Anti cancer alkaloids

The present study reveals an improved method for the evaluation of Adhatoda vasica extract by quantitation of major metabolite vasicine. The plant powder was extracted with methanol and evaporated in vaccuo to obtain an oily residue. The residue was diluted with aqueous solution of citric acid (1%) and was further extracted with chloroform. The preliminary screening for alkaloid was done with alkaloidal reagents and the presence of vasicine was assessed by thin layer chromatography (TLC). The extractive was then subjected to column chromatography using a mixture of ethyl acetate and methanol adjusted to pH 9.5 with liquid ammonia as mobile phase. The TLC chromatograms of the collected column fractions were developed and the fractions indicated the presences of vasicine were combined together. The residue obtained from evaporation of solvent was subjected to preparative TLC along with reference standard to get pure crystalline vasicine. The compound vasicine was ascertained by UV-Vis, FT-IR and LCMS/MS analyses. The quantitative estimation of vasicine was carried out by reversed phase HPLC method. About 99.50% of pure vasicine (647 mg) compared to reference standard was obtained from 250 gm of leaf powder (0.2588% w/w).

A phytochemical study of the roots and aerial parts of Cryptocarya alba (Mol.) Looser (Lauraceae), an endemic Chilean tree and the southernmost Cryptocarya species, led for the first time to the isolation and unambiguous characterization of four known alkaloids by NMR techniques: boldine, laurolitsine, laurotetanine and norglaucine, in addition to the previously identified reticuline, and the identification via UHPLC-MS of seven more alkaloids, coclaurine, N-methylcoclaurine, norreticuline, isocorydine, N-methyllaurotetanine, predicentrine and glaucine. In spite of this fairly broad variety of benzyltetrahydroisoquinolines and aporphines, the concentrations of these alkaloids in the different organs of C. alba are quite low, which is in contrast with the sometimes generous yields of alkaloids in this genus.

Sanguinarine, an alkaloid present in various medicinal plants, has been associated with detrimental effects on different types of cancer cells. The aim of our study was to analyze the cytotoxic effects of sanguinarine on C32 human amelanotic melanoma cells. The cells were exposed to various concentrations of sanguinarine (0.5, 1, and 2 µM) for 24 h and displayed a dose-dependent decrease in cell viability; the sanguinarine-induced oxidative stress in C32 cells affected the activity of antioxidant enzymes and generated lipid peroxidation. Moreover, we observed an enhanced expression of heat shock proteins 60, 70, and 90 in response to the stress exerted by this alkaloid. The increased p53 protein expression and Bax/Bcl-2 ratio revealed the susceptibility of C32 cells to apoptosis. Our study demonstrated that sanguinarine induced cytotoxicity in melanoma cells that ultimately resulted in cell death. These results emphasize the antigrowth efficiency of sanguinarine against amelanotic melanoma cells, but further research is needed in order to obtain more potent antitumor effects of this alkaloid.

Several 1,4-dihydropyridine derivatives overcome the multidrug resistance in tumors, but their intrinsic cytotoxic mechanisms remain unclear. Here we addressed if mitochondria are involved in the cytotoxicity of the novel 1,4-dihydropyridine derivative VE-3N [ethyl 6-chloro-5-formyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate] towards cancer cells by employing hepatic carcinoma (HepG2) cells and isolated rat liver mitochondria. In HepG2 cells, VE-3N induced mitochondrial membrane potential dissipation, ATP depletion, annexin V/propidium iodide double labeling, and Hoechst staining; events indicating apoptosis induction. In isolated rat liver mitochondria, VE-3N promoted mitochondrial uncoupling by exerting protonophoric actions and by increasing membrane fluidity. Mitochondrial uncoupling was evidenced by an increase in resting respiration, dissipation of mitochondrial membrane potential, inhibition of Ca(2+) uptake, stimulation of Ca(2+) release, decrease in ATP sy...

Hypoxic cells, which are a common feature of solid tumors, but not normal tissues, are resistant to both anticancer drugs and radiation therapy. Thus the identification of drugs with selective toxicity toward hypoxic cells is a n important objective in anticancer chemotherapy. The benzotriazine diN oxide (SR 4233, Tirapazamine) has been shown to be a n efficient and selective cytotoxin for hypoxic cells. Since the bioreductive activation of Tirapazamine is thought to be due to the presence of the l,4-diN oxide moiety, a series of 3-aminoquinoxaline-2-carbonitrile 1,Cdi-N-oxides with a range of electron-donating and-withdrawing substituents in the 6and/or 7-positions has been synthesized and evaluated for toxicity to hypoxic cells. Electrochemical studies of the quinoxaline diN oxides and Tirapazamine showed that as the electron-withdrawing nature of the 6(7)-substituent increases, the reduction potential becomes more positive and the compound is more readily reduced. Apart from the unsubstituted 6a and the 6,7-dimethyl derivative 6c, the quinoxaline diN oxides have reduction potentials significantly more positive than Tirapazamine (Epc-0.90 V). The most potent cytotoxins to cells in culture were the 6,7-dichloro and 6,7-difluoro derivatives 6i and 61, which were 30-fold more potent than Tirapazamine. The 6(7)-fluoro and 6(7)-chloro compounds, 6e and 6h, showed the greatest hypoxia selectivity. Four of the compounds, 6e, 6f, 6h and 64 killed the inner cells of multicellular tumor spheroids in vitro. In vivo Balb/c mice tolerated a dose of these four compounds twice the size of that of Tirapazamine. This study demonstrates that quinoxaline 1,4-diN oxides could provide useful hypoxia-selective therapeutic agents. * Department of Toxicology.

Background: Cancer is the major cause of death throughout the world. In the developing world, the rate of death increases due to old age and changes in the lifestyle of people. At present, the researchers from multidisciplinary areas are focusing on strategies to combat this disease. Several chemotherapeutic, cytotoxic and immunomodulatory drugs are being explored from natural sources like plants, insects and marine organisms. Alkaloids belonging to the phenanthroindolizidine class are an example of such phytochemicals isolated from natural sources and found to exhibit interesting pharmacological properties. These alkaloids are well known for their cytotoxic activity, due to the inhibition of protein and nucleic acid synthesis. Hence numerous approaches to synthesize the phenanthroindolizidines and their analogues have been reported. Method and findings: This review will hence provide an overview on the anticancer effects of Phenanthroindolizidine Alkaloids (PAs) reported from scientific and patent literature. The details of the mode of actions, study models, effective dosages, combination therapy and other pharmacological aspects of the alkaloid will be highlighted. Some of these alkaloids were found to possess anti-cancer activity by inhibiting the overexpression of COX-2 enzyme and NF-kB receptors, the deregulation of which is found to cause tumors. Further studies related to the in-silico docking studies confirm their interaction with COX-2 protein which is one of the important targets for treating inflammation based cancer.

The incorporation of berberine into jatrorrhizine is demonstrated. The protoberberine alkaloids, one of the larger classes of isoquinoline alkaloids, exhibit much variability in their methylation/methylenation patterns. Considering only the more common 2,3,9,10 substituted protoberberines, all of the monohydroxy and most of the dihydroxy possibilities are known natural products. Biosynthetically, this presents

The antitumor drug 3-amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ (1)) along with a number of newly synthesized tirapazamine derivatives (TPZs) bearing substitutions at the 3-amine position of TPZ (1) were estimated for their antibacterial activity against representative Gram-negative Escherichia coli (ATCC 25922) and Salmonella enterica (SL 5676), as well as Gram-positive Staphylococcus aureus (ATCC 25923) bacterial strains. Their activities in terms of minimum inhibitory concentrations (MICs) varied in the range of 1.1 µM (0.25 µg/mL)-413 µM (128 µg/mL). Amongst the most potent derivatives (1-6), acetyl-and methoxycarbonyl-substituted TPZs (2 and 4) were the strongest agents, which exhibited approximately 4-30 fold greater activities compared to those of TPZ (1) along with the reference drugs chloramphenicol (CAM) and nitrofurantoin (NFT). The inhibitory activities of the compounds were highly impacted by their structural features. No reliable relationships were established between activities and the electron-accepting potencies of the whole set of studied compounds, while the activities of TPZ drug (1) and the structurally uniform set of molecules (2-6) were found to increase with an increase in their electron-accepting potencies obtained by means of density functional theory (DFT) computation. A greater steric, lipophilic and polar nature of the substituents led to a lower activity of the compounds. The combined antibacterial in vitro trial gave clear evidence that TPZs coupled with the commonly utilized antibiotics ciprofloxacin (Cipro) and nitrofurantoin (NFT) could generate enhanced (suggestive of partial and virtually complete synergistic) and additive effects. The strongest effects were defined for TPZs-NFT combinations, which resulted in a notable reduction in the MICs of diN oxides. These preliminary findings suggest that the synthesized novel diN oxides might be used as sole agents or applied as antibiotic complements.

Background: The search for new anticancer compounds is a crucial element of natural products research. Purpose: In this study the effects of naturally occurring homochelidonine in comparison to chelidonine on cell cycle progression and cell death in leukemic T-cells with different p53 status are described. Methods: The mechanism of cytotoxic, antiproliferative, apoptosis-inducing effects and the effect on expressions of cell cycle regulatory proteins was investigated using XTT assay, Trypan blue exclusion assay, flow cytometry, Western blot analysis, xCELLigence, epi-fluorescence and 3D super resolution microscopy. A549 cells were used for xCELLigence, clonogenic assay and for monitoring microtubule stability. Results: We found that homochelidonine and chelidonine displayed significant cytotoxicity in examined blood cancer cells with the exception of HEL 92.1.7 and U-937 exposed to homochelidonine. Unexpectedly, homochelidonine and chelidonine-induced cytotoxicity was more pronounced in Jurkat cells contrary to MOLT-4 cells. Homochelidonine showed an antiproliferative effect on A549 cells but it was less effective compared to chelidonine. Biphasic dose-depended G1 and G2/M cell cycle arrest along with the population of sub-G1 was found after treatment with homochelidonine in MOLT-4 cells. In variance thereto, an increase in G2/M cells was detected after treatment with homochelidonine in Jurkat cells. Treatment with chelidonine induced cell cycle arrest in the G2/M cell cycle in both MOLT-4 and Jurkat cells. MOLT-4 and Jurkat cells treated with homochelidonine and chelidonine showed features of apoptosis such as phosphatidylserine exposure, a loss of mitochondrial membrane potential and an increase in the caspases-3/7,-8 and-9. Western blots indicate that homochelidonine and chelidonine exposure activates Chk1 and Chk2. Studies conducted with fluorescence microscopy demonstrated that chelidonine and homochelidonine inhibit tubulin polymerization in A549 cells. Conclusion: Collectively, the data indicate that chelidonine and homochelidonine are potent inducers of cell death in cancer cell lines, highlighting their potential relevance in leukemic cells.

A great number of alkaloids exhibit high potential in cancer research. Some of them are anticancer drugs with well-defined clinical uses, exerting their action on microtubules dynamics or DNA replication and topology. On the other hand, mitochondria have been recognized as an essential organelle in the establishment of tumor characteristics, especially the resistance to cell death, high proliferative capacity and adaptation to unfavorable cellular environment. Interestingly, many alkaloids exert their anticancer activities affecting selectively some functions of the tumor mitochondria by 1) modulating OXPHOS and ADP/ATP transport, 2) increasing ROS levels and mitochondrial potential dissipation by crosstalk between endoplasmic reticulum (ER) and mitochondria, 3) inducing mitochondria-dependent apoptosis and autophagy, 4) inhibiting mitochondrial metabolic pathways and 5) by alteration of the morphology and biogenesis of this organelle. These antecedents show the relevance of developing research about the effects of alkaloids on functions controlled by tumor mitochondria, offering an attractive target for the design of new alkaloid derivatives, considering organelle-specific delivery strategies. This review describes mitochondria as a central component in the anticancer action of a set of alkaloids, in a way to illustrate the importance of this organelle in medicinal chemistry.

Cancer cell metabolism is largely controlled by oncogenic signals and nutrient availability. Here, we highlighted that the glucocorticoid-induced leucine zipper (GILZ), an intracellular protein influencing many signaling pathways, reprograms cancer cell metabolism to promote proliferation. We provided evidence that GILZ overexpression induced a significant increase of mitochondrial oxidative phosphorylation as evidenced by the augmentation in basal respiration, ATP-linked respiration as well as respiratory capacity. Pharmacological inhibition of glucose, glutamine and fatty acid oxidation reduced the activation of GILZ-induced mitochondrial oxidative phosphorylation. At glycolysis level, GILZ-overexpressing cells enhanced the expression of glucose transporters in their plasmatic membrane and showed higher glycolytic reserve. 1 H NMR metabolites quantification showed an up-regulation of amino acid biosynthesis. The GILZ-induced metabolic reprograming is present in various cancer cell lines regardless of their driver mutations status and is associated with higher proliferation rates persisting under metabolic stress conditions. Interestingly, high levels of OXPHOS made GILZ-overexpressing cells vulnerable to cell death induced by mitochondrial pro-oxidants. Altogether, these data indicate that GILZ reprograms cancer metabolism towards mitochondrial OXPHOS and sensitizes cancer cells to mitochondria-targeted drugs with pro-oxidant activities.

Cancer cells can undergo a metabolic reprogramming from oxidative phosphorylation to glycolysis that allows them to adapt to nutrient-poor microenvironments, thereby imposing a selection for aggressive variants. However, the mechanisms underlying this reprogramming are not fully understood. Using complementary approaches in validated cell lines and freshly obtained human specimens, we report here that mitochondrial respiration and oxidative phosphorylation are slowed in metastatic melanomas, even under normoxic conditions due to the persistence of a high nuclear expression of hypoxia-inducible factor-1α (HIF-1α). Pharmacologic or genetic blockades of the HIF-1α pathway decreased glycolysis and promoted mitochondrial respiration via specific reduction in the expression of pyruvate dehydrogenase kinase-3 (PDK3). Inhibiting PDK3 activity by dichloroacetate (DCA) or siRNA-mediated attenuation was sufficient to increase pyruvate dehydrogenase activity, oxidative phosphorylation, and mito...

Adhatoda vasica Nees (Acanthaceace) is a well known medicinal plant from which certain alkaloids, phenolics, flavonoids, sterols and their glycoside derivatives have been isolated. Its diverse medicinal activities include cardiovascular protection, abortifacient, antitubercular, antimutagenic, antiulcer, antiasthmatic activities, hepatoprotective, antibacterial and antitussive activities. It is commonly used in indigenous and traditional folk medicine system in SouthEast -Asia. An up-to-date data on phytochemical compositions and pharmacological properties of different parts of Adhatoda vasica are reviewed and commented in this article.

Plant secondary metabolites have enormous potential for research and new drug development. Many secondary metabolites have complex and unique structure and their production can be enhanced by introducing different types of additives into the basal media. An efficient in vitro callus induction system in Stephania tetrandra S. Moore (Fan fang ji, an important Chinese medicinal herb) was established on MS medium supplemented with 3% sucrose and different concentrations (0.5 to 2.0 mg/L) of plant growth regulators i.e. auxins (2,4D, IAA and NAA) and cytokinins (BA, kinetin, TDZ and zeatin) in the dark. The effects of various auxins and cytokinin on the growth and accumulation of benzylisoquinoline alkaloids i.e. Fangchinoline (Fan) and Tetrandrine (Tet) were investigated. MS medium supplemented with 1.0 mg/L BA and 0.5 mg/L TDZ supported callus growth and its proliferation. A maximum amount of dry biomass (7.8 fold) was produced 45 days after culture. High Performance Liquid Chromatographic analysis of methanol extracts from callus revealed an accumulation of Fan and Tet alkaloids. The addition of casein hydrolysate (500 mg/L) and coconut milk (10%), respectively, enhanced Fan and Tet accumulation. The established in vitro callus induction system in S. tetrandra can be utilized for biomass production of pharmaceutically important alkaloids such as Fan and Tet.

The total contents and qualitative compositions of alkaloids in seeds of 10 Old World lupin species (73 accessions) were surveyed using gas chromatography. The obtained results, combined with those for three lupin crops, Lupinus angustifolius, Lupinus albus, and Lupinus luteus, provide the most complete and up-to-date overview of alkaloid profiles of 13 lupin species originating from the Mediterranean Basin. The qualitative alkaloid compositions served as useful supplementary tools of species discrimination. On the basis of the most abundant major alkaloids, lupanine, lupinine, and multiflorine, the Old World lupin species were divided into four groups. Those containing lupanine (L. angustifolius, L. albus, and Lupinus mariae-josephi), containing lupinine (Lupinus luteus, Lupinus hispanicus, and Lupinus × hispanicoluteus), containing lupinine and multiflorine (Lupinus atlanticus, Lupinus palaestinus, Lupinus anatolicus, Lupinus digitatus, Lupinus pilosus, and Lupinus cosentinii), an...

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The leaves of Duguetia vallicola, a fairly common, large evergreen tree from the coastal regions of Panama, Colombia and Venezuela, contain (6aS)-glaziovine (1) as a major constituent. The abundance and renewable character of the plant material make it an attractive source for this rare, psychoactive alkaloid. The availability of glaziovine and its Omethyl derivative pronuciferine (2) has made complete 1 H and 13 C NMR assignments of proaporphines possible for the first time.

with drugs in recent natural product discovery approaches. I further report here a few purified natural products as examples that provide molecular interventions in cancer therapeutics to give the reader a glimpse of the current trends of approach for discovering useful anticancer drugs. Chapter 2: Literature Review (Part A) Saha SK Recent approaches towards molecular cancer therapies with purified natural products Cancer is a disease of uncontrolled proliferation and growth of cells at inappropriate times and locations in the body. When cells acquire mutations that affect the regulation of Chapter 2: Literature Review (Part A

A new dihydroisoquinoline-N-oxide alkaloid 1 together with the previously known methyl 4-hydroxybenzoate 2 were isolated for the first time from the seeds of Calycotome villosa subsp. intermedia. Their structures were elucidated by extensive spectroscopic analysis and in the case of the new alkaloid 1-hydroxymethyl-6,7-dimethoxy-3,4-dihydroisoquinoline-N-oxide 1 by X-ray diffraction analysis.

The indigenous medicinal plant, Adhatoda vasica (L.) Nees. (Acanthaceae), commonly known as vasaka, is used as a herbal remedy for allergen-induced bronchial obstruction, asthma, and tuberculosis and possesses hepatoprotective activity. This plant is a natural source of vitamin C. Tissue cultures of A. vasica, initiated on Murashige and Skoog's medium supplemented with various plant growth regulators, showed the presence of alkaloids, vasicine and vasicinone. Water extracts of shoot cultures contained high levels of these alkaloids. The vasicine and vasicinone contents in these extracts were 5.98% and 5.2% of dry weight and the water extracts of the selected elite parent plant contained 3-4% dry weight of vasicine. The methanolic extracts of the parent plant and shoot cultures showed quantitative differences in the level of both vasicine and vasicinone. Maximum free radical-scavenging activity of DPPH radicals was observed in the water extracts.

From the stems of Abicta pcthrii, eight isoquinoline alkaloids were isolated and identified by spectroscopic methods and chemical correlations. Three of the bis-benzylisoquinoline alkaloids are new and were assigned the structures 2'-N-nordaurisoline, 2-N-methyllindoldhamine and 2'-N-methyllindoldhamine. The other known alkaloids were coclaurine, daurisoline, lindoldhamine, dimethyllindoldhamine, stepharine and thalifoline.

Mitochondria are the key energy provider to highly proliferating cancer cells, and are subsequently considered one of the critical targets in cancer therapeutics. Several compounds have been studied for their mitochondria-targeting ability in cancer cells. These studies’ outcomes have led to the invention of “mitocans”, a category of drug known to precisely target the cancer cells’ mitochondria. Based upon their mode of action, mitocans have been divided into eight classes. To date, different synthetic compounds have been suggested to be potential mitocans, but unfortunately, they are observed to exert adverse effects. Many studies have been published justifying the medicinal significance of large numbers of natural agents for their mitochondria-targeting ability and anticancer activities with minimal or no side effects. However, these natural agents have never been critically analyzed for their mitochondria-targeting activity. This review aims to evaluate the various natural agents...

Background: Sternbergia clusiana belongs to the Amaryllidaceae family and is recognized for the valuable biological activity of its major bioactive compounds. The aim of the current is to evaluate the anticancer effects of the ethanolic bulb extract of Sternbergia clusiana (ScBEE) on breast cancer cells in vitro and to further reveal the underlying cellular mechanism. Methods: An MTS cell viability assay was performed on MDA-MB-231 and MCF-7 cells, along with cell cycle analysis, cell death ELISA, Western blot analysis and an ROS production assay to decipher the mechanism of death. LC-MS/MS was also performed to identify the chemical composition of this ethanolic extract. Results: The results show a selective antiproliferative effect on both cell lines with no effect on normal mesenchymal stem cells. Further analysis suggested the activation of the apoptotic pathway as reflected by the increase in cellular and DNA fragmentation and alterations in apoptotic proteins such as Bax, Bcl-...

Benzyltetrahydroisoquinoline (BTHIQ) molecules are able to adopt widely differing conformations that depend on the presence or absence of N-substituents. To assess the possible role of BTHIQ conformation on the affinity of these compounds for α 1-adrenergic receptors, of interest for the management of hypertension, the racemic N-unsubstituted BTHIQ norlaudanosine and a series of N-alkylated derivatives were assessed for binding to rat brain cortical sites labelled with the radioligand [ 3 H]prazosin. The α 1-adrenergic affinity in this series increased with the bulk of the substituent on the nitrogen atom, from the N-ethyl to the N-propyl analogue. Comparison of these results with published data for related BTHIQs and for the rigid mimics of the fully extended and semi-folded conformations of laudanosine, tetrahydropalmatine and glaucine, suggested that the α 1-adrenergic receptor binding site is able to accommodate either conformation. The presence of a bulky substituent on the nitrogen atom seems to favor receptor binding independently of the favored conformation, and that the orientation in which BTHIQs are bound probably differs depending on the presence or absence of a hydroxyl group at a key position.

Protein crops have gained increasing interest in recent years, as a transition towards plant-protein based diets appears pivotal to ensure global food security and preserve the environment. The Andean species Lupinus mutabilis emerges as an ideal protein crop with great potential for Europe and other regions with temperate climates. This species is characterized by oil and protein content similar to soybean and is highly valued for its adaptability to colder climates and low input agriculture on marginal land. However, its introduction outside the Andes has yet to take off. To date, L. mutabilis remains an understudied crop, lacking high yield, early maturity and a consistent breeding history. This review paper identifies L. mutabilis limitations and potential uses, and suggests the main breeding targets for further improvement of this crop. It also highlights the potential of new molecular tools and available germplasm resources that can now be used to establish L. mutabilis as a viable protein crop.

The total contents and qualitative compositions of alkaloids in seeds of 10 Old World lupin species (73 accessions) were surveyed using gas chromatography. The obtained results, combined with those for three lupin crops, Lupinus angustifolius, Lupinus albus, and Lupinus luteus, provide the most complete and up-to-date overview of alkaloid profiles of 13 lupin species originating from the Mediterranean Basin. The qualitative alkaloid compositions served as useful supplementary tools of species discrimination. On the basis of the most abundant major alkaloids, lupanine, lupinine, and multiflorine, the Old World lupin species were divided into four groups. Those containing lupanine (L. angustifolius, L. albus, and Lupinus mariae-josephi), containing lupinine (Lupinus luteus, Lupinus hispanicus, and Lupinus × hispanicoluteus), containing lupinine and multiflorine (Lupinus atlanticus, Lupinus palaestinus, Lupinus anatolicus, Lupinus digitatus, Lupinus pilosus, and Lupinus cosentinii), an...

A great number of alkaloids exhibit high potential in cancer research. Some of them are anticancer drugs with well-defined clinical uses, exerting their action on microtubules dynamics or DNA replication and topology. On the other hand, mitochondria have been recognized as an essential organelle in the establishment of tumor characteristics, especially the resistance to cell death, high proliferative capacity and adaptation to unfavorable cellular environment. Interestingly, many alkaloids exert their anticancer activities affecting selectively some functions of the tumor mitochondria by 1) modulating OXPHOS and ADP/ATP transport, 2) increasing ROS levels and mitochondrial potential dissipation by crosstalk between endoplasmic reticulum (ER) and mitochondria, 3) inducing mitochondria-dependent apoptosis and autophagy, 4) inhibiting mitochondrial metabolic pathways and 5) by alteration of the morphology and biogenesis of this organelle. These antecedents show the relevance of developing research about the effects of alkaloids on functions controlled by tumor mitochondria, offering an attractive target for the design of new alkaloid derivatives, considering organelle-specific delivery strategies. This review describes mitochondria as a central component in the anticancer action of a set of alkaloids, in a way to illustrate the importance of this organelle in medicinal chemistry.

Mitochondrial integrity is critical for the regulation of cellular energy and apoptosis. Metformin is an energy disruptor targeting complex I of the respiratory chain. We demonstrate that metformin induces endoplasmic reticulum (ER) stress, calcium release from the ER and subsequent uptake of calcium into the mitochondria, thus leading to mitochondrial swelling. Metformin triggers the disorganization of the cristae and inner mitochondrial membrane in several cancer cells and tumors. Mechanistically, these alterations were found to be due to calcium entry into the mitochondria, because the swelling induced by metformin was reversed by the inhibition of mitochondrial calcium uniporter (MCU). We also demonstrated that metformin inhibits the opening of mPTP and induces mitochondrial biogenesis. Altogether, the inhibition of mPTP and the increase in mitochondrial biogenesis may account for the poor pro-apoptotic effect of metformin in cancer cells.

Adhatoda vasica Nees (Acanthaceace) is a well known medicinal plant from which certain alkaloids, phenolics, flavonoids, sterols and their glycoside derivatives have been isolated. Its diverse medicinal activities include cardiovascular protection, abortifacient, antitubercular, antimutagenic, antiulcer, antiasthmatic activities, hepatoprotective, antibacterial and antitussive activities. It is commonly used in indigenous and traditional folk medicine system in SouthEast -Asia. An up-to-date data on phytochemical compositions and pharmacological properties of different parts of Adhatoda vasica are reviewed and commented in this article.

This chapter describes research on natural aziridine alkaloids isolated from both terrestrial and marine species, as well as their lipophilic semisynthetic and/or synthetic analogues. Over 100 biologically active aziridine-containing compounds demonstrate confirmed pharmacological activity including antitumor, antimicrobial, and antibacterial effects. The structures, origin, and biological activities of aziridine alkaloids are reviewed. Consequently, this

Benzyltetrahydroisoquinoline (BTHIQ) molecules are able to adopt widely differing conformations that depend on the presence or absence of N-substituents. To assess the possible role of BTHIQ conformation on the affinity of these compounds for α 1-adrenergic receptors, of interest for the management of hypertension, the racemic N-unsubstituted BTHIQ norlaudanosine and a series of N-alkylated derivatives were assessed for binding to rat brain cortical sites labelled with the radioligand [ 3 H]prazosin. The α 1-adrenergic affinity in this series increased with the bulk of the substituent on the nitrogen atom, from the N-ethyl to the N-propyl analogue. Comparison of these results with published data for related BTHIQs and for the rigid mimics of the fully extended and semi-folded conformations of laudanosine, tetrahydropalmatine and glaucine, suggested that the α 1-adrenergic receptor binding site is able to accommodate either conformation. The presence of a bulky substituent on the nitrogen atom seems to favor receptor binding independently of the favored conformation, and that the orientation in which BTHIQs are bound probably differs depending on the presence or absence of a hydroxyl group at a key position.

All chemicals were bought from Sigma Aldrich Chemical Company, USA and E. Merck India Ltd, India. All chemical reactions were carried out in oven dried apparatus and solvents used were dried and distilled. Column chromatography was carried out on silica gel (100-200 mess). Reactions were monitored on TLC, using silica gel 60F254 aluminium plates and visualized under ultraviolet light at 254 nm. Melting points were recorded on electro thermal apparatus. NMR spectra were recorded on BRUKER-AV400 spectrometer (Bruker Co., Faellanden, Switzerland) in DMSO-d6 (1 H at 400 MHz and 13 C at 100 MHz). Chemical shifts (δ) are expressed in parts per million (ppm) and J (Coupling constant)values in Hz. Multiplicities are indicated as s (singlet), d (doublet), dd (doublet of doublets), t (triplet), q (quartet), m (multiplet) and br (broad spectrum). Mass spectra were recorded on Micromass Q-Tof (ESI-HRMS). The elemental analyses were performed for all compounds on a Perkin-Elmer 240-C analyses equipment. S1.2. General synthesis of diarylpyrimidine derivatives (1-6) A mixture of different types of aromatic amines (3.37 mmol) and K2CO3 (3.37 mmol) in 10 mL DMF was stirred at room temperature for 15 min. 2, 4-dichloropyrimidine (3.37 mmol) was added and the mixture was stirred at reflux for 4-6 h. Reaction was monitored on TLC for its completion. The solvent was evaporated and residue was partitioned between water and extracted with ethyl acetate (3×15mL). The organic layer was dried over anhydrous

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Isoquinoline (ISOQ) is a heterocyclic aromatic organic compound composed of a benzene ring fused to a pyridine ring, referred to as benzopyridines. The chemical formula is C9H7N with a molar mass of 129.162 g/mol. This ISOQ ring derives from the natural aromatic amino acid tyrosine. It is weak alkaline in nature but is more basic than quinoline. It appears as a yellowish oily liquid, having an unpleasant odour, hygroscopic when solid, has a density of 1.099 g/cm3, a melting point of 26°C to 28°C (79°F to 82°F), the boiling point of 242°C (468°F), and dipole moment of 2.49. In the preparation of this review article, a widespread examination of the published literature in varied pharmaceutical and medical databases such as PubMed, Google Scholar, etc. was fruitfully carried out and categorized consequently. The imperative review revealed the less known biological (anti-fungal, anti-Parkinsonism, anti-tubercular, anti-tumour, anti-glaucoma, anti-Alzheimer’s disease, anti-viral, anti-ba...

Pyrimidines and their fused derivatives form the heterocyclic core of nucleic acid bases. These ring systems are incorporated into drugs used for AIDS, cancer and anti-viral treatment. The discovery of the anti-HIV activity in AZT containing the pyrimidine nucleus has stimulated a renewed interest in these molecules and has prompted us to focus research on the synthesis and study of biological properties of newer series of pyrimidine derivatives. Several reports have appeared in the literature on the biological activities of carbazole, azacarbazole and quinoline derivatives in the search of newer physiologically active materials from these classes of compounds. Pyrimidine and their myriad derivatives have continued to capture the attention of chemists since their presence in the biologically active materials have been known to produce additive effect on the bio-efficacy of the molecules.

Berberis chilensis Gillies ex Hook is an endemic Chilean plant not used in traditional medicine from which some chemical structures have been isolated. Bisenzylisoquinolinic alkaloids have been characterized as being calcium antagonists of natural origin; 7-O-Demethylisothalicberine, O-Methylisothalicberine, Berbamine, and isothalicberine have been isolated from this type of structures. Berbamina is an alkaloid that has also been isolated from a Chinese plant, which is used to prevent heart attack, along with 7-O-demethylisothalicberine are the two most important bisbenzylisoquinolinic alkaloids of this Chilean species. It shows the similarity between the chemical structures of this same family of alkaloids, where tetrandrine is perhaps the most studied structure and has been characterized as one of the most important calcium antagonists, isolated from the Chinese plant Stephania tetrandra which is used from about 500 years before Christ as a medicinal plant by the Chinese people.

The emergence of chemoresistant cancers and toxicity related to existing chemotherapeutic agents, demand the search for new pharmacophore with enhanced anti-cancer activity and least toxicity. For this purpose, three new sesquiterpenes were isolated from ethyl acetate fraction of the aerial parts of the plant Polygonum barbatum and evaluated for their anti-cancer potential. The structural elucidation and characterization of the isolated compounds 1-3 were performed using various spectroscopic techniques such as mass, UV, IR, and extensive 1D/2D-NMR spectroscopy. Furthermore, the compounds 1-3 were subjected to screening of anti-cancer activity against different cell lines followed by brief analysis of apoptotic and anti-angiogenic potentials of the potent hit against non-small cell lung carcinoma cell line. All the compounds 1-3 were subjected to anti-proliferative potential against non-small cell lung carcinoma (NCI-H460), breast cancer (MCF-7), cervical cancer (HeLa) and normal mo...

Streptococcus pneumoniae (S.pn.) is the most common bacterial pathogen causing community acquired pneumonia. The pore-forming toxin pneumolysin (PLY) is the major virulence factor of S.pn. and supposed to affect alveolar epithelial cells thereby activating the immune system by liberation of danger-associated molecular patterns (DAMP). To test this hypothesis, we established a novel live-cell imaging based assay to analyse mitochondrial function and associated release of mitochondrial DNA (mtDNA) as DAMP in real-time. We first revealed that bacterially released PLY caused significant changes of the cellular ATP homeostasis and led to morphologic alterations of mitochondria in human alveolar epithelial cells in vitro and, by use of spectral live-tissue imaging, in human alveoli. This was accompanied by strong mitochondrial calcium influx and loss of mitochondrial membrane potential resulting in opening of the mitochondrial permeability transition pore and mtDNA release without activat...

The present study reveals an improved method for the evaluation of Adhatoda vasica extract by quantitation of major metabolite vasicine. The plant powder was extracted with methanol and evaporated in vaccuo to obtain an oily residue. The residue was diluted with aqueous solution of citric acid (1%) and was further extracted with chloroform. The preliminary screening for alkaloid was done with alkaloidal reagents and the presence of vasicine was assessed by thin layer chromatography (TLC). The extractive was then subjected to column chromatography using a mixture of ethyl acetate and methanol adjusted to pH 9.5 with liquid ammonia as mobile phase. The TLC chromatograms of the collected column fractions were developed and the fractions indicated the presences of vasicine were combined together. The residue obtained from evaporation of solvent was subjected to preparative TLC along with reference standard to get pure crystalline vasicine. The compound vasicine was ascertained by UV-Vis, FT-IR and LCMS/MS analyses. The quantitative estimation of vasicine was carried out by reversed phase HPLC method. About 99.50% of pure vasicine (647 mg) compared to reference standard was obtained from 250 gm of leaf powder (0.2588% w/w).

Adhatoda vasica Nees, commonly called Vasaka or Arusha has high medicinal value owing to its rich flavonoid and alkaloid contents. The alkaloid content of A. vasica is known to vary with genotype, and hence vegetative method is recommended for its propagation. Effective medium for A. vasica propagation is an area of interest to researchers. Suspension culture techniques have demonstrated that alkaloids can be recovered from the callus and the suspension cell cultures. In this context, we tried to emphasis upon the use of economically viable organic vermicompost and its extracts along with coelomic fluid as plant tissue culture medium without involving expensive chemicals. In the present study, an organic experimental economical medium being standardized using vermicompost, its extracts along with coelomic fluid and friable soft callus was obtained from leaf explants of A. vasica Nees without any chemical supplementation. Direct shoot formation with leaves was documented on MS medium...

The present study reveals an improved method for the evaluation of Adhatoda vasica extract by quantitation of major metabolite vasicine. The plant powder was extracted with methanol and evaporated in vaccuo to obtain an oily residue. The residue was diluted with aqueous solution of citric acid (1%) and was further extracted with chloroform. The preliminary screening for alkaloid was done with alkaloidal reagents and the presence of vasicine was assessed by thin layer chromatography (TLC). The extractive was then subjected to column chromatography using a mixture of ethyl acetate and methanol adjusted to pH 9.5 with liquid ammonia as mobile phase. The TLC chromatograms of the collected column fractions were developed and the fractions indicated the presences of vasicine were combined together. The residue obtained from evaporation of solvent was subjected to preparative TLC along with reference standard to get pure crystalline vasicine. The compound vasicine was ascertained by UV-Vis, FT-IR and LCMS/MS analyses. The quantitative estimation of vasicine was carried out by reversed phase HPLC method. About 99.50% of pure vasicine (647 mg) compared to reference standard was obtained from 250 gm of leaf powder (0.2588% w/w).

The lupins are an interesting group of legume crop species that produce large seeds containing up to 40% protein. The genus Lupinus is part of the tribe Genisteae. More than 170 species have been described from the New World and only 12 species from Europe, North and East Africa. Wild lupins are bitter and toxic because they produce quinolizidine alkaloids as a means of chemical defence. During domestication, lupins with low alkaloid contents were selected, leading to 'sweet' lupins with alkaloid contents below 0.02% in the protein-rich seeds, which can be used both for human and animal consumption. The domesticated lupins include Lupinus angustifolius, Lupinus albus, Lupinus luteus and Lupinus mutabilis. Blue or narrow-leafed lupin (L. angustifolius) is the most widely cultivated of them, with a worldwide production of more than 1.3 million t. Several challenges remain for lupin breeding, including the improvement of quantitative and qualitative traits, adaptation to alkaline soil and resistance to fungal pathogens.

Biological systems are hierarchically self-organized complex structures characterized by nonlinear interactions. Biochemical energy is transformed into work of physical forces required for various biological functions. We postulate that energy transduction depends on endogenous electrodynamic fields generated by microtubules. Microtubules and mitochondria colocalize in cells with microtubules providing tracks for mitochondrial movement. Besides energy transformation, mitochondria form a spatially distributed proton charge layer and a resultant strong static electric field, which causes water ordering in the surrounding cytosol. These effects create conditions for generation of coherent electrodynamic field. The metabolic energy transduction pathways are strongly affected in cancers. Mitochondrial dysfunction in cancer cells (Warburg effect) or in fibroblasts associated with cancer cells (reverse Warburg effect) results in decreased or increased power of the generated electromagnetic...

The Andean lupin (Lupinus mutabilis Sweet) is the only cultivated species of the genus Lupinus originating from South America. Attempts were made to introduce this species to European soil and climatic conditions. The main disadvantages of the Andean lupin include too long and non-uniform maturation of pods in a plant, dropping flowers and pod buds, and a high alkaloid content (up to 5%). The aim of this study was to identify in post-mutagen treated material genotypes with low alkaloid content in seeds, which would be useful for improving L. mutabilis by breeding. The iodine test was annually performed to test the presence of alkaloids in seeds, using Lugol’s solution (I in KI). Based on the turbidity of the test samples, the investigated plants were divided into four groups, labelled as follows: G – individuals with a high content of alkaloids (very bitter), P – individuals with an intermediate content of alkaloids (bitter), PS – individuals with a low alkaloid content (fairly swee...

Two new polycyclic pyrroloquinazoline alkaloids with unprecedented skeleton, anisulcusines A (1) and B (2), along with four known compounds (3-6), were identified from the aerial parts of Anisotes trisulcus (Forssk.) Nees. To our knowledge, anisulcusines A and B are the first polycyclic pyrroloquinazoline alkaloids that possess a unique N-methyl-1,2-dihydro-1'H-spiro[benzo[d][1,3]oxazine moiety. The chemical structures of the new compounds were elucidated through extensive spectroscopic analyses and highresolution mass spectroscopy. Anisulcusine B (2) exerted moderate cytotoxic effect on cultured human hepatoma (HuH7) cells, whereas compounds 1 and 3-5 exhibited mild cell proliferative or growth stimulatory activity. HIGHLIGHTS Two new polycyclic pyrroloquinazoline alkaloids from Anisotes trisulcus. Structures were elucidated on the basis of 1D-and 2D-NMR and HR-ESI-MS spectra. Compound (2) exerted moderate cytotoxic effect against human hepatoma (HuH7) cells. Compounds (1, 3-5) exhibited mild cell proliferative or growth stimulatory activity.