Chlorophyll: the ubiquitous photocatalyst of nature and its potential as an organo-photocatalyst in organic syntheses.

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.

Harnessing selective PET and EnT catalysis by chlorophyll to synthesize N-alkylated quinoline-2(1H)-ones, isoquinoline-1(2H)-ones and 1,2,4-trioxanes.

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.

Oxidative coupling of 1-(2-methyl-4-phenylquinolin-3-yl)ethanone with ethanol and unexpected deacetylative synthesis of 3-hydroxy quinoline.

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.

H2O2/DMSO-Promoted Regioselective Synthesis of 3,3'-Bisimidazopyridinylmethanes via Intermolecular Oxidative C(sp(2))-H Bond Activation of Imidazoheterocycles.

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.

Naturally Occurring Carbazole Alkaloids from Murraya koenigii as Potential Antidiabetic Agents.

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.

Transition-Metal-Free C-3 Arylation of Quinoline-4-ones with Arylhydrazines.

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.

Substrate Controlled Synthesis of Benzisoxazole and Benzisothiazole Derivatives via PhI(OAc)2-Mediated Oxidation Followed by Intramolecular Oxidative O-N/S-N Bond Formation.

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.

Murraya koenigii (L.) Spreng. ameliorates insulin resistance in dexamethasone-treated mice by enhancing peripheral insulin sensitivity.

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.

Antiproliferative action of Xylopia aethiopica fruit extract on human cervical cancer cells.

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.

Cassane diterpenes from Caesalpinia bonduc.

Three cassane diterpene hemiketals, caesalpinolide-C, caesalpinolide-D, caesalpinolide-E and one cassane furanoditerpene were isolated from Caesalpinia bonduc. The molecular structures were elucidated using NMR spectroscopy in combination with IR, UV and mass spectral data and relative stereochemistries were determined through ROESY correlation. The isolated compounds were tested for their antiproliferative activity against MCF-7 (breast adenocarcinoma), DU145 (prostate carcinoma), C33A (Cervical carcinoma) and Vero (African green monkey kidney fibroblast) cells.

Pyranocarbazole derivatives as potent anti-cancer agents triggering tubulin polymerization stabilization induced activation of caspase-dependent apoptosis and downregulation of Akt/mTOR in breast cancer cells.

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.

Fragmentation patterns of newly isolated cassane butenolide diterpenes and differentiation of stereoisomer by tandem mass spectrometry.

Different stereoisomers of active molecules often cause different physiological responses and hence pose a challenge for their identification. This study involves perceptive fragmentation behavior of newly isolated cassane butenolides, caesalpinolide A [1] and caesalpinolide B [2] (epimeric at the hemiketal position) by tandem MS. The electrospray ionization-mass spectrometry (ESI-MS)/collision-induced dissociation (CID; ESI-MS(2) and ESI-IT-MS(n)) were investigated. The effect of orientations of hemiketal hydroxyl at C-12 was clearly observed in the mass spectrum. Tandem mass spectra of 1, 1(A) or 2, 2(A) show stereospecific fragmentation resulting in significant abundance dissimilarity of [MH - H(2)O](+) as well as differences in fragmentation pathway. Both of these pathways seem to be influenced by the stereochemistry of the molecule. The differentiation can be clearly visualized from the [M + H - H(2)O](+)/[M + H](+) ratio of the two isomers where beta-isomer 2 was found to be five times higher than that of alpha-isomer 1 in full scan liquid chromatography-electrospray ionization mass spectrometry(LC-ESI-MS). In high-energy CID, the mass fingerprint of 1, 2, 1(A), and 2(A) was found to be different from one another.

Identification of pongamol and karanjin as lead compounds with antihyperglycemic activity from Pongamia pinnata fruits.

AIM OF THE STUDY: To identify pongamol and karanjin as lead compounds with antihyperglycemic activity from Pongamia pinnata fruits. MATERIAL AND METHODS: Streptozotocin-induced diabetic rats and hyperglycemic, hyperlipidemic and hyperinsulinemic db/db mice were used to investigate the antihyperglycemic activity of pongamol and karangin isolated from the fruits of Pongamia pinnata. RESULTS: In streptozotocin-induced diabetic rats, single dose treatment of pongamol and karanjin lowered the blood glucose level by 12.8% (p<0.05) and 11.7% (p<0.05) at 50mg /kg dose and 22.0% (p<0.01) and 20.7% (p<0.01) at 100mg/kg dose, respectively after 6h post-oral administration. The compounds also significantly lowered blood glucose level in db/db mice with percent activity of 35.7 (p<0.01) and 30.6 (p<0.01), respectively at 100mg/kg dose after consecutive treatment for 10 days. The compounds were observed to exert a significant inhibitory effect on enzyme protein tyrosine phosphatase-1B (EC 3.1.3.48). CONCLUSION: The results showed that pongamol and karangin isolated from the fruits of Pongamia pinnata possesses significant antihyperglycemic activity in Streptozotocin-induced diabetic rats and type 2 diabetic db/db mice and protein tyrosine phosphatase-1B may be the possible target for their activity.

Anti-colon cancer activity of Murraya koenigii leaves is due to constituent murrayazoline and O-methylmurrayamine A induced mTOR/AKT downregulation and mitochondrial apoptosis.

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.

Antileishmanial Activity of Pyrazolopyridine Derivatives and Their Potential as an Adjunct Therapy with Miltefosine.

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.

Furanoflavonoid glycosides from Pongamia pinnata fruits.

Pongamia pinnata fruits afforded three new furanoflavonoid glucosides, pongamosides A-C (1-3), and a new flavonol glucoside, pongamoside D (4). The structures of these compounds were established on the basis of spectroscopic studies. This is the first time that furanoflavone glucosides have been found as naturally occurring compounds.

Furanoflavonoids from Pongamia pinnata fruits.

Fruits of Pongamia pinnata afforded four new furanoflavonoids, pongapinnol A-D (1-4), and a new coumestan, pongacoumestan (5) along with thirteen known compounds 6-18. Compounds 16 and 17 are isolated for the first time from this plant. The structures of isolated compounds were elucidated on the basis of spectroscopic data interpretation.

Constituents of Pterocarpus marsupium: an ayurvedic crude drug.

Five new flavonoid C-glucosides, 6-hydroxy-2-(4-hydroxybenzyl)-benzofuran-7-C-beta-d-glucopyranoside (1), 3-(alpha-methoxy-4-hydroxybenzylidene)-6-hydroxybenzo-2(3H)-furanone-7-C-beta-d-glucopyranoside (2), 2-hydroxy-2-p-hydroxybenzyl-3(2H)-6-hydroxybenzofuranone-7-C-beta-d-glucopyranoside (4), 8-(C-beta-d-glucopyranosyl)-7,3',4'-trihydroxyflavone (5) and 1,2-bis(2,4-dihydroxy,3-C-glucopyranosyl)-ethanedione (6) and two known compounds C-beta-d-glucopyranosyl-2,6-dihydroxyl benzene (7) and sesquiterpene (8), were isolated from an aqueous extract of the heartwood of Pterocarpus marsupium. The structure has been established using spectroscopic data.

Amritosides A, B, C and D: clerodane furano diterpene glucosides from Tinospora cordifolia.

Four new clerodane furano diterpene glucosides (amritosides A, B, C and D) were isolated as their acetates from Tinospora cordifolia stems. The structures of these compounds were established on the basis of spectroscopic studies.

A withanolide coagulin-L inhibits adipogenesis modulating Wnt/ß-catenin pathway and cell cycle in mitotic clonal expansion.

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.