Ali M. El-Halawany

P-glycoprotein inhibitors of natural origin as potential tumor chemo-sensitizers: A review

Graphical abstract

Bioactive anthraquinones from endophytic fungus Aspergillus versicolor isolated from red sea algae

The marine fungus Aspergillus versicolor was isolated from the inner tissue of the Red Sea green alga Halimeda opuntia. The fungus was identified by its morphology and 18s rDNA. Cultivation of this fungal strain led to a new metabolite named isorhodoptilometrin-1-methyl ether (1) along with the known compounds emodin (2), 1-methyl emodin (3), evariquinone (4), 7-hydroxyemodin 6,8-methyl ether (5), siderin (6), arugosin C (7), and variculanol (8). The structures were elucidated on the basis of NMR spectroscopic analysis and mass spectrometry. The biological properties of ethyl acetate extract and compounds 1–3 and 6–8 were explored for antimicrobial activity, anti-cancer activity and inhibition of Hepatitis C virus (HCV) protease.

Estrogenic Activity of Chemical Constituents from Tephrosia candida

In a continued investigation of medicinal plants from the genus Tephrosia, phytochemical analysis of a methylene chloride-methanol (1:1) extract of the air-dried aerial parts of Tephrosia candida afforded two new 8-prenylated flavonoids, namely, tephrocandidins A (1) and B (2), a new prenylated chalcone, candidachalcone (3), a new sesquiterpene (4), and a previously reported pea flavonoid phytoalexin, pisatin (5). The structures of 1-4 were established by spectroscopic methods, including HREIMS, and 1H, 13C, DEPT, HMQC, and HMBC NMR experiments. The most potent estrogenic activity of these isolated natural products in an estrogen receptor (ERα) competitive-binding assay was for 3, which exhibited an IC50 value of 80 μM, compared with 18 nM for the natural steroid 17β-estradiol. Results were interpreted via virtual docking of isolated compounds to an ERα crystal structure.

Protective Effect of Aframomum melegueta phenolics Against CCl 4 -Induced Rat Hepatocytes Damage; Role of Apoptosis and Pro-inflammatory Cytokines inhibition

Aframomum melegueta is a commonly used African spice. Through a hepatoprotective bioassay-guided isolation, the chloroform fraction of A.melegueta seeds yielded one new diarylheptanoid named 3-(S)-acetyl-1-(4′-hydroxy-3′, 5′-di methoxyphenyl)-7-(3″,4″, 5″-trihydroxyphenyl)heptane (1), and two new hydroxyphenylalkanones, [8]-dehydrogingerdione (2) and [6]-dehydroparadol (3), in addition to six known compounds (4–9). The hepatoprotective effect of A. melegueta methanol extract, sub-fractions and isolated compounds was investigated using carbon tetrachloride (CCl4)-induced liver injury in a rat hepatocytes model. The methanol, chloroform extracts and compounds 1, 5, 8 and 9 of A. melegueta significantly inhibited the elevated serum alanine aminotransferase (ALT), thiobarbituric acid reactive substances (TBARS), tumor necrosis factor (TNFα), interleukin-1beta (Il-1β), caspase3 and 9 and enhanced the reduced liver glutathione (GSH) level caused by CCl4 intoxication. These results indicate that A.melegueta extracts, and isolated compounds play a protective role in CCl4 induced acute liver injury which might be due to elevated antioxidative defense potentials, suppressed inflammatory responses and apoptosis of liver tissue.

Isolation of antiosteoporotic compounds from seeds of Sophora japonica.

Chemical investigation of Sophora japonica seeds resulted in the isolation of seven metabolites identified as: genistin (1), sophoricoside (2), sophorabioside (3), sophoraflavonoloside (4), genistein 7,4’-di-O-β-D-glucopyransoide (5), kaempferol 3-O-α–L-rhamnopyranosyl(1→6)β-D-glucopyranosyl(1→2)β-D-glucopyranoside (6) and rutin (7). Compounds 1, 2 and 5 showed significant estrogenic proliferative effect in MCF-7 cell in sub-cytotoxic concentration range. Compounds 1 and 2 showed minimal cell membrane damaging effect using LDH leakage assay. Accordingly, compound 2 (sophoricoside, (SPH)) was selected for further in-vivo studies as a potential anti-osteoporosis agent. The anti-osteoporotic effect of SPH was assessed in ovarectomized (OVX) rats after oral administration (15 mg/kg and 30 mg/kg) for 45 days compared to estradiol (10 µg/kg) as a positive control. Only in a dose of 30 mg/kg, SPH regained the original mechanical bone hardness compared to normal non-osteoporotic group. However, SPH (15 mg/kg) significantly increased the level of alkaline phosphatase (ALP) to normal level. Treatment with SPH (30 mg/kg) increased the level of ALP to be higher than normal group. SPH (15 mg/kg) did not significantly increase the serum level of osteocalcin (OC) compared to OVX group. On the other hand, treatment with SPH (30 mg/kg) significantly increased the level of OC to 78% higher than normal non-ovarectomized animals group. In addition, SPH (15 mg/kg) decreased the bone resorption marker, acid phosphatase (ACP) to normal level and SPH (30 mg/kg) further diminished the level of serum ACP. Histopathologically, sophoricoside ameliorated the ovarectomy induced osteoporosis in a dose dependent manner. The drug showed thicker bony trabeculae, more osteoid, and more osteoblastic rimming compared to OVX group.

New xanthones and cytotoxic constituents from Garcinia mangostana fruit hulls against human hepatocellular, breast, and colorectal cancer cell lines

ETHNOPHARMACOLOGICAL RELEVANCE Cancer has proceeded to surpass one of the most chronic illnesses to be the major cause of mortality in both the developing and developed world. Garcinia mangostana L. (mangosteen, family Guttiferae) known as the queen of fruits, is one of the most popular tropical fruits. It is cultivated in Southeast Asian countries: Malaysia, Indonesia, Sri Lanka, Burma, Thailand, and Philippines. Traditionally, numerous parts of G. mangostana have been utilized to treat various ailments such as abdominal pain, haemorrhoids, food allergies, arthritis, leucorrhoea, gonorrhea, diarrhea, dysentery, wound infection, suppuration, and chronic ulcer. AIM OF STUDY Although anticancer activity has been reported for the plant, the goal of the study was designed to isolate and characterize the active metabolites from G. mangostana and measure their cytotoxic properties. In this research, the mechanism of antiproliferative/cytotoxic effects of the tested compounds was investigated. MATERIALS AND METHODS The CHCl3 fraction of the air-dried fruit hulls was repeatedly chromatographed on SiO2, RP18, Diaion HP-20, and polyamide columns to furnish fourteen compounds. The structures of these metabolites were proven by UV, IR, 1D, and 2D NMR measurements and HRESIMS. Additionally, the cytotoxic potential of all compounds was assessed against MCF-7, HCT-116, and HepG2 cell lines using SRB-U assay. Antiproliferative and cell cycle interference effects of potentially potent compounds were tested using DNA content flow cytometry. The mechanism of cell death induction was also studied using annexin-V/PI differential staining coupled with flow cytometry. RESULTS The CHCl3 soluble fraction afforded two new xanthones: mangostanaxanthones V (1) and VI (2), along with twelve known compounds: mangostanaxanthone IV (3), β-mangostin (4), garcinone E (5), α-mangostin (6), nor-mangostin (7), garcimangosone D (8), aromadendrin-8-C-β-D-glucopyranoside (9), 1,2,4,5-tetrahydroxybenzene (10), 2,4,3`-trihydroxybenzophenone-6-O-β-glucopyranoside (11), maclurin-6-O-β-D-glucopyranoside (rhodanthenone) (12), epicatechin (13), and 2,4,6,3`,5`-pentahydroxybenzophenone (14). Only compound 5 showed considerable antiproliferative/cytotoxic effects with IC50s ranging from 15.8 to 16.7µM. Compounds 3, 4, and 6 showed moderate to weak cytotoxic effects (IC50s ranged from 45.7 to 116.4µM). Using DNA content flow cytometry, it was found that only 5 induced significant cell cycle arrest at G0/G1-phase which is indicative of its antiproliferative properties. Additionally, by using annexin V-FITC/PI differential staining, 5 induced cells killing effect via the induction of apoptosis and necrosis in both HepG2 and HCT116 cells. Compound 3 produce necrosis and apoptosis only in HCT116 cells. On contrary, 6 induced apoptosis and necrosis in HepG2 cells and moderate necrosis in HCT116 cells. CONCLUSION Fourteen compounds were isolated from chloroform fraction of G. mangostana fruit hulls. Cytotoxic properties exhibited by the isolated xanthones from G. mangostana reinforce the avail of it as a natural cytotoxic agent against various cancers. These evidences could provide relevant bases for the scientific rationale of using G. mangostana in anti-cancer treatment.

Phenolics from Garcinia mangostana Inhibit Advanced Glycation Endproducts Formation: Effect on Amadori Products, Cross-Linked Structures and Protein Thiols

Accumulation of Advanced Glycation Endproducts (AGEs) in body tissues plays a major role in the development of diabetic complications. Here, the inhibitory effect of bioactive metabolites isolated from fruit hulls of Garcinia mangostana on AGE formation was investigated through bio-guided approach using aminoguanidine (AG) as a positive control. Including G. mangostana total methanol extract (GMT) in the reaction mixture of bovine serum albumin (BSA) and glucose or ribose inhibited the fluorescent and non-fluorescent AGEs formation in a dose dependent manner. The bioassay guided fractionation of GMT revealed isolation of four bioactive constituents from the bioactive fraction; which were identified as: garcimangosone D (1), aromadendrin-8-C-glucopyranoside (2), epicatechin (3), and 2,3′,4,5′,6-pentahydroxybenzophenone (4). All the tested compounds significantly inhibited fluorescent and non-fluorescent AGEs formation in a dose dependent manner whereas compound 3 (epicatechin) was found to be the most potent. In search for the level of action, addition of GMT, and compounds 2–4 inhibited fructosamine (Amadori product) and protein aggregation formation in both glucose and ribose. To explore the mechanism of action, it was found that addition of GMT and only compound (3) to reaction mixture increased protein thiol in both glucose and ribose while compounds 1, 2 and 4 only increased thiol in case of ribose. In conclusion, phenolic compounds 1–4 inhibited AGEs formation at the levels of Amadori product and protein aggregation formation through saving protein thiol.

Naturally occurring thiophenes: isolation, purification, structural elucidation, and evaluation of bioactivities

Thiophenes are a class of heterocyclic aromatic compounds based on a five-membered ring made up of one sulfur and four carbon atoms. The thiophene nucleus is well established as an interesting moiety, with numerous applications in a variety of different research areas. Naturally occurring thiophenes are characteristic secondary metabolites derived from plants belonging to the family Asteraceae, such as Tagetes,Echinops,Artemisia, Balsamorhiza,Blumea, Pluchea, Porophyllum and Eclipta. Furthermore, naturally occurring thiophenes are generally composed of one to five thiophene rings that are coupled together through their α-carbons, and carry alkyl chains on their free ortho-positions. Thiophene-containing compounds possess a wide range of biological properties, such as antimicrobial, antiviral, HIV-1 protease inhibitor, antileishmanial, nematicidal, insecticidal, phototoxic and anticancer activities. This review focuses on naturally occurring thiophene derivatives; their sources, physical and spectral data, and biological activities.

Screening for estrogenic and antiestrogenic activities of plants growing in Egypt and Thailand.

Background: There is a growing demand for the discovery of new phytoestrogens to be used as a safe and effective hormonal replacement therapy. Materials and Methods: The methanol extracts of 40 plants from the Egyptian and Thailand folk medicines were screened for their estrogen agonist and antagonist activities. The estrogenic and antiestrogenic effects of the tested extracts were carried out using the yeast two-hybrid assay system expressing ERα and ERβ. In addition, all the extracts were subjected to a naringinase treatment and retested for their estrogenic activity. Results: The methanol extracts of Derris reticulata and Dracaena lourieri showed the most potent estrogenic activity on both estrogen-receptor subtypes, while, the methanol extracts of Butea monosperma, Erythrina fusca, and Dalbergia candenatensis revealed significant estrogenic activity on ERβ only. Nigella sativa, Sophora japonica, Artabotrys harmandii, and Clitorea hanceana showed estrogenic effect only after naringinase treatment. The most potent antiestrogenic effect was revealed by Aframomum melegueta, Dalbergia candenatensis, Dracena loureiri, and Mansonia gagei.

Mangostanaxanthones III and IV: advanced glycation end-product inhibitors from the pericarp of Garcinia mangostana

Advanced glycation end-products (AGEs) are associated with a non-enzymatic reaction between the amino group of a protein and the carbonyl group of a sugar during hyperglycemia. The precipitation of AGEs in different tissues leads to many complications, such as endothelial dysfunction, cardiovascular complications, atherosclerosis, retinopathy, neuropathy, and Alzheimer’s disease. Garcinia mangostana L. (Clusiaceae) (GM) was selected owing to the ability of its polar and non-polar fractions to inhibit AGE formation. For the first time, the bioguided fractionation of its pericarp MeOH extract (GMT) gave rise to two new xanthones, namely, mangostanaxanthones III (1) and IV (3), in addition to six known compounds, β-mangostin (2), garcinone E (4), rubraxanthone (5), α-mangostin (6), garcinone C (7), and 9-hydroxycalabaxanthone (8), from the non-polar faction. Their structures were verified by various spectroscopic methods, including 1D and 2D NMR studies and high-resolution MS data. All of the isolated xanthones significantly inhibited both sugar (ribose) and dicarbonyl compound (methylglyoxal)-induced protein glycation in a dose-dependent manner. This is explained by the ability of the isolated xanthones to inhibit protein oxidation, as indicated by the decreases in dityrosine and N′-formylkynurenine formation.