C-H Bond Functionalization under Electrochemical Flow Conditions.

Electrochemical C-H functionalization is a rapidly growing area of interest in organic synthesis. To achieve maximum atom economy, the flow electrolysis process is more sustainable. This allows shorter reaction times, safer working environments, and better selectivities. Using this technology, the problem of overoxidation can be reduced and less emergence of side products or no side products are possible. Flow electro-reactors provide high surface-to-volume ratios and contain electrodes that are closely spaced where the diffusion layers overlap to give the desired product, electrochemical processes can now be managed without the need for a deliberately added supporting electrolyte. Considering the importance of flow electrochemical C-H functionalization, a comprehensive review is presented. Herein, we summarize flow electrolysis for the construction of C-C and C-X (X=O, N, S, and I) bonds formation. Also, benzylic oxidation and access to biologically active molecules are discussed.

Antioxidant, antinociceptive, anti-inflammatory, and hepatoprotective activities of pentacyclic triterpenes isolated from Ziziphus oxyphylla Edgew.

Ziziphus oxyphylla Edgew is in folk use in Pakistan as an analgesic, anti-inflammatory, and liver ailments. Therefore, we have investigated antioxidant, antinociceptive, anti-inflammatory, and hepatoprotective activities of the isolated compounds (ceanothic acid and zizybrenalic acid) from the chloroform fraction of Z. oxyphylla. Ceanothic acid and zizybrenalic acid showed significant DPPH and H2O2 scavenging activity as compared to control. In the acute toxicity study, ceanothic acid and zizybrenalic acid showed no toxic effects upto 200 mg/kg. The antinociceptive activity shown by ceanothic acid and zizybrenalic acid at 50 mg/kg was 64.28% and 65.35% compared to diclofenac sodium (72.3%) at 50 mg/kg. The percent inhibition of xylene-induced ear edema exhibited by ceanothic acid and zizybrenalic acid at 50 mg/kg was 51.33% and 58.66%, respectively, as compared to diclofenac sodium (72.66%). Both the isolated compounds exhibited inhibition of carrageenan-induced paw edema as compared to control. Hepatoprotection exhibited by zizybrenalic acid was more pronounced than ceanothic acid as observed from the decrease in carbon tetrachloride (CCl4)-induced elevation of serum biomarkers, antioxidant enzymes and lipid peroxidation. Furthermore, zizybrenalic acid produced a marked decline in CCl4-induced prolongation of phenobarbital-induced sleeping duration. Zizybrenalic acid exhibited 55.4 ± 1.37% inhibition of hypotonic solution-induced hemolysis compared to sodium salicylate (75.6 ± 2.15%). The histopathological damage caused by CCl4 was also countered by the administration of ceanothic acid and zizybrenalic acid. Ceanothic acid and zizybrenalic acid exhibited antioxidant, antinociceptive, anti-inflammatory, and hepatoprotective activities. Zizybrenalic acid exhibited better antioxidant, antinociceptive, anti-inflammatory, and hepatoprotective activity than ceanothic acid.

Potential roles of medicinal plants for the treatment of viral diseases focusing on COVID-19: A review.

The whole world is entangled by the coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), people are dying in thousands each day, and without an actual medication, it seems not possible for the bringing this global health crisis to a stop. Natural products have been in constant use since ancient times and are proven by time to be effective. Crude extract or pure compounds isolated from medicinal plants and/or herbs such as Artemisia annua, Agastache rugosa, Astragalus membranaceus, Cassia alata, Ecklonia cava, Gymnema sylvestre, Glycyrrhizae uralensis, Houttuynia cordata, Lindera aggregata, Lycoris radiata, Mollugo cerviana, Polygonum multiflorum, Pyrrosia lingua, Saposhnikoviae divaricate, Tinospora cordifolia etc. have shown promising inhibitory effect against coronavirus. Several molecules, including acacetin, amentoflavone, allicin, blancoxanthone, curcumin, daidzein, diosmin, epigallocatechin-gallate, emodin, hesperidin, herbacetin, hirsutenone, iguesterin, jubanine G, kaempferol, lycorine, pectolinarin, phloroeckol, silvestrol, tanshinone I, taxifolin, rhoifolin, xanthoangelol E, zingerol etc. isolated from plants could also be potential drug candidates against COVID-19. Moreover, these could also show promising inhibitory effects against influenza-parainfluenza viruses, respiratory syncytial virus, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome coronavirus (MERS-CoV). Here, we have reported 93 antiviral drug candidates which could be a potential area of research in drug discovery.

Chemical constituent with cytotoxicity from Sterculia diversifolia.

One new coumarin (stercularin), along with eleven known compounds, was isolated for the first time from ethyl acetate fraction of Sterculia diversifolia. The structures of isolated compounds were characterized by spectroscopic techniques such as EIMS, 1H-NMR and 13C-NMR. Compound 1 showed significant cytotoxicity by brine shrimp lethality assay (LD50: 8.00 µg/ml) and PC-3 cell lines protocol (IC50: 3.92 ± 0.20 µg/ml), respectively.

Fruits of Terminalia chebula Retz.: A review on traditional uses, bioactive chemical constituents and pharmacological activities.

Fruits of Terminalia chebula Retz. (Combretaceae) are widely used as crude drugs in various traditional medicine systems. The aim of this article is to review the available scientific information regarding the traditional uses, bioactive chemical constituents and the pharmacological activities of T. chebula. Numerous researches conducted on T. chebula have confirmed the presence of wide range of the phytochemicals such as flavonoids, tannins, phenolic acids and other bioactive compounds. T. chebula is also widely studied regarding its pharmacological activities such as antioxidant, hepatoprotective, neuroprotective, cytotoxic, antidiabetic, anti-inflammatory activities among others. However, more in vivo and clinical studies for mechanism-based pharmacological evaluation should be conducted in future to provide stronger scientific evidences for their traditional uses.

Ethyl acetate and n-butanol fraction of Cissus quadrangularis promotes the mineralization potential of murine pre-osteoblast cell line MC3T3-E1 (sub-clone 4).

In a sequel to investigate osteogenic potential of ethanolic extract of Cissus quadrangularis (CQ), the present study reports the osteoblast differentiation and mineralization potential of ethyl acetate (CQ-EA) and butanol (CQ-B) extracts of CQ on mouse pre-osteoblast cell line MC3T3-E1 (sub-clone 4) with an objective to isolate an antiosteoporotic compound. Growth curve, proliferation, and viability assays showed that both the extracts were nontoxic to the cells even at high concentration (100 µg/ml). The cell proliferation was enhanced at low concentrations (0.1 µg/ml and 1 µg/ml) of both the extracts. They also upregulated the osteoblast differentiation and mineralization processes in MC3T3-E1 cells as reflected by expression profile of osteoblast marker genes such as RUNX2, Osterix, Collagen (COL1A1), Alkaline Phosphatase (ALP), Integrin-related Bone Sialoprotein (IBSP), Osteopontin (OPN), and Osteocalcin (OCN). CQ-EA treatment resulted in early differentiation and mineralization as compared with the CQ-B treatment. These findings suggest that low concentrations of CQ-EA and CQ-B have proliferative and osteogenic properties. CQ-EA, however, is more potent osteogenic than CQ-B.

Kostchyienones A and B, new antiplasmodial and cytotoxicity of limonoids from the roots of Pseudocedrela kotschyi (Schweinf.) Harms.

Two new limonoids, kostchyienones A (1) and B (2), along with 12 known compounds 3-14 were isolated from the roots of Pseudocedrela kostchyi. Compound (7) was isolated for the first time from a natural source. Their structures were elucidated on the basis of spectroscopic evidence. Compounds 1-6 and 13-14 gave IC50 values ranging from 0.75 to 5.62 µg/mL for antiplasmodial activity against chloroquine-sensitive (Pf3D7) and chloroquine-resistant (PfINDO) strains of Plasmodium falciparum. Compound 5 showed moderate potential cytotoxicity against the HEK239T cell line with an IC50 value of 22.2±0.89 µg/mL. The antiplasmodial efficacy of the isolated compounds supports the medicinal value of this plant and its potential to provide novel antimalarial drugs.

Cytotoxic, Anti-inflammatory, and Leishmanicidal Activities of Diterpenes Isolated from the Roots of Caesalpinia pulcherrima.

A phytochemical investigation on the chloroform extract of Caesalpinia pulcherrima roots led to the isolation of ten known furanocassane diterpenoids, vouacapen-5α-ol (1), 8,9,11,14-didehydrovouacapen-5α-ol (2), 6ß-cinnamoyl-7ß-hydroxyvouacapen-5α-ol (3), pulcherrin A (4), pulcherrin B (5), pulcherrin J (6), pulcherrimin A (7), pulcherrimin B (8), pulcherrimin C (9), and pulcherrimin E (10). Chemical transformation of 3 and 7 gave compounds 6ß-hydroxyisovouacapenol C (11), 6ß-cinnamoyl-7ß-acetoxyvouacapen-5α-ol (12), and pulcherrimin D (13). Cytotoxicity of compounds 1-13 was evaluated against three cancer cell lines (MCF-7, HeLa, and PC-3). Anti-inflammatory potential of the compounds was evaluated via the oxidative burst assay using a luminol-amplified chemiluminescence technique. Leishmanicidal activity was tested against promastigotes of Leishmania major in vitro. Compounds 3, 4, 8, 9, and 10 were found active against all three cancer cell lines with IC50s ranging from 7.02 ± 0.31 to 36.49 ± 1.39 µM. Compounds 8 and 13 exhibited a potent inhibitory effect on reactive oxygen species generated from human whole blood phagocytes (IC50 = 15.30 ± 1.10 µM and 8.00 ± 0.80 µM, respectively). Compounds 3, 9, and 13 showed significant activity against promastigotes of L. major (IC50 = 65.30 ± 3.20, 58.70 ± 2.80, and 55.90 ± 2.40 µM, respectively).

Sensitive quantification of coixol, a potent insulin secretagogue, in Scoparia dulcis extract using high-performance liquid chromatography combined with tandem mass spectrometry and UV detection.

Diabetes is a major global health problem which requires new studies for its prevention and control. Scoparia dulcis, a herbal product, is widely used for treatment of diabetes. Recent studies demonstrate coixol as a potent and nontoxic insulin secretagog from S. dulcis. This study focuses on developing two quantitative methods of coixol in S. dulcis methanol-based extracts. Quantification of coixol was performed using high-performance liquid chromatography-tandem mass spectrometry (method 1) and high-performance liquid chromatography-ultraviolet detection (method 2) with limits of detection of 0.26 and 11.6 pg/µL, respectively, and limits of quantification of 0.78 and 35.5 pg/µL, respectively. S. dulcis is rich in coixol content with values of 255.5 ± 2.1 mg/kg (method 1) and 220.4 ± 2.9 mg/kg (method 2). Excellent linearity with determination coefficients >0.999 was achieved for calibration curves from 10 to 7500 ng/mL (method 1) and from 175 to 7500 ng/mL (method 2). Good accuracy (bias < -8.6%) and precision (RSD < 8.5%) were obtained for both methods. Thus, they can be employed to analyze coixol in plant extracts and herbal formulations.

Sesquiterpene lactone! a promising antioxidant, anticancer and moderate antinociceptive agent from Artemisia macrocephala jacquem.

BACKGROUND: Sesquiterpene lactones (STLs) make a diverse and huge group of bio-active constituents that have been isolated from several plant families. However, the greatest numbers are present in Asteraceae family having more than 3000 different reported structures. Recently several researchers have reported that STLs have significant antioxidant and anticancer potentials. METHODS: To investigate the antioxidant, anticancer and antinociceptive potentials of STLs, gravity column chromatography technique was used for isolation from the biologically rich chloroform fraction of Artemisia macrocephala Jacquem. The antioxidant activity of the isolated STLs was determined by DPPH and ABTS free radical scavenging activity, anticancer activity was determined on 3 T3, HeLa and MCF-7 cells by MTT assay while the antinociceptive activity was determined through acetic acid induced writhings, tail immersion method and formalin induced nociception method. RESULTS: The results showed that the STLs of Artemisia macrocephala possesses promising antioxidant activity and also it decreased the viability of 3 T3, HeLa and MCF-7 cells and mild to moderate antinociceptive activity. CONCLUSION: Sesquiterpenes lactones (STLs) are widely present in numerous genera of the family Asteraceae (compositae). They are described as the active constituents used in traditional medicine for the treatment of various diseases. The present study reveals the significant potentials of STL and may be used as an alternative for the management of cancer. Anyhow, the isolated compound is having no prominent antinociceptive potentials.

Cytotoxic effects of ergone, a compound isolated from Fulviformes fastuosus.

BACKGROUND: Mushrooms inspired the cuisines of many cultures and conventional medicaments for cancer. However, a substantial number of mushroom species are yet unexplored, possessing an unknown chemical, biological and pharmacological profiles. Fulviformes fastuosus is a terrestrial mushroom, which is commonly found in Sri Lankan woodlands. The current study was aimed at isolation and characterization of a potent cytotoxic compound from F. fastuosus and investigating the apoptotic effect induced by the active principle against cancer and normal cell lines. METHODS: Bioactivity guided isolation of active principles from the methanol extract of F. fastuosus was performed by a rapid extraction and isolation method using different chromatographic techniques. Potential cytotoxic compound was identified using one and two dimensional nuclear magnetic resonance spectroscopy and mass spectrometry. Isolated compound was screened for in vitro cytotoxicity against Hepatocellular carcinoma (HepG-2), Muscle rhabdomyosarcoma (RD) and Rat Wistar liver normal (CC-1) cell lines using 3 4, 5-(dimethylthiazol-2-yl) 2-5-diphenyl tetrazolium bromide (MTT) cell viability assay. Apoptotic features of cells were observed via microscopic examination and ethidium bromide/acridine orange fluorescent staining. RESULTS: The interpretation of spectral data resulted in the identification of the chemical structure as ergosta-4,6,8 (14),22-tetraen-3-one (ergone). Ergone exhibited promising cytotoxic properties against RD cells with less cytotoxicity effect on CC-1 cells. In addition, ergone also possesses a strong cytotoxic effect against HepG-2 cells showing low toxic level for CC-1 cells. Apoptotic features of treated cells were detected via morphological characterization and ethidium bromide/acridine orange staining. CONCLUSION: The present study elaborates the isolation of a potent cytotoxic compound; ergone, from F. fastuosus via a rapid and efficient isolation method. Importantly, ergone has exhibited greater cytotoxic activity against RD cells with high selectivity index compared to cytotoxicity against HepG-2 cells. Ergone can be used in the development of therapeutic strategies for curbing rhabdomyosarcoma.

Pharmacological screening of Monotheca buxifolia (Falc.) A. DC. for antinociceptive, anti-inflammatory and antipyretic activities.

BACKGROUND: Medicinal plants have proven their importance as a valuable source of molecules with therapeutic potential. Monotheca buxifolia (Falc.) A. DC. (family: Sapotaceae) is traditionally used as a hematinic, laxative, digestive, anthelmintic, antipyretic, and in the treatment of gastro-urinary disorders. To provide scientific evidence for its folkloric use, the present study investigated Monotheca buxifolia fruit hydro-ethanolic extract (MBHE) for its prospective antinociceptive, anti-inflammatory and antipyretic activities. MBHE was eluted through column chromatography to isolate the bioactive secondary metabolites which may probably involve in its beneficial properties. METHODS: The phytochemical constituents in MBHE was elucidated using UV, IR, (1)H-NMR, (13)C NMR, 2D-NMR spectra in combination with EIMS and FAB-MS spectrometric techniques and comparison with literature data of related compounds. The antinociceptive activity of MBHE was evaluated in the acetic acid induced abdominal constriction assay; the anti-inflammatory potential was assessed in the carrageenan induced paw edema, while the antipyretic effect was tested against brewer's yeast induced pyrexia in BALB/c mice at doses of 50, 100 and 150 mg/kg. RESULTS: Elution of MBHE along with various characterization techniques led to the isolation of oleanolic acid and isoquercetin. Significant attenuation of chemical induced nociception was observed with MBHE at tested doses of 50 mg/kg (P < 0.01, 68.87 %), 100 mg/kg (P < 0.01, 68.87 %) and 150 mg/kg (P < 0.001, 83.02 %). During a duration of 1-5 h in the carrageenan induced paw edema assay, significant ameliorative effect (P < 0.01, P < 0.001) was demonstrated by MBHE at 50 mg/kg (22.94-20 %), 100 mg/kg (33.23-21.13 %) and 150 mg/kg (38.23-25 %). MBHE also significantly alleviated the brewer's yeast induced pyrexic response when tested at doses of 50 mg/kg (P < 0.05 in 2nd h), 100 mg/kg (P < 0.05, P < 0.01 and P < 0.001 in 1-5 h) and 150 mg/kg (P < 0.01 and P < 0.001 in 1-5 h). CONCLUSION: These findings suggest that Monotheca buxifolia possess pain, inflammation and pyrexia ameliorating properties, probably mediated by the presence of oleanolic acid and isoquercetin contents, though the involvement of other important phytochemicals constituents cannot be ignored.

Beneficial Effects of Trillium govanianum Rhizomes in Pain and Inflammation.

Trillium govanianum rhizome is used as an analgesic and anti-inflammatory remedy in traditional medicine in northern Pakistan. In an attempt to establish its medicinal value, the present research evaluated the analgesic and anti-inflammatory potential of T. govanianum. The in vivo anti-inflammatory activity of extract and fractions was investigated in the carrageenan induced paw edema assay. The in vitro suppression of oxidative burst of extract, fractions and isolated compounds was assessed through luminol-enhanced chemiluminescence assay. The in vivo analgesic activity was assayed in chemical and thermal induced nociceptive pain models. The crude methanol extract and its solvent fractions showed anti-inflammatory and analgesic responses, exhibited by significant amelioration of paw edema and relieve of the tonic visceral chemical and acute phasic thermal nociception. In the oxidative burst assay, based on IC50, the crude methanol extract and n-butanol soluble fraction produced a significant inhibition, followed by chloroform and hexane soluble fractions as compared to ibuprofen. Similarly, the isolated compounds pennogenin and borassoside E exhibited significant level of oxidative burst suppressive activity. The in vivo anti-inflammatory and analgesic activities as well as the in vitro inhibition of oxidative burst validated the traditional use of T. govanianum rhizomes as a phytotherapeutic remedy for both inflammatory conditions and pain. The observed activities might be attributed to the presence of steroids and steroid-based compounds. Therefore, the rhizomes of this plant species could serve as potential novel source of compounds effective for alleviating pain and inflammation.

Potent Insulin Secretagogue from Scoparia dulcis Linn of Nepalese Origin.

Ethno-botanical inspired isolation from plant Scoparia dulcis Linn. (Sweet Broomweed) yielded six compounds, coixol (1), glutinol (2), glutinone (3), friedelin (4), betulinic acid (5), and tetratriacontan-1-ol (6). There structures were identified using mass and 1D- and 2D-NMR spectroscopy techniques. Compounds 1-6 were evaluated for their insulin secretory activity on isolated mice islets and MIN-6 pancreatic ß-cell line, and compounds 1 and 2 were found to be potent and mildly active, respectively. Compound 1 was further evaluated for insulin secretory activity on MIN-6 cells. Compound 1 was subjected to in vitro cytotoxicity assay against MIN-6, 3T3 cell lines, and islet cells, and in vivo acute toxicity test in mice that was found to be non-toxic. The insulin secretory activity of compounds 1 and 2 supported the ethno-botanic uses of S. dulcis as an anti-diabetic agent.

A new urease inhibitor from Viola betonicifolia.

Urease has attracted much attention, as it is directly involved in the formation of infection stones and contributes to the pathogenesis of urolithiasis, pyelonephritis, ammonia and hepatic encephalopathy, hepatic coma and urinary catheter encrustation. Moreover, urease is the major cause of pathologies induced by H. pylori, such as gastritis and peptic ulcer. In the present work, the new natural compound, 3-methoxydalbergione, was isolated from Viola betonicifolia. A mechanistic study of this compound as a natural urease inhibitor was performed by using enzyme kinetics and docking studies. 3-Methoxydalbergione could be considered as a lead molecule for drugs useful in the urease associated diseases.

Leishmanicidal evaluation of tetrahydroprotoberberine and spirocyclic erythrina-alkaloids.

Leishmaniasis is one of the World's most problematic diseases in developing countries. Traditional medicines to treat leishmaniasis have serious side effects, as well as significant parasite resistance problems. In this work, two alkaloids 1 and 2 were obtained from Corydalis govaniana Wall and seven alkaloids 3-9, were obtained from Erythrina verna. The structures of the compounds were confirmed by mass spectrometry and 1D- and 2D-NMR spectroscopy. The leishmanicidal activity of compounds 1-9 against Leishmania amazonensis was tested on promastigote forms and cytotoxicity against J774 (macrophage cell line) was assessed in vitro. Compound 1 showed potent activity (IC50 = 0.18 µg/mL), compared with the standard amphotericin B (IC50 = 0.20 µg/mL). The spirocyclic erythrina-alkaloids showed lower leishmanicidal activity than dibenzoquinolizine type alkaloids.

Himalayan lichen biomass for green synthesis of silver nanocolloids: growth kinetics, effect of pH and metal sensing.

Lichen is one of the most abundant non-vascular biomasses; however, a systematic study on the application of biomass in nanomaterial synthesis is very limited. In this study, an aqueous lichen extract was obtained from Hypotrachyna cirrhata, one of the most abundant Himalayan lichen biomasses, using a simple cold percolation method. The effects of extract-to-silver nitrate mixing ratio, pH and waiting time on the growth and stability of nanoparticles were systematically explored. The rate constant for bio-reduction was found to be 5.3 × 10-3 min-1. Transmission electron microscopy showed a narrow particle size distribution with a mean particle size of 11.1 ± 3.6 nm (n = 200). The X-ray diffraction and selected area electron diffraction techniques confirmed the formation of cubic crystals. The synthesized colloidal solution showed excellent response to Hg2+ and Cu2+ ions in spiked water samples. The limit of detection and calibration sensitivity for Hg2+ and Cu2+ ions were found to be 1 and 5 mg l-1 and 2.9 × 10-3 and 1.6 × 10-3 units ppm-1, respectively. These findings suggested that spherical silver nanoparticles with a narrow particle size distribution can be synthesized on a laboratory scale using an aqueous H. cirrhata lichen extract, and the colloidal solution can be used for the detection of selected heavy metals in water samples.

Antimicrobial screening of pecan shell extract and efficacy of pecan shell extract-pullulan coating against Listeria monocytogenes, Salmonella enterica, and Staphylococcus aureus on blueberries.

Pecan shell is considered an agricultural waste; however, it contains various bioactive compounds with potential inhibitory effect against microorganisms. This study evaluated the antimicrobial efficacy of pecan shell extract (PSE) in vitro using disc-diffusion method and in vivo on blueberries as an antimicrobial coating using pullulan. For in vitro study, 5 and 10 % of aqueous (A-PSE) or ethanol pecan shell extract (E-PSE) incorporated into pullulan film were tested against different bacterial and fungal strains. Pullulan film disc was used as control. The diameter of growth inhibition (mm) around discs was measured. For in vivo study, PSE-P (5 % w/v aqueous pecan shell extract+5 % w/v pullulan), P (5 % w/v pullulan) or control (water) were spray coated on blueberries inoculated (∼5 log CFU/g) with Listeria monocytogenes, Salmonella enterica or Staphylococcus aureus; and stored at 4 °C, 50 ± 10 % RH for 15 days. The effect of antimicrobial coating against pathogens and its impact on quality during storage were determined. A-PSE and E-PSE films were more effective against Gram-positive bacteria and showed no antifungal effect at tested concentrations when evaluated in vitro. Immediately after coating on blueberries, PSE-P significantly reduced Listeria monocytogenes by 2 log CFU/g and lowered survival until day 5 than control or P. Native aerobic microbial population was reduced (P < 0.05) by 0.7 log CFU/g immediately after coating. PSE-P coating or storage time had no significant effect (P > 0.05) on the survival of S. enterica, S. aureus and native fungal population. PSE-P maintained the firmness of blueberry with no significant effect on its color, TSS, and pH during 15 days storage. PSE-P significantly reduced (P < 0.05) the spoilage rate by 21 % than control (28.5 %) and P (37 %); and minimized (P < 0.05) weight loss during storage. Pecan shell extracts show promise as a potential antimicrobial compound whose application on various food products or packaging material could be further explored.

In silico identification and in vitro validation of alpha-hederin as a potent inhibitor of Wnt/ß-catenin signaling pathway in breast cancer stem cells.

Cancer stem cells (CSCs) play a vital role in metastasis, recurrence and chemoresistance in breast cancer. ß-catenin, which is a frequently over activated protein in CSCs, binds to T-cell factor/lymphoid enhancer factor (Tcf/Lef) family transcription factors leading to ectopic expression of Wnt pathway responsive genes necessary for the maintenance and action of CSCs. With the aim of identifying a small molecules that can effectively eliminate CSCs, molecular docking studies were performed against the Tcf/Lef binding hotspot on ß-catenin using a library of 100 natural or synthetic small molecules. Small molecule ligands giving docking energy better than - 7 kcal/mol were further investigated by binding interactions analysis and molecular dynamics (MD) simulations. These compounds were then investigated in vitro, for cytotoxicity against CSCs isolated from MDA-MB-231 triple negative breast cancer cells. Alpha-hederin (AH) was identified as the only compound in the selected library that has cytotoxicity against breast CSCs. AH was further investigated for it's ability to regulate Wnt pathway target genes (Cyclin D1 and CD44)and the tumor suppressor p53by real-time quantitative PCR. Absorption, distribution, metabolism, excretion and toxicity properties of the AH was predicted in silico. AH significantly down regulated the transcription of Cyclin D1 and CD44 while up-regulating the transcription of p53. AH was predicted to have acceptable drug likeness. Although AH is currently known to inhibit the growth of various cancer cells in vitro, present study demonstrated for the first time that it is a potent inhibitor of Wnt/ß-catenin signaling pathway and induce apoptosis in breast CSCs.

Isolation of a new bioactive cinnamic acid derivative from the whole plant of Viola betonicifolia.

A new cinnamic acid derivative was isolated from the whole plant of Viola betonicifolia as off white needle. On the basis of various modern spectroscopic techniques including HREI-MS and 1D and 2D NMR, its structure was elucidated as 2,4-dihydroxy, 5-methoxy-cinnamic acid. It showed marked inhibition against DPPH (diphenyl-2-picryl hydrazyl) free radicals with IC50 = 124 ± 5.76 µM. The antioxidant property of the compound was compared with α-tocopherole and vitamin C having IC50 values 96 ± 0.46 and 90 ± 0.56 µM, respectively. In case of antiglycation assay, the compound exhibited moderate activity (IC50 = 355 ± 7.56 µM) similar to standard compound, rutin (IC50 = 294 ± 0.56 µM). However, it was non-toxic to PC-3 cell line. It is concluded that 2,4-dihydroxy, 5-methoxy-cinnamic acid has antiglycation potential which was further augmented by its antioxidant activity and thus offered an ideal natural therapeutic option for the effective management of diabetes.