibbi, Beatrice; Nicolotti, Orazio; Campiani, Giuseppe; Aiello, Francesca; Saponara, Simona; Fusi, Fabio

doi:10.1016/j.bioorg.2022.106326

Cited by 5 publications

(4 citation statements)

References 53 publications

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“…Rings (3–4 mm wide) were cut from the thoracic aorta and mounted, under a passive tension of 1 g, in organ baths filled with KHS (composition in mM: 118 NaCl, 4.75 KCl, 1.19 KH 2 PO 4 , 1.19 MgSO 4 , 25 NaHCO 3 , 11.5 glucose, 2.5 CaCl 2 , gassed with carboxygen; pH 7.4) for isometric tension recordings, using a digital PowerLab data acquisition system (PowerLab 8/30; ADInstruments). Rings responding to 0.3–0.6 µM phenylephrine and 60 mM KCl were considered viable (Carullo et al., 2019, 2023; Carullo, Ahmed, Fusi, et al., 2020). When necessary, the endothelium was removed by gently rubbing the lumen of the ring with a forceps tip.…”

Section: Methodsmentioning

confidence: 99%

Nutritionally enriched tomatoes (Solanum lycopersicum L.) grown with wood distillate: chemical and biological characterization for quality assessment

Fedeli,

Marotta,

Frattaruolo

et al. 2023

Journal of Food Science

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Bio‐based products are nowadays useful tools able to affect the productivity and quality of conventionally cultivated crops. Several bio‐based products are currently on the market; one of the newest and most promising is the wood distillate (WD) derived from the pyrolysis process of waste biomass after timber. Its foliar application has been widely investigated and shown to promote the antioxidant profile of cultivated crops. WD was used here as additive for the cultivation of tomato (Solanum lycopersicum L.) plants. The application improved quality (chemical) parameters, minerals, polyphenols, and lycopene contents of tomato fruits. The extracts of WD‐treated and untreated tomatoes have been chemically and biologically characterized. The 1H‐NMR and ESI‐mass spectrometry analyses of the extracts revealed the presence of different fatty acids, amino acids and sugars. In particular, the WD‐treated tomatoes showed the presence of pyroglutamic acid and phloridzin derivatives, but also dihydrokaempferol, naringenin glucoside, cinnamic acid, and kaempferol‐3‐O‐glucoside. When tested in cells, the extracts showed a promising anti‐inflammatory profile in lipopolysaccharide (LPS)‐stimulated RAW 264.7 macrophages. Furthermore, the extracts displayed a slight vasorelaxant activity on rat aorta rings (either endothelium‐denuded or endothelium‐intact) pre‐contracted with phenylephrine or potassium chloride.Practical ApplicationWood distillate has been used for tomato plant growth. Tomatoes showed improved nutritional parameters, and their extracts displayed antioxidant and anti‐inflammatory activities.

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Section: Methodsmentioning

confidence: 99%

Nutritionally enriched tomatoes (Solanum lycopersicum L.) grown with wood distillate: chemical and biological characterization for quality assessment

Fedeli,

Marotta,

Frattaruolo

et al. 2023

Journal of Food Science

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“…Ester based derivative of quercetin improved its vasodilation activity by acting as large conductance potassium channel KCa1.1 stimulator (Carullo et al, 2020). Semisynthetic derivatives of morin, a naturally occurring flavonol, markedly improved its vasorelaxing activity through a decrease of calcium release from the sarcoplasmic reticulum, a blockade of voltage‐dependent calcium channel CaV1.2, and opening of large conductance potassium channel KCa1.1, all of which are implicated in the pathogenesis of hypertension suggesting their use in animal model of hypertension (Carullo et al, 2021; Carullo et al, 2023). Bonesi and colleagues synthesized a series of chalcone derivative as inhibitors against ACE and found that 3‐(3‐amino‐4‐methoxyphenyl)‐1‐(3,4,5‐trimethoxyphenyl) prop‐2‐en‐1‐one has the highest potency to inhibit ACE (Bonesi et al, 2010).…”

Section: Flavonoids and Vascular Tonementioning

confidence: 99%

Current insights and future perspectives of flavonoids: A promising antihypertensive approach

Harahap,

Syahputra,

Ahmed

et al. 2024

Phytotherapy Research

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Hypertension, or high blood pressure (BP), is a complex disease influenced by various risk factors. It is characterized by persistent elevation of BP levels, typically exceeding 140/90 mmHg. Endothelial dysfunction and reduced nitric oxide (NO) bioavailability play crucial roles in hypertension development. L‐NG‐nitro arginine methyl ester (L‐NAME), an analog of L‐arginine, inhibits endothelial NO synthase (eNOS) enzymes, leading to decreased NO production and increased BP. Animal models exposed to L‐NAME manifest hypertension, making it a useful design for studying the hypertension condition. Natural products have gained interest as alternative approaches for managing hypertension. Flavonoids, abundant in fruits, vegetables, and other plant sources, have potential cardiovascular benefits, including antihypertensive effects. Flavonoids have been extensively studied in cell cultures, animal models, and, to lesser extent, in human trials to evaluate their effectiveness against L‐NAME‐induced hypertension. This comprehensive review summarizes the antihypertensive activity of specific flavonoids, including quercetin, luteolin, rutin, troxerutin, apigenin, and chrysin, in L‐NAME‐induced hypertension models. Flavonoids possess antioxidant properties that mitigate oxidative stress, a major contributor to endothelial dysfunction and hypertension. They enhance endothelial function by promoting NO bioavailability, vasodilation, and the preservation of vascular homeostasis. Flavonoids also modulate vasoactive factors involved in BP regulation, such as angiotensin‐converting enzyme (ACE) and endothelin‐1. Moreover, they exhibit anti‐inflammatory effects, attenuating inflammation‐mediated hypertension. This review provides compelling evidence for the antihypertensive potential of flavonoids against L‐NAME‐induced hypertension. Their multifaceted mechanisms of action suggest their ability to target multiple pathways involved in hypertension development. Nonetheless, the reviewed studies contribute to the evidence supporting the useful of flavonoids for hypertension prevention and treatment. In conclusion, flavonoids represent a promising class of natural compounds for combating hypertension. This comprehensive review serves as a valuable resource summarizing the current knowledge on the antihypertensive effects of specific flavonoids, facilitating further investigation and guiding the development of novel therapeutic strategies for hypertension management.

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“…Traditional Chinese medicine (TCM) has been widely used to treat cardiovascular and cerebrovascular diseases with unique clinical benefits including multi-target pharmacological functions and fewer side effects [14][15][16]. Particularly, a panel of dietary flavonoids have been reported [17][18][19]. Scutellarin isolated from Scutellaria altissima L. has been reported to present excellent therapeutic effects on cardiovascular diseases and inflammation [20,21].…”

Section: Sudden Cardiac Death Caused By Malignant Cardiac Arrhythmias...mentioning

confidence: 99%

Synthesis and In Vivo Antiarrhythmic Activity Evaluation of Novel Scutellarein Analogues as Voltage-Gated Nav1.5 and Cav1.2 Channels Blockers

Yang,

Wang,

Cai

et al. 2023

Molecules

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Malignant cardiac arrhythmias with high morbidity and mortality have posed a significant threat to our human health. Scutellarein, a metabolite of Scutellarin which is isolated from Scutellaria altissima L., presents excellent therapeutic effects on cardiovascular diseases and could further be metabolized into methylated forms. A series of 22 new scutellarein derivatives with hydroxyl-substitution based on the scutellarin metabolite in vivo was designed, synthesized via the conjugation of the scutellarein scaffold with pharmacophores of FDA-approved antiarrhythmic medications and evaluated for their antiarrhythmic activity through the analyzation of the rat number of arrhythmia recovery, corresponding to the recovery time and maintenance time in the rat model of barium chloride-induced arrhythmia, as well as the cumulative dosage of aconitine required to induce VP, VT, VF and CA in the rat model of aconitine-induced arrhythmia. All designed compounds could shorten the time of the arrhythmia continuum induced by barium chloride, indicating that 4′-hydroxy substituents of scutellarein had rapid-onset antiarrhythmic effects. In addition, nearly all of the compounds could normalize the HR, RR, QRS, QT and QTc interval, as well as the P/T waves’ amplitude. The most promising compound 10e showed the best antiarrhythmic activity with long-term efficacy and extremely low cytotoxicity, better than the positive control scutellarein. This result was also approved by the computational docking simulation. Most importantly, patch clamp measurements on Nav1.5 and Cav1.2 channels indicated that compound 10e was able to reduce the INa and ICa in a concentration-dependent manner and left-shifted the inactivation curve of Nav1.5. Taken together, all compounds were considered to be antiarrhythmic. Compound 10e even showed no proarrhythmic effect and could be classified as Ib Vaughan Williams antiarrhythmic agents. What is more, compound 10e did not block the hERG potassium channel which highly associated with cardiotoxicity.

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Artificial intelligence-driven identification of morin analogues acting as CaV1.2 channel blockers: Synthesis and biological evaluation

Cited by 5 publications

References 53 publications

Nutritionally enriched tomatoes (Solanum lycopersicum L.) grown with wood distillate: chemical and biological characterization for quality assessment

Nutritionally enriched tomatoes (Solanum lycopersicum L.) grown with wood distillate: chemical and biological characterization for quality assessment

Current insights and future perspectives of flavonoids: A promising antihypertensive approach

Synthesis and In Vivo Antiarrhythmic Activity Evaluation of Novel Scutellarein Analogues as Voltage-Gated Nav1.5 and Cav1.2 Channels Blockers

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