Millettia isoflavonoids: a comprehensive review of structural diversity, extraction, isolation, and pharmacological properties.

There are approximately 260 known species in the genus Millettia, many of which are used in traditional medicine to treat human and other animal ailments in various parts of the world. Being in the Leguminosae (Fabaceae) family, Millettia species are rich sources of isoflavonoids. In the past three decades alone, several isoflavonoids originating from Millettia have been isolated, and their pharmacological activities have been evaluated against major diseases, such as cancer, inflammation, and diabetes. Despite such extensive research, no recent and comprehensive review of the phytochemistry and pharmacology of Millettia isoflavonoids is available. Furthermore, the structural diversity of isoflavonoids in Millettia species has rarely been reported. In this review, we comprehensively summarized the structural diversity of Millettia isoflavonoids, the methods used for their extraction and isolation protocols, and their pharmacological properties. According to the literature, 154 structurally diverse isoflavonoids were isolated and reported from the various tissues of nine well-known Millettia species. Prenylated isoflavonoids and rotenoids were the most dominant subclasses of isoflavonoids reported. Other subclasses of reported isoflavonoids include isoflavans, aglycone isoflavones, glycosylated isoflavones, geranylated isoflavonoids, phenylcoumarins, pterocarpans and coumaronochromenes. Although some isolated molecules showed promising pharmacological properties, such as anticancer, anti-inflammatory, estrogenic, and antibacterial activities, others remained untested. In general, this review highlights the potential of Millettia isoflavonoids and could improve their utilization in drug discovery and medicinal use processes. Supplementary Information: The online version contains supplementary material available at 10.1007/s11101-022-09845-w.

Isolation of Formononetin-7-O-β-D-glucopyranoside from the Grass of Ononis arvensis L. and the Assessment of its Effect on Induced Platelet Activation

Introduction. Analysis of the clinical and laboratory picture of the SARS-CoV-2 infection suggests the presence of microcirculation and oxygen transport disorders, hemolysis of erythrocytes, intra-alveolar fibrin formation and microthrombus formation in the patient’s pathogenesis. Accordingly, the search for potential anticoagulants, erythrocyte antiplatelet agents, membrane stabilizing drugs and mild thrombolytic drugs can prevent the development of life-threatening complications and reduce the mortality of COVID-19 patients. Aim. Isolation of formononetin-7-O-β-D-glucopyranoside from the grass of Ononis arvensis L. and identification of the molecular mechanisms of its effect on platelet activation in vitro, induced by TRAP-6 (Thrombin receptor activated peptide) and ADP (adenosine diphosphate). Materials and methods. Terrestrial parts of Ononis arvensis L. were collected in the SPCPU nursery of medicinal plants (Leningrad region, Vsevolozhsky district, Priozerskoe highway, 38 km). Isolation of formononetin-7-O-β-D-glucopyranoside was carried out by preparative high performance liquid chromatography on a Smartline device (Knauer, Germany) equipped with a spectrophotometric detector. The structure of formononetin-7-O-β-D-glucopyranoside was confirmed by one-dimensional and two-dimensional NMR spectroscopy (Bruker Avance III, 400 MHz, Germany), as well as high-resolution mass spectrometry (HR-ESI-MS) (Bruker Micromass Q-TOF, Germany). The study of the effect of formononetin-7-O-β-D-glucopyranoside on induced platelet activation was carried out on human platelets isolated from the blood of healthy volunteers. To research the effect of formononetin-7-О-β-D-glucopyranoside on platelet aggregation flow cytofluorometry with Cyto-FLEX (Beckman-Coulter, USA) was used. Results and discussion. According to the method of fractionation and purification of the total extract of O. arvensis developed in previous studies, formononetin-7-O-β-D-glucopyranoside was isolated in an individual form for subsequent biological studies with a total yield of 30 % in comparison with its content in the original extract. In samples with formononetin-7-O-β-D-glucopyranoside and ADP, there is a pronounced inhibition of platelet activation – the percentage of active platelets ranges from 6.3–6.6 % at doses of formononetin-7-O-β-D-glucopyranoside 1 μM, 3 μM and 30 μM. The inhibitory effect of formononetin-7-O-β-D-glucopyranoside is not dose-dependent (p ≤ 0.05). In samples with formononetin-7-O-β-D-glucopyranoside and TRAP, there is also a pronounced inhibition of platelet activation. The percentage of active platelets is 8 % at 1 μM formononetin-7-O-β-D-glucopyranoside doses, 15 % at 3 μM doses, and 16 % at 30 μM doses. Conclusion. Administration of formononetin-7-O-β-D-glucopyranoside at doses of 1 μM, 3 μM, 30 μM strongly inhibits platelet activation induced by ADP and TRAP-6. For ADP, there is no dose-dependent effect, while for TRAP there is a weak dose-dependent effect, the greatest inhibition efficiency is achieved with the minimum investigated dose of 1 μM. In all cases, the results obtained are statistically significant. © Bogoutdinova A. M., Whaley A. K., Ponkratova A. O., Orlova A. A., Goncharo M. Yu., Shpakova V. S., Farmanova N. T., Nurullaeva D. Kh., Sharipov A. T., Gambaryan S. P., Povydysh M. N., 2021.

Flavonoids as an effective sensitizer for anti-cancer therapy: insights into multi-faceted mechanisms and applicability towards individualized patient profiles.

Cost-efficacy of currently applied treatments is an issue in overall cancer management challenging healthcare and causing tremendous economic burden to societies around the world. Consequently, complex treatment models presenting concepts of predictive diagnostics followed by targeted prevention and treatments tailored to the personal patient profiles earn global appreciation as benefiting the patient, healthcare economy, and the society at large. In this context, application of flavonoids as a spectrum of compounds and their nano-technologically created derivatives is extensively under consideration, due to their multi-faceted anti-cancer effects applicable to the overall cost-effective cancer management, primary, secondary, and even tertiary prevention. This article analyzes most recently updated data focused on the potent capacity of flavonoids to promote anti-cancer therapeutic effects and interprets all the collected research achievements in the frame-work of predictive, preventive, and personalized (3P) medicine. Main pillars considered are: - Predictable anti-neoplastic, immune-modulating, drug-sensitizing effects; - Targeted molecular pathways to improve therapeutic outcomes by increasing sensitivity of cancer cells and reversing their resistance towards currently applied therapeutic modalities.

In Silico Studies of Some Isoflavonoids as Potential Candidates against COVID-19 Targeting Human ACE2 (hACE2) and Viral Main Protease (Mpro).

The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the "COVID-19" disease that has been declared by WHO as a global emergency. The pandemic, which emerged in China and widespread all over the world, has no specific treatment till now. The reported antiviral activities of isoflavonoids encouraged us to find out its in silico anti-SARS-CoV-2 activity. In this work, molecular docking studies were carried out to investigate the interaction of fifty-nine isoflavonoids against hACE2 and viral Mpro. Several other in silico studies including physicochemical properties, ADMET and toxicity have been preceded. The results revealed that the examined isoflavonoids bound perfectly the hACE-2 with free binding energies ranging from -24.02 to -39.33 kcal mol-1, compared to the co-crystallized ligand (-21.39 kcal mol-1). Furthermore, such compounds bound the Mpro with unique binding modes showing free binding energies ranging from -32.19 to -50.79 kcal mol-1, comparing to the co-crystallized ligand (binding energy = -62.84 kcal mol-1). Compounds 33 and 56 showed the most acceptable affinities against hACE2. Compounds 30 and 53 showed the best docking results against Mpro. In silico ADMET studies suggest that most compounds possess drug-likeness properties.