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1.
Org Biomol Chem ; 20(44): 8584-8598, 2022 11 16.
Article in English | MEDLINE | ID: mdl-36326294

ABSTRACT

Chlorophyll, the principal photoacceptor of green plants, plays a pivotal role in photosynthesis. In the recent past, chlorophyll has also been utilized as an efficient organo-photocatalyst in several organic syntheses. The inexpensive, ubiquitous nature of chlorophyll endorses it as an appealing green alternative to transition metal photocatalysts. This review is the first attempt to showcase and analyze the photocatalytic activity of chlorophyll in effecting different organic transformations. We intend to provide a holistic overview of the role of chlorophyll starting from photosynthesis to its contemporary synthetic applications in visible light photocatalysis. In addition, the photophysical and electrochemical properties of chlorophyll are elaborated to attain a clearer understanding of its mode of action as a visible light photocatalyst.


Subject(s)
Chlorophyll , Transition Elements , Catalysis , Light , Transition Elements/chemistry , Chemistry Techniques, Synthetic
2.
Org Biomol Chem ; 19(43): 9433-9438, 2021 11 10.
Article in English | MEDLINE | ID: mdl-34676851

ABSTRACT

Photocatalytic syntheses of quinoline-2(1H)-ones, isoquinoline-1(2H)-ones and 1,2,4-trioxanes were achieved by selective photo-induced electron transfer (PET) and energy transfer (EnT), respectively, by chlorophyll under visible light irradiation. Quinoline-2(1H)-ones, isoquinoline-1(2H)-ones and 1,2,4-trioxanes are biologically potent scaffolds and their syntheses following mild reaction protocols are highly sought after. This work showcases the divergent photocatalytic roles of chlorophyll viz., electron transfer in the case of quinolines or isoquinolines and energy transfer with allyl alcohols as substrates, affording their aerobic oxidation under green reaction conditions. The mechanistic investigations affirm that the catalytic cycle follows the electron-transfer pathway in carrying out the oxidation of N-alkyl(iso)quinolinium salts. Furthermore, the method provides an environmentally benign, simple reaction strategy for organic transformations of (N)-heterocycles.


Subject(s)
Quinolines
3.
Eur J Med Chem ; 167: 226-244, 2019 Apr 01.
Article in English | MEDLINE | ID: mdl-30772606

ABSTRACT

A series of new pyranocarbazole derivatives were synthesized via semi-synthetic modification of koenimbine (1a) and koenidine (1b) isolated from the leaves of Murraya koenigii. Among all, compound 3bg displayed significant anti-cancer activity against MDA-MB-231, DU145 and PC3 cell lines with the IC50 values of 3.8, 7.6 and 5.8 µM, respectively. It was also observed that the halogenated-benzyl substitution at N-9 position, C-3 Methyl and C-7 methoxy group on carbazole motif are favoured for anti-cancer activity. The detailed investigation was carried out with compound 3bg and its SEDDS (self-emulsifying drug delivery systems) formulation 3bgF. The in vivo drug release behavior study showed that the formulation enhanced slow release and better bioavailability at a tumor site. Compound 3bg and its formulation (3bgF) significantly inhibited cell proliferation and colony formation, induced G2/M arrest, reduced cellular ROS generation and induced caspase-dependent apoptosis in MDA-MB-231 cells. 3bg also induced significant alteration of Bax/Bcl expression ratio suggesting involvement of mitochondrial apoptosis. Additionally, 3bg caused down-regulation of mTOR/Akt survival pathway. 3bg do not bind to DNA, but interacts with tubulin as observed with in silico molecular docking studies. This interaction results in stabilization of tubulin polymerization similar to paclitaxel as detected in cell-free assay. Oral administration of 3bgF for 30 days at dose rate of 10 and 20 mg/kg body weight significantly reduced tumor growth in syngenic rat LA-7 mammary tumor model. These results indicated that the pyranocarbazole natural product based N-substituted analogues can act as potential anti-cancer lead.


Subject(s)
Antineoplastic Agents/chemical synthesis , Breast Neoplasms/drug therapy , Carbazoles/chemistry , Pyrans/chemistry , Tubulin/metabolism , Animals , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Carbazoles/pharmacology , Caspases , Cell Line, Tumor , Down-Regulation/genetics , Humans , Inhibitory Concentration 50 , PC-3 Cells , Polymerization , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Pyrans/pharmacology , Rats , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism
4.
Biomed Pharmacother ; 93: 510-521, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28675857

ABSTRACT

In recent years, many alkaloids of plant origin have attracted great attention due to their diverse range of biological properties including anti-hyperglycemic, anti-oxidant, anti-inflammatory, anti-diabetic and anti-tumor activity. Herein, the pyranocarbazole alkaloids were isolated from leaves of Murraya koenigii and their anti-cancer potential was investigated in different cancer cell lines. Among all tested compounds, murrayazoline and O-methylmurrayamine A demonstrated potent anti-cancer activity against DLD-1 colon cancer cells with the IC50 values of 5.7µM and 17.9µM, respectively, without any non-specific cytotoxicity against non-cancer HEK-293 and HaCaT cells. Further, studies of pure compounds revealed that the anti-cancer activity of compounds corresponds with altered cellular morphology, cell cycle arrest in G2/M phase, reactive oxygen species level and mitochondrial membrane depolarization of colon cancer cells. In addition, these compounds activated caspase-3 protein and upregulated Bax/Bcl-2 protein expression ratio leading to induction of caspase-dependent apoptosis in DLD-1 cells. These event induced by carbazole alkaloids also coincides with downregulation of Akt/mTOR suggesting downstream targeting of cell survival pathway. Thus, our in vitro studies not only provided scientific basis of the use of M. koenigii leaves in the traditional Indian Ayurveda medicines, but also expands possibilities of medicinal uses of M. koenigii leaves against colon cancer. Particularly, these findings will help in further investigating murrayazoline and O-methylmurrayamine A or their improvised derivatives as new therapeutics for the treatment of colon cancer.


Subject(s)
Apoptosis , Carbazoles/therapeutic use , Colonic Neoplasms/drug therapy , Down-Regulation , Mitochondria/metabolism , Murraya/chemistry , Plant Leaves/chemistry , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Carbazoles/chemistry , Carbazoles/pharmacology , Caspases/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Shape/drug effects , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Down-Regulation/drug effects , Humans , Intracellular Space/metabolism , Membrane Potential, Mitochondrial/drug effects , Mitochondria/drug effects , Phosphorylation/drug effects , Proliferating Cell Nuclear Antigen/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Reactive Oxygen Species/metabolism , TOR Serine-Threonine Kinases/metabolism
5.
J Med Chem ; 60(3): 1041-1059, 2017 02 09.
Article in English | MEDLINE | ID: mdl-28059524

ABSTRACT

A series of pyrazolo(dihydro)pyridines was synthesized and evaluated for antileishmanial efficacy against experimental visceral leishmaniasis (VL). Among all compounds, 6d and 6j exhibited better activity than miltefosine against intracellular amastigotes. Compound 6j (50 mg/kg/day) was further studied against Leishmania donovani/BALB/c mice via the intraperitoneal route for 5 days and displayed >91 and >93% clearance of splenic and liver parasitic burden, respectively. Combination treatment of 6j with a subcurative dose of miltefosine (5 mg/kg) in BALB/c mice almost completely ameliorated the disease (>97% inhibition) by augmenting nitric oxide generation and shifting the immune response toward Th1. Furthermore, investigating the effect of 6j on Leishmania promastigotes revealed that it induced molecular events, such as a loss in mitochondrial membrane potential, externalization of phosphatidylserine, and DNA fragmentation, that ultimately resulted in the programmed cell death of the parasite. These results along with pharmacokinetic studies suggest that 6j could be a promising lead for treating VL as an adjunct therapy with miltefosine.


Subject(s)
Antiprotozoal Agents/pharmacology , Leishmania/drug effects , Phosphorylcholine/analogs & derivatives , Pyrazoles/pharmacology , Pyridines/pharmacology , Animals , Antiprotozoal Agents/pharmacokinetics , Antiprotozoal Agents/therapeutic use , Mice , Mice, Inbred BALB C , Phosphorylcholine/pharmacokinetics , Phosphorylcholine/therapeutic use , Pyrazoles/pharmacokinetics , Pyrazoles/therapeutic use , Pyridines/pharmacokinetics , Pyridines/therapeutic use
6.
Org Biomol Chem ; 15(5): 1080-1085, 2017 Feb 01.
Article in English | MEDLINE | ID: mdl-28067392

ABSTRACT

An efficient one pot method for the synthesis of anti-α,ß-epoxy ketones from 1-(2-methyl-4-phenylquinolin-3-yl)ethanone and ethanol has been developed by a modified Darzen reaction. The reaction occurs under oxidative conditions via a cascade sequence of bromination, aldol condensation followed by substitution. The reaction in the presence of NBS and a base however, in the absence of an oxidant, led to the formation of the corresponding 3-hydroxylated product via an unusual rearrangement.

7.
J Org Chem ; 81(17): 7626-34, 2016 09 02.
Article in English | MEDLINE | ID: mdl-27487477

ABSTRACT

In the past decade, metal-free approaches for C-C bond formation have attracted a great deal of attention due to their ease of use and low cost. This report represents a novel and metal-free synthesis of 3,3'-bisimidazopyridinylmethanes via intermolecular oxidative C(sp(2))-H bond functionalization of imidazo[1,2-a]pyridines with dimethyl sulfoxide as the carbon synthon (CH2) using H2O2 as a mild oxidant under air. A library of 3,3'-bis(2-arylimidazo[1,2-a]pyridin-3-yl)methanes has been achieved in good to excellent yields. The present methodology has been successfully applied to imidazo[2,1-b]thiazoles and imidazo[2,1-b]benzothiazoles. Furthermore, the current approach was also extended for the synthesis of unsymmetrical 3,3'-bisimidazopyridinylmethanes under optimized reaction conditions. A mechanistic pathway is proposed on the basis of experiments with radical scavengers and DMSO-d6 and ESI-MS observations.

8.
J Nat Prod ; 79(5): 1276-84, 2016 05 27.
Article in English | MEDLINE | ID: mdl-27136692

ABSTRACT

This study identified koenidine (4) as a metabolically stable antidiabetic compound, when evaluated in a rodent type 2 model (leptin receptor-deficient db/db mice), and showed a considerable reduction in the postprandial blood glucose profile with an improvement in insulin sensitivity. Biological studies were directed from the preliminary in vitro evaluation of the effects of isolated carbazole alkaloids (1-6) on glucose uptake and GLUT4 translocation in L6-GLUT4myc myotubes, followed by an investigation of their activity (2-5) in streptozotocin-induced diabetic rats. The effect of koenidine (4) on GLUT4 translocation was mediated by the AKT-dependent signaling pathway in L6-GLUT4myc myotubes. Moreover, in vivo pharmacokinetic studies of compounds 2 and 4 clearly showed that compound 4 was 2.7 times more bioavailable than compound 2, resulting in a superior in vivo efficacy. Therefore, these studies suggested that koenidine (4) may serve as a promising lead natural scaffold for managing insulin resistance and diabetes.


Subject(s)
Carbazoles/isolation & purification , Carbazoles/pharmacology , Hypoglycemic Agents/isolation & purification , Hypoglycemic Agents/pharmacology , Murraya/chemistry , Alkaloids/pharmacology , Animals , Blood Glucose/metabolism , Carbazoles/chemistry , Diabetes Mellitus, Experimental/metabolism , Glucose/metabolism , Glucose Transporter Type 4/metabolism , Hypoglycemic Agents/chemistry , Insulin/pharmacology , Insulin Resistance , Male , Mice , Molecular Structure , Muscle Fibers, Skeletal/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Rats , Signal Transduction/drug effects , Streptozocin/pharmacology
9.
J Org Chem ; 80(24): 12410-9, 2015 Dec 18.
Article in English | MEDLINE | ID: mdl-26565748

ABSTRACT

A phenyliodine(III) diacetate (PIDA)-mediated, highly efficient and tandem approach for the synthesis of aryldiazenylisoxazolo(isothiazolo)arenes from simple 2-amino-N'-arylbenzohydrazides has been developed. The reaction proceeds via formation of (E)-(2-aminoaryl)(aryldiazenyl)methanone as the key intermediate, followed by intramolecular oxidative O-N/S-N bond formation in one pot at room temperature. The quiet different reactivity of the substrate is due to the formation of a diazo intermediate which encounters a nucleophilic attack by carbonyl oxygen on the electrophilic amine to produce isoxazole products, as compared to the previous reportsa,b,4 in which an N-acylnitrenium ion intermediate is intramolecularly trapped by an amine group.

10.
J Org Chem ; 80(10): 5369-76, 2015 May 15.
Article in English | MEDLINE | ID: mdl-25897680

ABSTRACT

A transition-metal-free C-3-arylation of quinolin-4-ones in the presence of base has been achieved by using arylhydrazines as aryl radical source and air as oxidant. The reaction proceeds smoothly at room temperature and does not require any prefunctionalization and N-protection of quinoline-4-ones. The utility of this methodology is further demonstrated in synthesis of quinoline-quinolone hybrid as well as 6-aryl-benzofuro[3,2-c]quinoline scaffold.


Subject(s)
Hydrazines/chemistry , Metals/chemistry , Quinolones/chemistry , Quinolones/chemical synthesis , Transition Elements/chemistry , Catalysis , Molecular Structure
11.
J Sci Food Agric ; 94(11): 2282-8, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24395372

ABSTRACT

BACKGROUND: Murraya koenigii (L.) Spreng. is an important medicinal plant used traditionally as an antiemetic, antidiarrhoeal agent and blood purifier and as a medicine for a variety of ailments. This study investigated the effects of ethanolic extract of M. koenigii (MK) on diabetes-associated insulin resistance induced in mice by chronic low-dose injection of dexamethasone. RESULTS: Mice treated with dexamethasone exhibited hyperglycaemia and impaired glucose tolerance. Treatment with MK reduced the extent of dexamethasone-induced hyperglycaemia and decreased insulin resistance as indicated by improved glucose tolerance and increased insulin-stimulated AKT phosphorylation in skeletal muscle tissue. Further evaluation in clonal skeletal muscle cell lines suggested that MK increased glucose uptake in L6 skeletal muscle cells by increasing cell surface GLUT4 density via an AKT-mediated pathway. CONCLUSION: MK can ameliorate dexamethasone-induced hyperglycaemia and insulin resistance in part by increasing glucose disposal into skeletal muscle.


Subject(s)
Blood Glucose/metabolism , Glucose Intolerance/drug therapy , Hyperglycemia/drug therapy , Insulin Resistance , Murraya , Muscle Fibers, Skeletal/drug effects , Phytotherapy , Animals , Dexamethasone , Glucose Intolerance/blood , Glucose Intolerance/chemically induced , Glucose Transporter Type 4/metabolism , Hyperglycemia/blood , Hyperglycemia/chemically induced , Insulin/blood , Male , Mice , Muscle Fibers, Skeletal/metabolism , Phosphorylation , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Plant Leaves , Proto-Oncogene Proteins c-akt/metabolism
12.
Phytomedicine ; 21(4): 406-14, 2014 Mar 15.
Article in English | MEDLINE | ID: mdl-24252344

ABSTRACT

Obesity is a result of adipocyte hypertrophy followed by hyperplasia. It is a risk factor for several metabolic disorders such as dyslipidemia, type-2 diabetes, hypertension, and cardiovascular diseases. Coagulanolides, particularly coagulin-L isolated from W. coagulan has earlier been reported for anti-hyperglycemic activity. In this study, we investigated the effect of coagulin-L on in vitro models of adipocyte differentiation including 3T3-L1 pre-adipocyte, mouse stromal mesenchymal C3H10T1/2 cells and bone marrow derived human mesenchymal stem cells (hMSCs). Our results showed that, coagulin-L reduces the expressions of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), the major transcription factors orchestrating adipocyte differentiation. Detailed analysis further proved that early exposure of coagulin-L is sufficient to cause significant inhibition during adipogenesis. Coagulin-L inhibited mitotic clonal expansion (MCE) by delayed entry in G1 to S phase transition and S-phase arrest. This MCE blockade was caused apparently by decreased phosphorylation of C/EBPß, modulation in expression of cell cycle regulatory proteins, and upregulation of Wnt/ß-catenin pathway, the early stage regulatory proteins of adipogenic induction. Taken together all evidences, a known anti-hyperglycemic agent coagulin-L has shown potential to inhibit adipogenesis significantly, which can be therapeutically exploited for treatment of obesity and metabolic syndrome.


Subject(s)
Adipogenesis/drug effects , CCAAT-Enhancer-Binding Protein-alpha/antagonists & inhibitors , TOR Serine-Threonine Kinases/antagonists & inhibitors , Withania , Withanolides/pharmacology , 3T3-L1 Cells , Animals , Cyclin-Dependent Kinase Inhibitor p27/metabolism , Humans , Mice , Mitosis/drug effects , Obesity/drug therapy , PPAR gamma/antagonists & inhibitors , Phytotherapy , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Stem Cells/drug effects , Withanolides/therapeutic use , Wnt Proteins/metabolism , beta Catenin/metabolism
13.
ACS Med Chem Lett ; 4(2): 165-9, 2013 Feb 14.
Article in English | MEDLINE | ID: mdl-24900640

ABSTRACT

Novel 3,3-spiroanellated 5-aryl, 6-arylvinyl-substituted 1,2,4-trioxanes 19-34 have been synthesized and appraised for their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice by oral route at doses ranging from 96 mg/kg × 4 days to 24 mg/kg × 4 days. The most active compound of the series (compound 25) provided 100% protection at 24 mg/kg × 4 days, and other 1,2,4-trioxanes 22, 26, 27, and 30 also showed promising activity. In this model, ß-arteether provided 100 and 20% protection at 48 mg/kg × 4 days and 24 mg/kg × 4 days, respectively, by oral route. Compound 25 displayed a similar in vitro pharmacokinetic profile to that of reference drug ß-arteether. The activity results demonstrated the importance of an aryl moiety at the C-5 position on the 1,2,4-trioxane pharmacophore.

14.
J Ethnopharmacol ; 142(1): 72-9, 2012 Jun 26.
Article in English | MEDLINE | ID: mdl-22855944

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Wrightia tomentosa Roem. & Schult. (Apocynaceae) is known in the traditional medicine for anti-cancer activity along with other broad indications like snake and scorpion bites, renal complications, menstrual disorders etc. However, the anti-cancer activity of this plant or its constituents has never been studied systematically in any cancer types so far. AIM OF THE STUDY: To evaluate the anti-cancer activities of the ethanolic extract of W. tomentosa and identified constituent active molecule(s) against breast cancer. MATERIAL AND METHODS: Powdered leaves of W. tomentosa were extracted with ethanol. The ethanolic extract, subsequent hexane fractions and fraction F-4 of W. tomentosa were tested for its anti-proliferative and pro-apoptotic effects in breast cancer cells MCF-7 and MDA-MB-231. RESULTS: The ethanolic extract, subsequent hexane fractions and fraction F-4 of W. tomentosa inhibited the proliferation of human breast cancer cell lines, MCF-7 and MDA-MB-231. The fraction F-4 obtained from hexane fraction inhibited proliferation of MCF-7 and MDA-MB-231 cells in concentration and time dependent manner with IC50 of 50 µg/ml and 30 µg/ml for 24 h, 28 µg/ml and 22 µg/ml for 48 h and 25 µg/ml and 20 µg/ml for 72 h respectively. The fraction F-4 induced G1 cell cycle arrest, reactive oxygen species (ROS) generation, loss of mitochondrial membrane potential and subsequent apoptosis. Apoptosis is indicated in terms of increased Bax/Bcl-2 ratio, enhanced Annexin-V positivity, caspase 8 activation and DNA fragmentation. The active molecule isolated from fraction F-4, oleanolic acid and urosolic acid inhibited cell proliferation of MCF-7 and MDA-MB-231 cells at IC50 value of 7.5 µM and 7.0 µM respectively, whereas there is devoid of significant cell inhibiting activity in non-cancer originated cells, HEK-293. In both MCF-7 and MDA-MB-231, oleanolic acid and urosolic acid induced cell cycle arrest and apoptosis as indicated by significant increase in Annexin-V positive apoptotic cell counts. CONCLUSION: Our results suggest that W. tomentosa extracts has significant anti-cancer activity against breast cancer cells due to induction of apoptosis pathway. Olenolic and urosolic acid are important constituent molecules in the extract responsible for anti-cancer activity of W. tomentosa.


Subject(s)
Antineoplastic Agents/pharmacology , Apocynaceae , Oleanolic Acid/pharmacology , Plant Extracts/pharmacology , Triterpenes/pharmacology , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Ethanol/chemistry , HEK293 Cells , Humans , L-Lactate Dehydrogenase/metabolism , Plant Leaves , Solvents/chemistry , Ursolic Acid
15.
Phytomedicine ; 19(8-9): 682-5, 2012 Jun 15.
Article in English | MEDLINE | ID: mdl-22541636

ABSTRACT

The ethanolic extract and fractions of Wrightia tomentosa Roem. & Schult (Apocynaceae) leaves were tested in vivo for their antidyslipidemic activity in high fat diet (HFD) induced dyslipidemic hamsters. Activity guided isolation resulted in identification of antidyslipidemic compounds ß-AA and ß-AP. Compounds ß-AA and ß-AP decrease the levels of LDL by 36% and 44%, and increase the HDL-C/TC ratio by 49% and 28%, respectively, at a dose of 10mg/kg. In addition, the isolated compounds ß-AA and ß-AP showed significant HMG-CoA-reductase inhibition, which was further established by docking studies.


Subject(s)
Apocynaceae/chemistry , Dyslipidemias/drug therapy , Hypolipidemic Agents/pharmacology , Oleanolic Acid/analogs & derivatives , Animals , Cholesterol/blood , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Cricetinae , Diet, High-Fat/adverse effects , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Dyslipidemias/etiology , Dyslipidemias/metabolism , Hydroxymethylglutaryl CoA Reductases/chemistry , Hydroxymethylglutaryl CoA Reductases/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Male , Mesocricetus , Models, Molecular , Molecular Structure , Oleanolic Acid/chemistry , Oleanolic Acid/pharmacology , Plant Leaves/chemistry , Plants, Medicinal/chemistry
16.
Fitoterapia ; 83(2): 272-80, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22179036

ABSTRACT

The natural Cassane and norcassane diterpenes are biosynthetic rearrangement products of Pimarane precursor in the biosynthetic pathway of diterpenes. Their distribution is highly restricted to various genera of Fabaceae family (especially to Caesalpinia genus). A comprehensive account of the structural diversity (322 structures, 114 references) is given in this review along with biological activities of cassane and norcassane diterpenes up to September 2011.


Subject(s)
Diterpenes/chemistry , Diterpenes/pharmacology , Fabaceae/chemistry , Abietanes/metabolism , Caesalpinia/chemistry , Diterpenes/metabolism , Plants, Medicinal/chemistry
17.
Eur J Pharmacol ; 670(1): 22-8, 2011 Nov 16.
Article in English | MEDLINE | ID: mdl-21939653

ABSTRACT

Insulin-stimulated glucose uptake in skeletal muscle is decreased in type 2 diabetes due to impaired translocation of insulin-sensitive glucose transporter 4 (GLUT4) from intracellular pool to plasma membrane. Augmenting glucose uptake into this tissue may help in management of type 2 diabetes. Here, the effects of an identified antihyperglycemic molecule, karanjin, isolated from the fruits of Pongamia pinnata were investigated on glucose uptake and GLUT4 translocation in skeletal muscle cells. Treatment of L6-GLUT4myc myotubes with karanjin caused a substantial increase in the glucose uptake and GLUT4 translocation to the cell surface, in a concentration-dependent fashion, without changing the total amount of GLUT4 protein and GLUT4 mRNA. This effect was associated with increased activity of AMP-activated protein kinase (AMPK). Cycloheximide treatment inhibited the effect of karanjin on GLUT4 translocation suggesting the requirement of de novo synthesis of protein. Karanjin-induced GLUT4 translocation was further enhanced with insulin and the effect is completely protected in the presence of wortmannin. Moreover, karanjin did not affect the phosphorylation of AKT (Ser-473) and did not alter the expression of the key molecules of insulin signaling cascade. We conclude that karanjin-induced increase in glucose uptake in L6 myotubes is the result of an increased translocation of GLUT4 to plasma membrane associated with activation of AMPK pathway, in a PI-3-K/AKT-independent manner.


Subject(s)
Benzopyrans/pharmacology , Glucose Transporter Type 4/metabolism , Millettia/chemistry , Muscle, Skeletal/cytology , Muscle, Skeletal/drug effects , Phosphatidylinositol 3-Kinase/metabolism , AMP-Activated Protein Kinases/metabolism , Androstadienes/pharmacology , Animals , Cell Membrane/drug effects , Cell Membrane/metabolism , Cycloheximide/pharmacology , Deoxyglucose/metabolism , Enzyme Activation/drug effects , Gene Expression Regulation/drug effects , Glucose Transporter Type 4/chemistry , Glucose Transporter Type 4/genetics , Insulin/pharmacology , Muscle Fibers, Skeletal/cytology , Muscle Fibers, Skeletal/drug effects , Muscle Fibers, Skeletal/metabolism , Muscle, Skeletal/enzymology , Muscle, Skeletal/metabolism , Phosphorylation/drug effects , Protein Transport/drug effects , Protein Tyrosine Phosphatases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Wortmannin
18.
Phytother Res ; 25(10): 1558-63, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21698670

ABSTRACT

The anticancer potential of Xylopia aethiopica fruit extract (XAFE), and the mechanism of cell death it elicits, was investigated in various cell lines. Treatment with XAFE led to a dose-dependent growth inhibition in most cell lines, with selective cytotoxicity towards cancer cells and particularly the human cervical cancer cell line C-33A. In this study, apoptosis was confirmed by nuclear fragmentation and sub-G(0)/G(1) phase accumulation. The cell cycle was arrested at the G(2)/M phase with a decreased G(0)/G(1) population. A semi-quantitative gene expression study revealed dose-dependent up-regulation of p53 and p21 genes, and an increase in the Bax/Bcl-2 ratio. These results indicate that XAFE could be a potential therapeutic agent against cancer since it inhibits cell proliferation, and induces apoptosis and cell cycle arrest in C-33A cells.


Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Apoptosis/drug effects , Cell Cycle/drug effects , Phytotherapy , Plant Extracts/therapeutic use , Uterine Cervical Neoplasms/drug therapy , Xylopia , Antineoplastic Agents, Phytogenic/pharmacology , Cell Division/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin-Dependent Kinase Inhibitor p21/metabolism , DNA-Binding Proteins/metabolism , Dose-Response Relationship, Drug , Female , Fruit , G2 Phase/drug effects , Gene Expression/drug effects , Humans , Nuclear Proteins/metabolism , Plant Extracts/pharmacology , Tumor Protein p73 , Tumor Suppressor Proteins/metabolism , Up-Regulation , Uterine Cervical Neoplasms/metabolism
19.
Mol Cell Endocrinol ; 339(1-2): 98-104, 2011 Jun 06.
Article in English | MEDLINE | ID: mdl-21497640

ABSTRACT

Skeletal muscle is the major site of postprandial glucose disposal and augmenting glucose uptake into this tissue may attenuate insulin resistance that precedes type 2 diabetes mellitus. Here, we investigated the effect of pongamol, an identified lead molecule from the fruits of Pongamia pinnata, on glucose uptake and GLUT4 translocation in skeletal muscle cells. In L6-GLUT4myc myotubes treatment with pongamol significantly promoted both glucose transport and GLUT4 translocation to the cell surface in a concentration-dependent manner, without changing the total amount of GLUT4 protein and GLUT4 mRNA, effects that were also additive with insulin. Cycloheximide treatment inhibited the effect of pongamol on GLUT4 translocation suggesting the requirement of new protein synthesis. The pongamol-induced increase in GLUT4 translocation was completely abolished by wortmannin, and pongamol significantly potentiated insulin-mediated phosphorylation of AKT (Ser-473). We conclude that pongamol-induced increase in glucose uptake in L6 myotubes is the result of an increased translocation of GLUT4 to plasma membrane, driven by a PI-3-K/AKT dependent mechanism.


Subject(s)
Benzofurans/pharmacology , Fruit/chemistry , Glucose/metabolism , Millettia/chemistry , Muscle Fibers, Skeletal/drug effects , Plant Extracts/pharmacology , Androstadienes/pharmacology , Animals , Cell Line , Cell Membrane/metabolism , Cycloheximide/pharmacology , Glucose Transporter Type 4/genetics , Glucose Transporter Type 4/metabolism , Insulin/pharmacology , Muscle Fibers, Skeletal/metabolism , Phosphoinositide-3 Kinase Inhibitors , Phosphorylation , Protein Transport , Proto-Oncogene Proteins c-akt/metabolism , Rats , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Transcription, Genetic , Wortmannin
20.
Org Lett ; 13(9): 2156-9, 2011 May 06.
Article in English | MEDLINE | ID: mdl-21446696

ABSTRACT

ent-Homoabyssomicins A (1) and B (2) are new complex polycyclic spirotetronate metabolites isolated from Streptomyces sp. isolate Ank 210. The structures of 1 and 2 were elucidated by detailed spectroscopic analyses of 1D and 2D NMR data. The absolute configuration of 1 was established by subsequent single-crystal X-ray diffraction studies.


Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemistry , Streptomyces/chemistry , Heterocyclic Compounds, 4 or More Rings/isolation & purification , Models, Molecular , Molecular Structure
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