New Bioactive Molecules Isolated for the First Time from Hyoscyamus albus L. and their Mechanisms Underlying the Anticancer Effects

Zerumbone (ZER) isolated fromZingiber zerumbetwas previously encapsulated with hydroxypropyl-β-cyclodextrin (HPβCD) to enhance ZER’s solubility in water, thus making it highly tolerable in the human body. The anticancer effects of this new ZER-HPβCD inclusion complex via apoptosis cell death were assessed in this study for the first time in liver hepatocellular cells, HepG2. Apoptosis was ascertained by morphological study, nuclear stain, and sub-G1 cell population accumulation with G2/M arrest. Further investigations showed the release of cytochrome c and loss of mitochondrial membrane potential, proving mitochondrial dysfunction upon the ZER-HPβCD treatment as well as modulating proapoptotic and anti-apototic Bcl-2 family members. A significant increase in caspase 3/7, caspase 9, and caspase 8 was detected with the depletion of BID cleaved by caspase 8. Collectively, these results prove that a highly soluble inclusion complex of ZER-HPβCD could be a promising anticancer agent for the treatment of hepatocellular carcinoma in humans.

Download Full-text

Late-Stage β-C(sp3)–H Deuteration of Carboxylic Acids

10.26434/chemrxiv.14537865.v2 ◽

2021 ◽

Author(s):

Alexander Uttry ◽

Sourjya Mal ◽

Manuel van Gemmeren

Keyword(s):

Carboxylic Acid ◽

Carboxylic Acids ◽

Late Stage ◽

Bioactive Molecules ◽

Wide Range ◽

Catalyst Systems ◽

First Time

Carboxylic acid moieties are highly abundant in bioactive molecules. In this study we describe the late-stage β-C(sp<sup>3</sup>)–H deuteration of free carboxylic acids. Based on our finding that the C–H activation with our catalyst systems is reversible, the de-deuteration process was first optimized. The resulting conditions involve ethylenediamine-based ligands, which, amongst other positions, for the first time enables the functionalization of non-activated methylene β-C(sp<sup>3</sup>)–H bonds and can be used to achieve the desired deuteration when using a deuterated solvent. The reported method allows for the functionalization of a wide range of free carboxylic acids with diverse substitution patterns, as well as the late-stage deuteration of bioactive molecules and related frameworks.

Download Full-text

Non-directed highly para-selective C-H functionalization of TIPS-protected phenols promoted by a proton shuttle

10.21203/rs.3.rs-1114441/v1 ◽

2021 ◽

Author(s):

Jingyao Geng ◽

Zhang Fang ◽

Guangliang Tu ◽

Yingsheng Zhao

Keyword(s):

Bioactive Molecules ◽

Protecting Group ◽

Mechanism Study ◽

Phenol Derivatives ◽

Site Selectivity ◽

Palladium Catalyzed ◽

Direct Functionalization ◽

Poor Site ◽

Site Selective ◽

First Time

Abstract Palladium-catalyzed non-directed C-H functionalization provides an efficient approach for direct functionalization of arenes, but it usually suffers from poor site selectivity, limiting its wide application. Herein, it is reported for the first time that the proton shuttle of 3,5-dimethyladamantane-1-carboxylic acid (1-DMAdCO2H) can affect the site selectivity during the C-H activation step in palladium-catalyzed non-directed C-H functionalization, leading to highly para-selective C-H olefination of TIPS-protected phenols. This transformation displayed good generality in realizing various other para-selective C-H functionalization reactions such as hydroxylation, halogenation, and allylation reactions. A wide variety of phenol derivatives including bioactive molecules of triclosan, thymol, and propofol, were compatible substrates, leading to the corresponding para-selective products in moderate to good yields. A preliminary mechanism study revealed that the spatial repulsion factor between proton shuttle and bulky protecting group resulted in the selective C-H activation at the less sterically hindered para-position. This new model non-directed para-selective C-H functionalization can provide a straightforward route for remote site-selective C-H activations.

Download Full-text

Quantification of Urinary Phenyl-γ-Valerolactones and Related Valeric Acids in Human Urine on Consumption of Apples

Metabolites ◽

10.3390/metabo9110254 ◽

2019 ◽

Vol 9 (11) ◽

pp. 254 ◽

Cited By ~ 4

Author(s):

Andrea Anesi ◽

Pedro Mena ◽

Achim Bub ◽

Marynka Ulaszewska ◽

Daniele Del Rio ◽

...

Keyword(s):

Small Intestine ◽

Phase Ii ◽

Glucuronic Acid ◽

Blood Stream ◽

Bioactive Molecules ◽

Beneficial Effects ◽

Within Subjects ◽

Excretion Rates ◽

First Time ◽

Cumulative Excretion

Flavan-3-ols are dietary bioactive molecules that have beneficial effects on human health and reduce the risk of various diseases. Monomeric flavan-3-ols are rapidly absorbed in the small intestine and released in the blood stream as phase II conjugates. Polymeric flavan-3-ols are extensively metabolized by colonic gut microbiota into phenyl-γ-valerolactones and their related phenylvaleric acids. These molecules are the main circulating metabolites in humans after the ingestion of flavan-3-ol rich-products; nevertheless, they have received less attention and their role is not understood yet. Here, we describe the quantification of 8 phenyl-γ-valerolactones and 3 phenylvaleric acids in the urine of 11 subjects on consumption of apples by using UHPLC-ESI-Triple Quad-MS with pure reference compounds. Phenyl-γ-valerolactones, mainly as sulfate and glucuronic acid conjugates, reached maximum excretion between 6 and 12 after apple consumption, with a decline thereafter. Significant differences were detected in the cumulative excretion rates within subjects and in the ratio of dihydroxyphenyl-γ-valerolactone sulfate to glucuronide conjugates. This work observed for the first time the presence of two distinct metabotypes with regards to the excretion of phenyl-γ-valerolactone phase II conjugates.

Download Full-text

Application of Hansen solubility approach for the subcritical and supercritical selective extraction of phlorotannins from Cystoseira abies-marina

RSC Advances ◽

10.1039/c6ra16862k ◽

2016 ◽

Vol 6 (97) ◽

pp. 94884-94895 ◽

Cited By ~ 21

Author(s):

A. P. Sánchez-Camargo ◽

L. Montero ◽

A. Cifuentes ◽

M. Herrero ◽

E. Ibáñez

Keyword(s):

Theoretical Approach ◽

Selective Extraction ◽

Bioactive Molecules ◽

Solubility Parameters ◽

Green Solvent ◽

Hansen Solubility Parameters ◽

Brown Macroalgae ◽

First Time ◽

Hansen Solubility

A new theoretical approach based on Hansen solubility parameters has been employed for the first time to select the best green solvent to extract complex bioactive molecules such as phlorotannins from brown macroalgae Cystoseira abies-marina.

Download Full-text

The Mechanisms Underlying the Protective Action of Selenium Nanoparticles against Ischemia/Reoxygenation Are Mediated by the Activation of the Ca2+ Signaling System of Astrocytes and Reactive Astrogliosis

International Journal of Molecular Sciences ◽

10.3390/ijms222312825 ◽

2021 ◽

Vol 22 (23) ◽

pp. 12825

Author(s):

Elena G. Varlamova ◽

Egor A. Turovsky ◽

Valentina A. Babenko ◽

Egor Y. Plotnikov

Keyword(s):

Cerebral Cortex ◽

Protective Action ◽

Selenium Nanoparticles ◽

Ip3 Receptor ◽

Extracellular Medium ◽

Phosphoinositide Signaling ◽

Anticancer Effects ◽

Paracrine Activation ◽

First Time ◽

The Brain

In recent years, much attention has been paid to the study of the therapeutic effect of the microelement selenium, its compounds, especially selenium nanoparticles, with a large number of works devoted to their anticancer effects. Studies proving the neuroprotective properties of selenium nanoparticles in various neurodegenerative diseases began to appear only in the last 5 years. Nevertheless, the mechanisms of the neuroprotective action of selenium nanoparticles under conditions of ischemia and reoxygenation remain unexplored, especially for intracellular Ca2+ signaling and neuroglial interactions. This work is devoted to the study of the cytoprotective mechanisms of selenium nanoparticles in the neuroglial networks of the cerebral cortex under conditions of ischemia/reoxygenation. It was shown for the first time that selenium nanoparticles dose-dependently induce the generation of Ca2+ signals selectively in astrocytes obtained from different parts of the brain. The generation of these Ca2+ signals by astrocytes occurs through the release of Ca2+ ions from the endoplasmic reticulum through the IP3 receptor upon activation of the phosphoinositide signaling pathway. An increase in the concentration of cytosolic Ca2+ in astrocytes leads to the opening of connexin Cx43 hemichannels and the release of ATP and lactate into the extracellular medium, which trigger paracrine activation of the astrocytic network through purinergic receptors. Incubation of cerebral cortex cells with selenium nanoparticles suppresses ischemia-induced increase in cytosolic Ca2+ and necrotic cell death. Activation of A2 reactive astrocytes exclusively after ischemia/reoxygenation, a decrease in the expression level of a number of proapoptotic and proinflammatory genes, an increase in lactate release by astrocytes, and suppression of the hyperexcitation of neuronal networks formed the basis of the cytoprotective effect of selenium nanoparticles in our studies.

Download Full-text

Transcriptomic Analysis of Marine Gastropod Hemifusus tuba Provides Novel Insights into Conotoxin Genes

Marine Drugs ◽

10.3390/md17080466 ◽

2019 ◽

Vol 17 (8) ◽

pp. 466 ◽

Cited By ~ 2

Author(s):

Ronghua Li ◽

Michaël Bekaert ◽

Luning Wu ◽

Changkao Mu ◽

Weiwei Song ◽

...

Keyword(s):

High Throughput Sequencing ◽

De Novo ◽

Average Length ◽

Bioactive Molecules ◽

Asian Countries ◽

Marine Gastropod ◽

Sequencing Technologies ◽

First Time ◽

Aquaculture Development ◽

Simple Sequence

The marine gastropod Hemifusus tuba is served as a luxury food in Asian countries and used in traditional Chinese medicine to treat lumbago and deafness. The lack of genomic data on H. tuba is a barrier to aquaculture development and functional characteristics of potential bioactive molecules are poorly understood. In the present study, we used high-throughput sequencing technologies to generate the first transcriptomic database of H. tuba. A total of 41 unique conopeptides were retrieved from 44 unigenes, containing 6-cysteine frameworks belonging to four superfamilies. Duplication of mature regions and alternative splicing were also found in some of the conopeptides, and the de novo assembly identified a total of 76,306 transcripts with an average length of 824.6 nt, of which including 75,620 (99.1%) were annotated. In addition, simple sequence repeats (SSRs) detection identified 14,000 unigenes containing 20,735 SSRs, among which, 23 polymorphic SSRs were screened. Thirteen of these markers could be amplified in Hemifusus ternatanus and seven in Rapana venosa. This study provides reports of conopeptide genes in Buccinidae for the first time as well as genomic resources for further drug development, gene discovery and population resource studies of this species.

Download Full-text

Bioassay-guided Isolation of Antiproliferative Triterpenoids from Euonymus alatus Twigs

Natural Product Communications ◽

10.1177/1934578x1501001131 ◽

2015 ◽

Vol 10 (11) ◽

pp. 1934578X1501001 ◽

Cited By ~ 5

Author(s):

Hee Rae Kang ◽

Hee Jeong Eom ◽

Seoung Rak Lee ◽

Sang Un Choi ◽

Ki Sung Kang ◽

...

Keyword(s):

Cell Lines ◽

Ursolic Acid ◽

Anticancer Agent ◽

Meoh Extract ◽

Isolation And Identification ◽

Maslinic Acid ◽

Euonymus Alatus ◽

Anticancer Effects ◽

Korean Traditional Medicine ◽

First Time

Euonymus alatus (Celastraceae) has been used as an anticancer agent in Korean traditional medicine. However, the potential bioactive contributors to the anticancer effects have not been thoroughly studied. Our screening test revealed that the MeOH extract of E. alatus twigs exhibited significant cytotoxicity against A549, SK-OV-3, and SK-MEL-2 cell lines. A bioassay-guided separation of the MeOH extract of E. alatus twigs resulted in the isolation and identification of 14 triterpenes as main phytochemicals. The structures of the compounds were elucidated on the basis of spectroscopic evidence as lupeol (1), betulin (2), 3β,28,30-lup-20(29)-ene triol (3), lupenone (4), betulone (5), 28,30-dihydroxy-3-oxolup-20(29)-ene (6), messagenin (7), glut-5-en-3β-ol (8), maslinic acid (9), hederagenin (10), 3-oxo-11α-methoxyolean-12-ene (11), 3β-hydroxy-1-oxo-olean-12-en-28-oic acid (12), ursolic acid (13), and 2α-hydroxy-ursolic acid (14). Of these compounds, 3, 6–8, and 10–14 were isolated for the first time from this plant. All isolated triterpenoids had consistent antiproliferative activities against A549, SK-OV-3, SK-MEL-2, and HCT-15 cell lines. Compounds 2, 5, and 7 showed significant cytotoxicity against all four cell lines tested, with IC50 values of 3.26–8.61 μM.

Download Full-text

Natural Products to Fight Cancer: A Focus on Juglans regia

Toxins ◽

10.3390/toxins10110469 ◽

2018 ◽

Vol 10 (11) ◽

pp. 469 ◽

Cited By ~ 13

Author(s):

Elena Catanzaro ◽

Giulia Greco ◽

Lucia Potenza ◽

Cinzia Calcabrini ◽

Carmela Fimognari

Keyword(s):

Natural Products ◽

Essential Fatty Acids ◽

Juglans Regia ◽

Therapeutic Index ◽

Natural World ◽

Bioactive Molecules ◽

Human Society ◽

Beneficial Effects ◽

Anticancer Effects ◽

Pharmacologic Activity

Even if cancer represents a burden for human society, an exhaustive cure has not been discovered yet. Low therapeutic index and resistance to pharmacotherapy are two of the major limits of antitumour treatments. Natural products represent an excellent library of bioactive molecules. Thus, tapping into the natural world may prove useful in identifying new therapeutic options with favourable pharmaco-toxicological profiles. Juglans regia, or common walnut, is a very resilient tree that has inhabited our planet for thousands of years. Many studies correlate walnut consumption to beneficial effects towards several chronic diseases, such as cancer, mainly due to the bioactive molecules stored in different parts of the plant. Among others, polyphenols, quinones, proteins, and essential fatty acids contribute to its pharmacologic activity. The present review aims to offer a comprehensive perspective about the antitumour potential of the most promising compounds stored in this plant, such as juglanin, juglone, and the ellagitannin-metabolites urolithins or deriving from walnut dietary intake. All molecules and a chronic intake of the fruit provide tangible anticancer effects. However, the scarcity of studies on humans does not allow results to be conclusive.

Download Full-text

Gas-Liquid Chromatography-Mass Spectrometry Investigation of Tropane Alkaloids in Hyoscyamus albus L. from Morocco

Zeitschrift für Naturforschung C ◽

10.1515/znc-2012-9-1003 ◽

2012 ◽

Vol 67 (9-10) ◽

pp. 461-465 ◽

Cited By ~ 3

Author(s):

Ahmed El Bazaoui ◽

My Ahmed Bellimam ◽

Ibn Toumert Lançar ◽

Abdelmajid Soulaymani

Keyword(s):

Mass Spectrometry ◽

Liquid Chromatography ◽

Tropane Alkaloids ◽

Gas Liquid Chromatography ◽

Liquid Chromatography Mass Spectrometry ◽

Plant Organs ◽

Chromatography Mass Spectrometry ◽

New Compounds ◽

First Time ◽

Hyoscyamus Albus

Thirty-four alkaloids were identified in the organs of Hyoscyamus albus L. by gas-liquid chromatography-mass spectrometry (GLC-MS). Eight new compounds for the roots, eleven for the stems, twelve for the leaves, nineteen for the flowers, and seven for the seeds were detected. The alkaloids 5-(2-oxopropyl)-hygrine (8) and phygrine (20) are new for this species and 3-(hydroxyacetoxy)tropane (9), 6,7-dehydro-3-phenylacetoxytropane (15), 3-(2’-phenylpropionyloxy) tropane (17), 6,7-dehydro-3-apotropoyloxytropane (18), 3-(3’-methoxytropoyloxy)tropane (23), and aponorscopolamine (25) are described for the first time for the genus Hyoscyamus. Hyoscyamine was the main alkaloid in the plant organs

Download Full-text