Hypervalent Iodine Amino Acid Building Blocks for Bioorthogonal Peptide Macrocyclization.

Ethynylbenziodoxol(on)es (EB(X)xs) reagents have emerged as useful reagents for peptide/protein modification due to their versatile reactivity and high selectivity. Herein, we report the successful introduction of ethynylbenziodoxoles (EBxs) on different amino acid building blocks (Lys/Orn/Dap), and show their compatibility with both solid phase peptide synthesis (SPPS) and solution phase peptide synthesis (SPS). The selective incorporation of the EBx core into peptide sequences enable efficient macrocyclizations under mild conditions for the synthesis of topologically unique cyclic and bicyclic peptides.

Alpha-lipoic Acid: An Antioxidant with Anti-Aging Properties for Disease Therapy.

The anti-aging effects of alpha-lipoic acid (αLA), a natural antioxidant synthesized in human tissues, have attracted a growing interest in recent years. αLA is a short- -chain sulfur-containing fatty acid occurring in the mitochondria of all kinds of eukaryotic cells. Both the oxidized disulfide of αLA and its reduced form (dihydrolipoic acid, DHLA) exhibit prominent antioxidant function. The amount of αLA inside the human body gradually decreases with age resulting in various health disorders. Its lack can be compensated by supplying from external sources such as dietary supplements or medicinal dosage forms. The primary objectives of this study were the analysis of updated information on the latest two-decade research regarding the use of αLA from an anti-aging perspective. The information was collected from PubMed, Wiley Online Library, Scopus, ScienceDirect, SpringerLink, Google Scholar, and clinicaltrials.gov. Numerous in silico, in vitro, in vivo, and clinical studies revealed that αLA shows a protective role in biological systems by direct or indirect reactive oxygen/nitrogen species quenching. αLA demonstrated beneficial properties in the prevention and treatment of many age-related disorders such as neurodegeneration, metabolic disorders, different cancers, nephropathy, infertility, and skin senescence. Its preventive effects in case of Alzheimer's and Parkinson's diseases are of particular interest. Further mechanistic and clinical studies are highly recommended to evaluate the wide spectrum of αLA therapeutic potential that could optimize its dietary intake for prevention and alleviation disorders related to aging.

Medicinal Plant-Derived Phytochemicals in Detoxification.

The average worldwide human life expectancy is 70 years, with a significantly higher value in Western societies. Many modern diseases are not associated with premature mortality but with a decreased quality of life in aged patients and an excessive accumulation of various toxic compounds in the human body during life. Today, scientists are especially interested in finding compounds that can help increase a healthy lifespan by detoxifying the body. Phytotherapy with specific approaches is used in alternative medicine to remove toxins from the body. Worldwide, research is conducted to identify medicinal plant-derived molecules that, with few or no side effects, may protect the liver and other organs. This review provides updated information about the detoxification process, the traditional and modern use of the most effective medicinal plants, their active metabolites as detoxifying agents, and the mechanisms and pathways involved in the detoxification process. Among medicinal plants with substantial detoxifying properties, a major part belongs to the Asteraceae family (Silybum marianum, Cynara scolymus, Arctium lappa, Helichrysum spp, Inula helenium, and Taraxacum officinale). The most widely used hepatoprotective phytocomponent is silymarin, a standardized extract from the Silybum marianum seeds containing a mixture of flavonolignans. Many polysaccharides, polyphenols, and terpenoids have a detoxifying effect. Overall, scientific data on medicinal plants used in phytotherapeutic practice worldwide provides an understanding and awareness of their efficacy in detoxification.

Anti-viral and Anti-inflammatory Isoflavonoids from Ukrainian Iris aphylla Rhizomes: Structure-Activity Relationship Coupled with ChemGPS-NP Analysis.

Dried Iris rhizomes have been used in Chinese and European traditional medicine for the treatment of various diseases such as bacterial infections, cancer, and inflammation, as well as for being astringent, laxative, and diuretic agents. Eighteen phenolic compounds including some rare secondary metabolites, such as irisolidone, kikkalidone, irigenin, irisolone, germanaism B, kaempferol, and xanthone mangiferin, were isolated for the first time from Iris aphylla rhizomes. The hydroethanolic Iris aphylla extract and some of its isolated constituents showed protective effects against influenza H1N1 and enterovirus D68 and anti-inflammatory activity in human neutrophils. The promising anti-influenza effect of apigenin (13: , almost 100% inhibition at 50 µM), kaempferol (14: , 92%), and quercetin (15: , 48%) were further confirmed by neuraminidase inhibitory assay. Irisolidone (1: , almost 100% inhibition at 50 µM), kikkalidone (5: , 93%), and kaempferol (14: , 83%) showed promising anti-enterovirus D68 activity in vitro. The identified compounds were plotted using ChemGPS-NP to correlate the observed activity of the isolated phenolic compounds with the in-house database of anti-influenza and anti-enterovirus agents. Our results indicated that the hydroethanolic Iris aphylla extract and Iris phenolics hold the potential to be developed for the management of seasonal pandemics of influenza and enterovirus infections.

Phenological Variations in the Content of Polyphenols and Triterpenoids in Epilobium angustifolium Herb Originating from Ukraine.

The composition of secondary metabolites undergoes significant changes in plants depending on the growth phase and the influence of environmental factors. Therefore, it is important to determine the harvesting time of plant material for the optimum secondary metabolite profile and therapeutic activity of the primary material. The shoots of Epilobium angustifolium are used as a healing tea due to the presence of polyphenolic compounds. The aim of this study was to assess the composition of phenolic compounds and triterpenoid saponins in E. angustifolium leaves and flowers and to estimate the dynamics of their content depending on the flowering phase. Qualitative and quantitative characterisation of polyphenols and triterpenoids in E. angustifolium samples from Ukraine of three flowering phases were performed using the high-performance liquid chromatography photo diode array (HPLC-PDA) method. During the present study, 13 polyphenolic compounds and seven triterpenoids were identified in the plant material. It was noted that the largest content and the best polyphenol profile was in late flowering. The most important polyphenolic compounds in the plant material were chlorogenic acid, hyperoside, isoquercitin, and oenothein B. The triterpenoid profile was at its maximum during mass flowering, with corosolic and ursolic acids being the dominant metabolites. The results of the analysis revealed that the quantity of many of the tested metabolites in the raw material of E. angustifolium is dependent on the plant organ and flowering phase. The largest content of most metabolites in the leaves was in late flowering. In the flowers, the quantity of the metabolites studied was more variable, but decreased during mass flowering and increased significantly again in late flowering. The results show that E. angustifolium raw material is a potential source of oenothein B and triterpenoids.

Effective Isolation of Picrocrocin and Crocins from Saffron: From HPTLC to Working Standard Obtaining.

Saffron is widely cultivated and used as a spice. Recently published data on the chemical composition and pharmacological potential of saffron determine its use in pharmacy and medicine. The proposed high-performance thin-layer chromatography (HPTLC) method allows good separation of 11 analytes. The saffron quality (Iran, Ukraine, Spain, Morocco samples) assessment was based on the European Pharmacopoeia monograph and ISO 3632. The HPTLC method for the safranal, crocin, and picrocrocin quantification was proposed and validated. The crocins content in Ukrainian saffron was from 17.80% to 33.25%. Based on qualitative and quantitative assessment results, the saffron sample from Zaporizhzhia (Ukraine) had the highest compounds content and was chosen to obtain the working standards of picrocrocin and crocins (trans-4GG, trans-2G, trans-3Gg) by preparative chromatography. The compounds were isolated from lyophilized extract of saffron using a Symmetry Prep C18 column (300 × 19 mm × 7 µm), and identified by spectroscopic techniques (HPLC-DAD, UPLC-ESI-MS/MS). The purity of crocins and picrocrocin was more than 97%. A novel method proposed to obtain working standards is simple and reproducible for the routine analysis of saffron quality control.

Innovative GACP Approaches for Obtaining the Quality Iris hybrida Leaves for the Pharmaceutical Industry.

The ever-growing demand for active compounds of plant origin contributes to the implementation of cultivation methods for medicinal plants, according to the WHO guideline "Good Agricultural and Collection Practice (GACP) for Starting Materials of Herbal Origin" to obtain high-quality raw material with the stable phytocomponent composition. Therefore, the development of the cultivation and processing stages of Iris varieties leaves is necessary and promising. The present article showed the potential of proper cultivation with GACP recommendations on affecting the phenolic compounds content in Iris×hybrida hort. 'Indian Pow Waw', Iris×hybrida hort. 'Galleon Gold', and Iris×hybrida hort. 'Mini Dinamo' leaves. The cultivation process was carried out on the experimental sites of the flowering and ornamental plants department of M.M. Hryshko National Botanical Garden of the National Academy of Sciences of Ukraine (Kyiv, Ukraine) during 2018-2021. A positive effect of Iris samples proper cultivation and content of isoflavonoids (tectoridin, nigricin D-glucoside, genistin, iristectorigenin B, nigricin, irigenin, irisolidone), xanthone mangiferin, and also chlorogenic acid in Irises leaves by HPLC has been established. According to the analysis mangiferin (7.57∼28.75 µg/g), genistin (3324.82∼14642.10 µg/g), irisolidone (673.53∼2015.81 µg/g), and irigenin (3904.37∼1595.94 µg/g) were the dominant components and these compounds can be proposed as chemical markers for Iris raw material. The obtained results indicate a significant positive effect of the introduction and observance of the proper cultivation of medicinal plants to obtain a stable bioactive compounds content, in this case, on the example of Iris genus plants. Further work on the implementation of the good practice recommendation is planned to be carried out for various medicinal plants, since only controlled cultivation makes it possible to obtain high-quality raw materials with a standardized composition.

Comparative analysis of apocarotenoids and phenolic constituents of Crocus sativus stigmas from 11 countries: Ecological impact.

The chemical compositions of 15 saffron samples from 11 countries (Morocco, India, Italy, Spain, Germany, Switzerland, Iran, Lithuania, Ukraine, Australia, and Azerbaijan) were evaluated. The samples were analyzed regarding the impact of environmental factors on the composition of apocarotenoids and phenolic constituents. Quantification of saffron metabolites was carried out using high-performance liquid chromatography. It was found that the high content of chlorogenic acid (0.2 mg/g, Ukraine) and ferulic acid (0.28 mg/g, India) was controlled by the duration of solar radiation during plant development. The accumulation of caffeic acid (the higher content 4.88 mg/g, Ukraine) in stigmas depended on the average air temperature. In contrast, the total crocins content according to the correlation analysis depended on the duration of solar radiation, the solar UV index, and the soil type. Rutin was found in all samples (0.83-8.74 mg/g). The highest amount of crocins (average 382.45 mg/g) accumulated in saffron from Italy and Ukraine. Crocins, picrocrocin, safranal, and rutin can further serve as saffron quality markers. All validation parameters were satisfactory and high-performance liquid chromatography methods could be successfully applied for the composition assessment of saffron metabolites. Saffron extracts showed the highest antibacterial activity against Bacillus subtilis, Staphylococcus aureus, and Escherichia coli (MICs 62.5-125 µg/ml).

Effective and simple approach for colchicine determination in saffron parts.

Crocus sativus (Iridaceae) or saffron is important for its flavoring properties in the food industry and its medicinal properties in the pharmaceutical industry. Real saffron must meet the quality requirements set to FDA or ISO specifications, and in addition, must be safe and non-toxic. An "autumn crocus" or scientific name Colchicum spp. (Colchicaceae) is a plant that contains a highly toxic alkaloid colchicine. The problem is that Colchicum autumnale is often mistaken for C. sativus. This study aim is to develop the high-performance liquid chromatography method for determining the presence of colchicine in C. sativus stigma, flowers and corms, and then for solving the issue of saffron possible falsification and toxicity. The chromatographic separation was performed on ACE C18 column (5.0 µm, 250 mm × 4.6 mm), by using 0.1% acetic acid in water and acetonitrile as the mobile phase and UV detector (350 nm). Current analysis showed that all Crocus raw materials didn't contain colchicine. This confirms the safety of saffron and its parts for using in the development of substances based on them. The proposed method was successfully applied on C. autumnale corms and showed good separation and colchicine identification. The presence of tricyclic proto-alkaloid colchicine in plant products is not a new phenomenon, however, the need for new sensitive analytical methods that can detect it in food and medicine still exists. The identification and confirmation of colchicine absence in saffron raw materials are important for further herbal drug development and for the food industry.

Bio-guided bioactive profiling and HPLC-DAD fingerprinting of Ukrainian saffron (Crocus sativus stigmas): moving from correlation toward causation.

BACKGROUND: Saffron or stigmas of Crocus sativus L. is one of the most valuable food products with interesting health-promoting properties. C. sativus has been widely used as a coloring and flavoring agent. Stigmas secondary metabolites showed potent cytotoxic effects in previous reports. METHODS: The present study investigated the chemical composition and the cytotoxic effect of Ukrainian saffron crude extracts and individual compounds against melanoma IGR39, triple-negative breast cancer MDA-MB-231, and glioblastoma U-87 cell lines in vitro using MTT assay. Several bioactivity in vitro assays were performed. The chemical profile of the water and hydroethanolic (70%, v/v) crude extracts of saffron stigmas was elucidated by HPLC-DAD analysis. RESULTS: Seven compounds were identified including crocin, picrocrocin, safranal, rutin, apigenin, caffeic acid, ferulic acid. Crocin, picrocrocin, safranal, rutin, and apigenin were the major active constituents of Ukrainian C. sativus stigmas. The hydroethanolic extract significantly reduced the viability of MDA-MB-231 and IGR39 cells and the effect was more potent in comparison with the water extract. However, the water extract was almost 5.6 times more active against the U-87 cell line (EC50 of the water extract against U-87 was 0.15 ± 0.02 mg/mL, and EC50 of the hydroethanolic extract was 0.83 ± 0.03 mg/mL). The pure compounds, apigenin, and caffeic acid also showed high cytotoxic activity against breast cancer, melanoma, and glioblastoma cell lines. The screening of the biological activities of stigmas water extract (up to 100 µg/mL) including anti-allergic, anti-virus, anti-neuraminidase, and anti-inflammatory effects revealed its inhibitory activity against neuraminidase enzyme by 41%. CONCLUSIONS: The presented results revealed the qualitative and quantitative chemical composition and biological activity of Crocus sativus stigmas from Ukraine as a source of natural anticancer and neuraminidase inhibitory agents. The results of the extracts' bioactivity suggested future potential applications of saffron as a natural remedy against several cancers.

Comparative Analysis of the Major Metabolites of Ukrainian Saffron Samples by HPLC.

Crocus sativus L. is one of the most valuable crops, which stigmas are used as the food supplement and herbal medicine. In Ukraine, the cultivation of C. sativus began in 2015, and in this regard, it became possible to conduct a comparative content analysis of the major metabolites (crocin, picrocrocin, safranal) using the validated HPLC method in the stigmas from the different country regions. The grinding technique of Crocus stigmas in liquid nitrogen was used for the first time, which influenced an increase in the yield of trans-crocetin bis(ß-D-gentiobiosyl) ester in 3.5 times compared with a normal grinding. Samples from the northeastern regions of cultivation such as Zaporizhia and Chernigiv had the higher amount of crocin (205 and 226 mg/g, respectively), while in the samples of the southwestern region the decrease of the amount of crocin was observed (180 mg/g and less), which was due to the climatic features of the country. These results can be utilized in the pharmaceutical and food industries for creating food additives for human nutrition.

The Comparative Analysis of Carboxylic Acid Composition of Four Iris Species from Ukraine.

The present article reports results of analysis of carboxylic acids in leaves of Iris species from Ukraine using a gas chromatography (GC) method with mass spectrometric (MS) detection (GC/MS). Carboxylic acids play significant roles in contemporary society as evidenced by multiple applications in fields of medicine, agriculture, pharmacy, food, and other industries. Study of natural plant products as a source of organic acids is of particular interest. Carboxylic acid composition of leaves of Iris hungarica Waldst. & Kit., Iris germanica L., Iris pallida Lam., and Iris variegate L. was studied for the first time applying GC/MS method. The mass spectrums of compounds were matched with NIST and WILEY Libraries. The GC/MS analysis revealed the presence of 26 common acids in the plant raw materials studied. The short-chain carboxylic acids, such as citric (1337.5-12364.4 mg/kg), malic (50.8-4558.0 mg/kg) and oxalic (1199.0-3435.2 mg/kg) acids were contained in significantly high quantity in all samples. Ferulic, p-coumaric and vanillic acids were the most abundant among phenolic acids. α-Linolenic acid was dominant in the leaves of I. germanica (869.5 mg/kg), I. pallida (753.3 mg/kg), and I. variegate (250.3 mg/kg) among polyunsaturated fatty acids, however, linoleic acid prevailed in the plant raw material of I. hungarica (1150.7 mg/kg). Since the leaves of Iris species studied contain carboxylic acids with diverse pharmacological activity, extracts of these raw materials are perspective for development food supplements and medicines.

Pharmacological Potential and Chemical Composition of Crocus sativus Leaf Extracts.

Crocus sativus L. (saffron) has been traditionally used as a food coloring or flavoring agent, but recent research has shown its potent pharmacological activity to tackle several health-related conditions. Crocus sp. leaves, and petals are the by-products of saffron production and are not usually used in the medicine or food industries. The present study was designed to determine the chemical composition of the water and ethanolic extracts of C. sativus leaves and test their cytotoxic activity against melanoma (IGR39) and triple-negative breast cancer (MDA-MB-231) cell lines by MTT assay. We also determined their anti-allergic, anti-inflammatory, and anti-viral activities. HPLC fingerprint analysis showed the presence of 16 compounds, including hydroxycinnamic acids, xanthones, flavonoids, and isoflavonoids, which could contribute to the extracts' biological activities. For the first time, compounds such as tectoridin, iristectorigenin B, nigricin, and irigenin were identified in Crocus leaf extracts. The results showed that mangiferin (up to 2 mg/g dry weight) and isoorientin (8.5 mg/g dry weight) were the major active ingredients in the leaf extracts. The ethanolic extract reduced the viability of IGR39 and MDA-MB-231 cancer cells with EC50 = 410 ± 100 and 330 ± 40 µg/mL, respectively. It was more active than the aqueous extract. Kaempferol and quercetin were identified as the most active compounds. Our results showed that Crocus leaves contain secondary metabolites with potent cytotoxic and antioxidant activities.

Qualitative and Quantitative Analysis of Ukrainian Iris Species: A Fresh Look on Their Antioxidant Content and Biological Activities.

The major groups of antioxidant compounds (isoflavonoids, xanthones, hydroxycinnamic acids) in the rhizome methanol extracts of four Ukrainian Iris sp. (Iris pallida, Iris hungarica, Iris sibirica, and Iris variegata) were qualitatively and quantitatively analyzed using HPLC-DAD and UPLC-MS/MS. Gallic acid, caffeic acid, mangiferin, tectoridin, irigenin, iristectorigenin B, irisolidone, 5,6-dihydroxy-7,8,3',5'-tetramethoxyisoflavone, irisolidone-7-O-ß-d-glucopyranoside, germanaism B, and nigricin were recognized by comparing their UV/MS spectra, chromatographic retention time (tR) with those of standard reference compounds. I. hungarica and I. variegata showed the highest total amount of phenolic compounds. Germanaism B was the most abundant component in the rhizomes of I. variegata (7.089 ± 0.032 mg/g) and I. hungarica (6.285 ± 0.030 mg/g). The compound analyses showed good calibration curve linearity (r2 > 0.999) and low detection and quantifications limit. These results validated the method for its use in the simultaneous quantitative evaluation of phenolic compounds in the studied Iris sp. I. hungarica and I. variegata rhizomes exhibited antioxidant activity, as demonstrated by the HPLC-ABTS system and NRF2 expression assay and anti-inflammatory activity on respiratory burst in human neutrophils. Moreover, the extracts showed anti-allergic and cytotoxic effects against cancer cells. Anti-coronavirus 229E and lipid formation activities were also evaluated. In summary, potent antioxidant marker compounds were identified in the examined Iris sp.

Effect of ecological factors on the accumulation of phenolic compounds in Iris species from Latvia, Lithuania and Ukraine.

INTRODUCTION: It is important to conduct studies on the influence of environmental factors on the accumulation of secondary metabolites in plants, as well as the cultivation of plants and harvesting of their raw material. OBJECTIVE: In this study, we examined the influence of habitat types, soil composition, climatic factors and altitude on the content of phenolic compounds in Iris species from different populations in Latvia, Lithuania and Ukraine. METHODOLOGY: According to high-performance liquid chromatography (HPLC) analysis, 25 compounds (flavonoids, isoflavonoids, isoflavonoid glucosides, xanthones, phenolcarboxylic acids) were identified in the methanol extracts of 16 samples of Iris rhizomes. The quantitative data were further analysed by principal component analysis (PCA) to reveal the impact of environmental factors on the accumulation of compounds in plants. RESULTS: Iris pseudacorus from Latvia and Lithuania had a more diverse composition of phenolic compounds than samples from Ukraine. Sampled plants of the Iris subg. Iris had a higher content of the analysed compounds than those of Iris subg. Limniris. PCA results showed that the levels of phenolic compounds in Iris rhizomes were influenced by the content of soil nutrients. The phosphorus and potassium content had a significant impact on the levels of phenolic compounds, whereas the impact of nitrogen content was not significant. Meteorological factors had a small impact; however, sunshine duration had a significant positive effect and the amount of precipitation had a significant negative impact. CONCLUSION: The results of this study suggest that rhizomes of Iris species may be an important source of pharmacologically active compounds such as flavonoids, isoflavonoids and xanthones. Studies on the effect of environmental factors on the production and accumulation of secondary metabolites in Iris species are important because they contribute to knowledge of quantitative parameters of secondary metabolites in medicinal plants and could be employed for the cultivation and harvesting of raw material for medicinal purposes.