Anticancer Potential of ß-Carboline Alkaloids: An Updated Mechanistic Overview.

his comprehensive review is designed to evaluate the anticancer properties of ß-carbolines derived from medicinal plants, with the ultimate goal of assessing their suitability and potential in cancer treatment, management, and prevention. An exhaustive literature survey was conducted on a wide array of ß-carbolines including, but not limited to, harmaline, harmine, harmicine, harman, harmol, harmalol, pinoline, tetrahydroharmine, tryptoline, cordysinin C, cordysinin D, norharmane, and perlolyrine. Various analytical techniques were employed to identify and screen these compounds, followed by a detailed analysis of their anticancer mechanisms. Natural ß-carbolines such as harmaline and harmine have shown promising inhibitory effects on the growth of cancer cells, as evidenced by multiple in vitro and in vivo studies. Synthetically derived ß-carbolines also displayed noteworthy anticancer, neuroprotective, and cognitive-enhancing effects. The current body of research emphasizes the potential of ß-carbolines as a unique source of bioactive compounds for cancer treatment. The diverse range of ß-carbolines derived from medicinal plants can offer valuable insights into the development of new therapeutic strategies for cancer management and prevention.

Ferulic acid promotes muscle glucose uptake and modulate dysregulated redox balance and metabolic pathways in ferric-induced pancreatic oxidative injury.

The antidiabetic properties of ferulic acid and its protective role against Fe2+ -induced oxidative pancreatic injury were investigated in this study using in vitro and ex vivo models. Induction of oxidative injury in the pancreas was achieved by incubating normal pancreatic tissue with 0.1 mM FeSO4 and treated by co-incubating with different concentrations of ferulic acid for 30 min at 37°C. Ferulic acid inhibited the activities of α-glucosidase, α-amylase, and pancreatic lipase significantly (p < .05) and promoted glucose uptake in isolated rat psoas muscles. Induction of oxidative pancreatic injury caused significant (p < .05) depletion of glutathione (GSH) level, superoxide dismutase (SOD), and catalase activities, as well as elevation of malondialdehyde (MDA) and nitric oxide (NO) levels, acetylcholinesterase and chymotrypsin activities. Treatment of tissues with ferulic acid significantly (p < .05) reversed these levels and activities. LC-MS analysis of the extracted metabolites revealed 25% depletion of the normal metabolites with concomitant generation of m-Chlorohippuric acid, triglyceride, fructose 1,6-bisphosphate, and ganglioside GM1 in oxidative-injured pancreatic tissues. Treatment with ferulic acid restored uridine diphosphate glucuronic acid and adenosine tetraphosphate and generated P1,P4-Bis(5'-uridyl) tetraphosphate and L-Homocysteic acid, while totally inactivating oxidative-generated metabolites. Ferulic acid also inactivated oxidative-activated pathways, with concomitant reactivation of nucleotide sugars metabolism, starch and sucrose metabolism, and rostenedione metabolism, estrone metabolism, androgen and estrogen metabolism, porphyrin metabolism, and purine metabolism pathways. Taken together, our results indicate the antidiabetic and protective potential of ferulic acid as depicted by its ability to facilitate muscle glucose uptake, inhibit carbohydrate and lipid hydrolyzing enzymes, and modulate oxidative-mediated dysregulated metabolisms. PRACTICAL APPLICATIONS: There have been increasing concerns on the side effects associated with the use of synthetic antidiabetic drug, coupled with their expenses particularly in developing countries. This has necessitated continuous search for alternative treatments especially from natural products having less or no side effects and are readily available. Ferulic acid is among the common phenolics commonly found in fruits and vegetables. In this present study, ferulic acid was able to attenuate oxidative stress, cholinergic dysfunction, and proteolysis in oxidative pancreatic injury, as well as inhibit carbohydrate digesting enzymes. Thus, indicating the ability of the phenolic to protect against complications linked to diabetes. Crops rich in ferulic acid maybe beneficial in managing this disease.

Curcumin modulates multiple cell death, matrix metalloproteinase activation and cardiac protein release in susceptible and resistant Plasmodium berghei-infected mice.

Pro-inflammatory signaling, cell death, and metalloproteinases activation are events in Plasmodium infection. However, it is not known if treatment with mefloquine (MF), and curcumin (CM) supplementation, will modulate these conditions. Malaria was induced in two different studies using susceptible (NK 65, study 1) and resistant (ANKA, study 2) strains of mouse malaria parasites (Plasmodium berghei) in thirty male Swiss mice (n = 5) in each study. Following confirmation of parasitemia, mice received 10 mL/kg distilled water (infected control), MF (10 mg/kg), MF and CM (25 mg/kg), MF and CM (50 mg/kg), CM (25 mg/kg) and CM (50 mg/kg). Five mice (not infected) were used as control. After treatment, the animals were sacrificed, serum obtained and liver mitochondria were isolated. Serum Tumour Necrosis Factor alpha (TNF-α), C-reactive protein (CRP), Interleukins-1 beta (IL-1ß) and Interleukins-6 (IL-6) as well as caspases-3, 9 (C3 and C9), p53, serum troponin I (TI) and creatine kinase (CK), were assayed using ELISA techniques. Mitochondrial membrane permeability transition (mPT) pore opening, mitochondrial F0F1 ATPase activity, and lipid peroxidation (mLPO) were determined spectrophotometrically. Matrix metalloproteinases 2 (MMP-2) and 9 (MMP-9) expressions were determined using electrophoresis. CM supplementation (25 mg/kg) significantly decreased serum p53, TNF-α, CRP and IL-6 compared with MF. In the resistant model, CM prevented mPT pore opening, significantly decreased F0F1 ATPase activity and mLPO. MF activated caspase-3 while supplementation with CM significantly decreased this effect. Furthermore, MMP-2 and MMP-9 were selectively expressed in the susceptible model. Malarial treatment with mefloquine elicits different cell death responses while supplementation with curcumin decreased TI level and CK activities.

Oxidative testicular injury: effect of L-leucine on redox, cholinergic and purinergic dysfunctions, and dysregulated metabolic pathways.

The antioxidant and anti-proinflammatory activities of L-leucine were investigated on oxidative testicular injury, ex vivo. In vitro analysis revealed L-leucine to be a potent scavenger of free radicals, while inhibiting acetylcholinesterase activity. Oxidative injury was induced in testicular tissues using FeSO4. Treatment with L-leucine led to depletion of oxidative-induced elevated levels of NO, MDA, and myeloperoxidase activity, with concomitant elevation of reduced glutathione and non-protein thiol levels, SOD and catalase activities. L-leucine caused a significant (p < 0.05) alteration of oxidative-elevated acetylcholinesterase and chymotrypsin activities, while concomitantly elevating the activities of ATPase, ENTPDase and 5'-nucleotidase. L-leucine conferred a protective effect against oxidative induced DNA damage. Molecular docking revealed molecular interactions with COX-2, IL-1 beta and iNOS. Treatment with L-leucine led to restoration of oxidative depleted ascorbic acid-2-sulfate, with concomitant depletion of the oxidative induced metabolites: D-4-Hydroxy-2-oxoglutarate, L-cystine, adenosine triphosphate, maleylacetoacetic acid, cholesteryl ester, and 6-Hydroxy flavin adenine dinucleotide. Treatment with L-leucine reactivated glycolysis while concomitantly deactivating oxidative-induced citrate cycle and increasing the impact-fold of purine metabolism pathway. L-leucine was predicted not to be an inhibitor of CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4, with a predicted LD50 value of 5000 mg/Kg and toxicity class of 5. Additionally, L-leucine showed little or no in vitro cytotoxicity in mammalian cells. These results suggest the therapeutic potentials of L-leucine on oxidative testicular injury, as evident by its ability to attenuate oxidative stress and proinflammation, while stalling cholinergic dysfunction and modulating nucleotide hyrolysis; as well as modulate oxidative dysregulated metabolites and their pathways.

Bioactive compounds of African star apple (Chrysophyllum albidum G. Don) and its modulatory effect on metabolic activities linked to type 2 diabetes in isolated rat psoas muscle.

The infusion of Chrysophyllum albidum was investigated for its antidiabetic mechanism by studying its ability to promote glucose uptake and utilization as well as its modulatory effect on metabolic activities linked to type 2 diabetes in isolated psoas muscle. Isolated psoas muscle was incubated with different concentrations of the infusion in the presence of glucose at 37°C for 2 hr. The infusion improved muscle glucose uptake, with concomitant elevated muscular levels of glutathione, superoxide dismutase, catalase, and ectonucleotidase activities, while depleting malondialdehyde, nitric oxide, adenosine triphosphatase, acetylcholinesterase, glycogen phosphorylase, glucose 6-phosphatase, fructose-1,6-biphosphatase, and lipase activities. It also maintained muscular morphology, while increasing magnesium, calcium, and iron levels. The infusion inhibited α-glucosidase and α-amylase activities in vitro. LC-MS analysis of the infusion revealed the presence of phenolics. These results indicate that C. albidum may mediate antidiabetic activities by stimulating muscle glucose uptake and modulation of key metabolisms linked to diabetes. PRACTICAL APPLICATIONS: The African star apple is among the underutilized fruits consumed for nutritional and medicinal purposes in Western Africa. The fruits are usually wasted during its season leading to postharvest loss owing to poor utilization. The present study gives credence to its use in treating diabetes and its complications. Thus, the fruits can be utilized in the development of cheap and affordable nutraceuticals for the management of diabetes which has been reported for its high-cost treatment. Utilization of the fruits will also reduce its postharvest loss and improve its economic values.

Sequential extracts of red honeybush (Cyclopia genistoides) tea: Chemical characterization, antioxidant potentials, and anti-hyperglycemic activities.

The antioxidant, antidiabetic, and anti-obesogenic potentials of different extracts (dichloromethane, ethyl acetate, ethanol, and aqueous) of the red honeybush (Cyclopia genistoides) tea were investigated in vitro and ex vivo. All extracts exhibited significant scavenging and reducing power activities, with the aqueous and ethyl acetate extracts being the most potent. In vitro antidiabetic analysis revealed the extracts to be potent inhibitors of α-glucosidase and lipase activities. All extracts increased catalase and SOD activities, and glutathione level in oxidative pancreatic injury. GC-MS analysis revealed the presence of fatty acids, fatty acid ester, phytols, sterols, saccharide, ketones, and triterpenes. These results imply that the sequential extracts of honeybush tea (particularly the aqueous and ethyl acetate extracts) may not only exhibit antioxidant potentials but also mediate anti-hyperglycemia activities by inhibiting lipid and carbohydrate digestion. PRACTICAL APPLICATIONS: Red honeybush tea is enjoyed widely in South Africa and around the world due to its no caffeine and very low tannin content, as well as many healthcare attributes. There are however no scientific reports for its sequential extraction of different solvents on antidiabetic effects. The different extracts of honeybush tea (particularly the aqueous and ethyl acetate extracts) inhibited lipid and carbohydrate digestive enzymes linked to type 2 diabetes (T2D), as well as modulate oxidative pancreatic injury. These findings will promote its utilization as a potential nutraceutical in the management of diabetes and its complications.

Catechol protects against iron-mediated oxidative brain injury by restoring antioxidative metabolic pathways; and modulation of purinergic and cholinergic enzymes activities.

OBJECTIVES: This study was aimed at investigating neuroprotective effect of catechol on redox imbalance, cholinergic dysfunctions, nucleotide hydrolysing enzymes activities, and dysregulated metabolic pathways in iron-mediated oxidative brain injury. METHODS: Oxidative injury was induced in brain tissues by incubating with 0.1 mm FeSO4 and treated with different concentrations of catechol. KEY FINDINGS: Catechol significantly elevated glutathione level, superoxide dismutase and catalase activities, while depleting malondialdehyde and nitric oxide levels. It also inhibited the activities of acetylcholinesterase, butyrylcholinesterase, and ATPase, with concomitant elevation of ENTPDase activity. GC-MS analysis revealed that treatment with catechol completely depleted oxidative-generated lipid metabolites. While LC-MS analysis revealed depletion of oxidative-generated metabolites in brain tissues treated with catechol, with concomitant restoration of oxidative-depleted metabolites. Catechol also led to reactivation of oxidative-inactivated taurine and hypotaurine, purine, glutathione, glycerophospholipid, nicotinate and nicotinamide, fructose and mannose, pyrimidine metabolisms and pentose phosphate pathways. Catechol was predicted in silico to be permeable across the blood-brain barrier with a predicted oral LD50 value of 100 mg/kg and a toxicity class of 3. CONCLUSION: These results suggest the neuroprotective effects of catechol in iron-mediated oxidative brain injury.

Vanillin and vanillic acid modulate antioxidant defense system via amelioration of metabolic complications linked to Fe2+-induced brain tissues damage.

The therapeutic effect of phenolics on neurodegenerative diseases has been attributed to their potent antioxidant properties. In the present study, the neuroprotective activities of vanillin and vanillic acid were investigated in Fe2+- induced oxidative toxicity in brain tissues by investigating their therapeutic effects on oxidative imbalance, cholinergic and nucleotide-hydrolyzing enzymes activities, dysregulated metabolic pathways. Their cytotoxicity was investigated in hippocampal neuronal cell lines (HT22). The reduced glutathione level, SOD and catalase activities were ameliorated in tissues treated with the phenolics, with concomitant depletion of malondialdehyde and nitric oxide levels. They inhibited acetylcholinesterase and butyrylcholinesterase activities, while concomitantly elevated ATPase activity. Treatment with vanillin led to restoration of oxidative-depleted metabolites and reactivation of the pentose phosphate and purine metabolism pathways, with concomitant activation of pathways for histidine and selenoamino metabolisms. While vanillic acid restored and reactivated oxidative-depleted metabolites and pathways but did not activate any additional pathway. Both phenolics portrayed good binding affinity for catalase, with vanillic acid having the higher binding energy of -7.0 kcal/mol. Both phenolics were not cytotoxic on HT22 cells, and their toxicity class were predicted to be 4. Only vanillin was predicted to be permeable across the blood brain barrier (BBB). These results insinuate that vanillin and vanillic acid confer a neuroprotective effect on oxidative brain damage, when vanillin being the most potent.

Raffia palm (Raphia hookeri) wine inhibits glucose diffusion; improves antioxidative activities; and modulates dysregulated pathways and metabolites in oxidative pancreatic injury.

Raffia palm wine is a natural drink from the stem of Raffia palm (Raphia hookeri) tree with nutritional and medicinal properties. The effect of fermentation was investigated on its antidiabetic and antioxidative effects in yeast cells and pancreatic tissues, respectively. Both unfermented and fermented palm wine significantly increased glucose uptake, reduced glutathione level (GSH), superoxide dismutase, and catalase activities. They also inhibited glucose diffusion, myeloperoxidase, and ATPase activities as well as decreased malondialdehyde and nitric oxide levels. They also led to the inactivation of oxidative metabolic pathways in oxidative pancreas with the generation of adenosine, sugar and inositol metabolites, selenium (enzyme co-factor) and vitamin metabolites owing to concomitant activation of vitamins, lipid, steroids, inositol, and sulfate/sulfite metabolic pathways. The results suggest the antidiabetic and antioxidative potentials of unfermented and fermented palm wine and may be attributed to the LC-MS-identified compounds which were mainly polyphenols and its glycosides, vitamins, and amino acids. PRACTICAL APPLICATIONS: Raffia palm wine is among the natural beverages employed for social, nutritional, and medicinal purposes. However, there are limited studies on its medicinal properties. This study reports for the first time, the ability of Raffia palm wine to stimulate glucose uptake, inhibit glucose diffusion, and ameliorate pancreatic oxidative injury, as well as the possible associated metabolic pathways that may be involved. These findings will further contribute in understanding the antidiabetic effect of Raffia palm wine, and the possible metabolic pathways involved.

Vernonia Amygdalina Del. stimulated glucose uptake in brain tissues enhances antioxidative activities; and modulates functional chemistry and dysregulated metabolic pathways.

Brain glucose uptake is usually reduced in type 2 diabetes owing to downregulation of brain glucose transporters. The ability of Vernonia amygdalina to stimulate glucose uptake as well as ameliorate glucose-induced oxidative stress and proinflammation were investigated in rat brain. Hot infusion of V. amygdalina leaves was incubated with rat brain tissues for 2 h in the presence of glucose. Another incubation with glucose only, served as negative control while metformin served as positive control. Incubation of brain tissues with V. amygdalina led to significant (p < 0.05) increase in glucose uptake, reduced glutathione, nitric oxide and non-thiol proteins levels, superoxide dismutase, catalase and ATPase activities, while concomitantly decrease in myeloperoxidase activity and malondialdehyde level compared to the negative control. Incubation with glucose only, led to the development of nitrate, amide II and amide I functional groups which were removed on incubation with the infusion. LC-MS analysis revealed depletion of oxidative stress-induced 2-keto-glutaramic acid and cysteinyl-tyrosine metabolites in brain tissues, with concomitant generation of S-formylglutathione and adenosine tetraphosphate by the infusion. Pathway analysis of the metabolites revealed an activation of pyruvate metabolism pathway in the negative control, with the infusion reducing the intensity fold. LC-MS analysis of the infusion revealed the presence of l-serine, l-cysteine, l-proline, nicotinic acid, cumidine, salicylic acid, isoquinoline, 3-methyl-, and γ-octalactone. Except for l-serine, l-cysteine and l-proline, the other compounds were predicted to be permeable across the blood brain barrier. These results indicate the brain glucose uptake stimulatory and neuroprotective effect of V. amygdalina.

Concentrated hot water-infusion of phragmanthera incana improves muscle glucose uptake, inhibits carbohydrate digesting enzymes and abates Fe2+-induced oxidative stress in hepatic tissues.

Chronic hyperglycemia has been implicated in the development of oxidative stress and as a major factor in etiology of secondary complication in diabetes. In the present study, the antidiabetic potential of Phragamenthra incana (P. incana) hot infusion and its possible inhibitory effects on carbohydrate digesting enzymes, promotion of muscle glucose uptake, and the antioxidative potentials in Fe2+-induced oxidative stress in hepatic tissue were investigated. The infusion significantly (p < 0.05) scavenged free radicals (DPPH) and displayed favourable ferric reducing antioxidant power (FRAP) with increasing concentrations. It also significantly ameliorated Fe2+-induced oxidative stress in hepatic tissues by increasing superoxide dismutase (SOD) and catalase activities and depleting malondialdehyde (MDA) level. The results further showed that the infusion significantly (p < 0.05) inhibited α-amylase and α-glucosidase activity, and enhanced muscle glucose uptake, with and without insulin. Liquid Chromatography-Mass Spectroscopy (LCMS) analysis of the infusion revealed the presence of 2-methoxythiazole; l-cysteine; nicotinic acid; S-methyl-l-cysteine; isoquinoline, 1-methyl-; and 1H-indole-2,3-dione,5-methyl. The results of this study suggest that the observed antidiabetic and antioxidative potentials of P. incana could be attributed to its identified phytochemical constituents, however, this supports folkloric medicinal use of this plant.

Application of Decafluorobiphenyl (DFBP) Moiety as a Linker in Bioconjugation.

Considerable attention has been devoted to fluorinated compounds due to their unique and interesting properties. Many modern pharmaceuticals contain fluorinated substituents, which are commonly synthesized using selective fluorinating reagents. Decafluorobiphenyl (DFBP) as a fluorinated linker is susceptible to nucleophilic attack. This nucleophilic reaction has been widely studied using various nucleophiles. Sulfur and nitrogen containing nucleophiles have been of particular interest, especially in bioconjugated reactions. This review focuses on the SNAr reactivity of DFBP in formation of C-X (X = S, N) bonds, to be applied in bioconjugation in organic chemistry. The review aims to highlight the crucial factors that govern the chemistry behind the activation of F-CAr-CAr-F bonds as a linker in the synthesis of novel peptides, proteins, and biologics.

Caffeine - rich infusion from Cola nitida (kola nut) inhibits major carbohydrate catabolic enzymes; abates redox imbalance; and modulates oxidative dysregulated metabolic pathways and metabolites in Fe2+-induced hepatic toxicity.

The antioxidative and antidiabetic effects and toxicity of caffeine-rich infusion of Cola nitida were investigated using in vitro, ex vivo and in silico models. C. nitida was infused in boiling water and allowed to cool before concentrating at <50°C. HPLC analysis of the infusion revealed a caffeine content of 80.08%. The infusion showed potent in vitro antioxidant activity by significantly (p<0.05) scavenging 2,2'-diphenyl-1-picrylhydrazyl (DPPH). It significantly (p<0.05) inhibited α-glucosidase and α-amylase activities. Treatment of Fe2+ induced oxidative hepatic tissues with the infusion led to increase Superoxide Dismutase (SOD) and catalase activities, and glutathione (GSH) level as well as decreased malondialdehyde (MDA) level. FTIR spectroscopy of hepatic metabolite revealed restoration of oxidative-induced depleted functional groups by the infusion. LC-MS analysis of the metabolite also revealed restoration of most depleted metabolites with concomitant generation of 4-O-Methylgallic, (-)-Epicatechin sulfate, L-Arginine, L-tyrosine, Citric acid and Decanoic acid in infusion-treated tissues. Pathway analysis of the identified metabolites revealed the presence of 21 metabolic pathways involved in normal hepatic tissues, 12 in oxidative injured tissues and 17 in the treated tissues. Treatment with the infusion restored 4 metabolic pathways common to the normal tissue and further activated 4 additional pathways. Prediction of oral toxicity of caffeine showed it to belong to class 3, with a LD50 of 127mg/kg. Its toxicity target was predicted as Adenosine Receptor A2a. It was also predicted to be an inhibitor of CYP1A2. These results suggest the antioxidative and antidiabetic properties of C. nitida infusion, with caffeine as the major constituent.

Anti-adhesion potential of non-polar compounds and extracts from Ficus natalensis

Abstract Four triterpenoids, ergosta-4,6,8(14),22-tetraene-3-one 1, stigma-4-ene-3-one 2, 3β-hydroxy-21β-H-hop-22(29)-ene 3, sitosterol and a quinone, tectoquinone 4, were isolated from the leaf, stem bark and fruit extracts of Ficus natalensis subsp. natalensis, Moraceae, a medicinal fig found in Africa. The pure compounds 1-4 and crude extracts were tested for their antibacterial activity against five Gram-negative and seven Gram-positive strains and for their potential anti-biofilm activity. Antimicrobial susceptibility was observed with all pure compounds tested at 250 µg against the majority of Gram-negative and Gram-positive strains. The dichloromethane-soluble fruit extract was active against sensitive and resistant Staphylococcus aureus strains, Enterococcus faecalis and Staphylococcus xylosus. Compounds 2, 3 and 4 demonstrated broad-spectrum antibiotic effects against eight of the twelve bacterial strains tested. In the anti-biofilm assay, exposure to ethyl acetate, methanol and aqueous methanol leaf, stem bark and fruit extracts decreased adhesion with a biofilm reduction of ≥100% for all three tested organisms: Escherichia coli, Pseudomonas aeruginosa and S. aureus. The methanol leaf extract demonstrated the most potent anti-adhesion potential against E. coli (218% biofilm reduction). The greatest ability to decrease adhesion was observed with compounds 2, 3 and 5 against P. aeruginosa at the lowest concentration tested (100 µg ml−1).

IN VITRO CHEMO-PREVENTATIVE ACTIVITY OF STRELITZIA NICOLAI ARIL EXTRACT CONTAINING BILIRUBIN.

BACKGROUND: The discovery of the only animal pigment, bilirubin, in the plant Strelitzia nicolai has triggered a vast number of questions regarding bilirubin's formation and its role in the human body. Recent studies have confirmed that bilirubin at certain levels have many medical benefits. Various case studies have revealed that bilirubin is a potent antioxidant. Cervical cancer is one of South Africa's largest womens' health crises. It is estimated that it affects one out of 41 South African women and kills approximately 8 women in the country every day. Thus, the aim of this study was to investigate if the aril extract of Strelitzia nicolai (Regel and Körn.) containing bilirubin possesses anti-cancer activity and to determine its effect on the induction of apoptosis. MATERIALS AND METHODS: The DPPH activity was firstly used to determine the antioxidant effect of the extract. Thereafter, the cytotoxic effect was tested using the XTT assay. Apoptosis was confirmed and quantified using the Annexin V-PE kit and the morphology was studied using acridine orange and ethidium bromide. RESULTS: The aril extract decreased cell viability by 52% and induced apoptosis in HeLa cells; as shown by the Annexin V-PE Apoptosis detection kit and morphological studies with acridine orange/ethidium bromide staining. CONCLUSION: The activity of the extract as a potent antioxidant was immensely enhanced as compared to the bilirubin standard. These results suggest that S. nicolai aril extract containing bilirubin works synergistically as opposed to bilirubin on its own. Furthermore, this extract might be a good candidate for the therapeutic intervention of cervical cancer.

Synthesis, Characterization, Anticancer and Antibacterial Activity of Some Novel Pyrano[2,3-d]pyrimidinone Carbonitrile Derivatives.

BACKGROUND: Pyrimidines have widespread activity and have shown potent antibacterial and anticancer activity. OBJECTIVE: To synthesise a range of pyrimidine diones and test them for their antibacterial and anticancer activity. METHOD: The pyranopyrimidin-2,4-dione derivatives (1-7) were synthesized in a one-pot reaction by reacting malononitrile and barbituric acid with several aromatic aldehydes in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) in aqueous medium. The compounds were tested for their antibacterial activity using the broth microdilution method and for their cytotoxicity against three cell lines, HeLa (cervical cancer), Caco-2 (human colon adenocarcinoma) and HEK 293 (human embryonic kidney cells) using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) assay. RESULTS: Compounds 1-7 were successfully synthesized in yields of >90%. The 3,4-dihydroxyaryl (3) and the 2,5- dimethoxyaryl (7) derivatives were novel. Compounds 3, 5 (4'-methoxy derivative) and 6 (2',3'-dimethoxy derivative) showed antibacterial activity comparable to or better than the standard ampicillin. All the test compounds 1-7 showed good anticancer activity. The IC50 values ranged from 3.46 to 37.13 µM (HeLa); 136.78 to 297.05 µM (Caco-2) and 137.84 to 333.81 µM (HEK293). The best activity was seen in the HeLa cell line when compared to the standard 5FU (5-Fluorouracil IC50 of 41.85 µM), with 1, 2, 5 and 7 having IC50 values of 10.64, 3.46, 4.36 and 4.44 µM respectively. Additionally, two representative compounds (1 and 7) found to be potent against the two cell lines (HeLa and HEK 293) were docked into the binding site of human kinesin Eg5 with the aim of predicting their binding propensities and to establish their mechanism of action. The Lipinski parameters of these compounds were also computed and analysed for their drug-likeness. CONCLUSION: Compound 6 is an excellent candidate for a broad spectrum antibiotic with MBCs of 45.6-365.2 µM, while both 3 and 6 have the potential to be developed into an antibiotic against MRSA, with MBCs of 183-199 µM. Since all synthesized compounds showed IC50 values of 10 µM or less especially against the HeLa cells, they can be considered good lead compounds for anticancer agents. Additionally, the docking simulations suggested a good binding affinity of the compounds with Eg5 and indicated their anti-cancer action, at least partially, through its inhibition. The predicted Lipinski descriptors also indicated the potential of these compounds as an orally active drug.

Sulfoximine substituted quinazolines for pharmaceutical compositions US 20150005278 (A1): a patent evaluation.

Mnk1 and Mnk2 are protein kinases responsible for phosphorylating eIF4E, a eukaryotic initiation factor responsible for initiating translation. Inhibiting Mnk1 and Mnk2 could therefore play a role in treating metabolic diseases such as cancer, diabetes, and hyperlipidemia. A wide range of sulfoximine substituted quinazolines were synthesised and evaluated for their Mnk1 and Mnk2 inhibitory activity. Amongst these compounds, 26 quinazolines showed activity against Mnk1 at <100 nM and 54 showed activity against Mnk2 at 1 nM. The results indicate that this scaffold is much more active against Mnk2 than Mnk1. The synthesised compounds may be future drugs in the treatment of metabolic diseases.

A Review on the Synthesis and Anti-cancer Activity of 2-substituted Quinolines.

Quinolines substituted at C-2 on the quinoline scaffold have shown interesting anticancer activity in a number of anticancer assays such as breast (MCF-7, MDA-MB 231), human cervical epithelioid (HeLa), oral squamous cell carcinoma (SAS), human stomach adenocarcinoma (AGS, MKN45), hepatocellular (SKHep, HepG-2, Hep-3B), prostate (PC-3, DU145), lung (A549, H-460), gastric (HGC, MNK-74), leukemia (K562, U937, REH, NALM6, CEM/ADR 5000), colon (Colo-205, HCT 116, SW620, Caco-2, HT29), neuroblastoma (IMR32), CNS (SF-268), oesophageal (EAC) and melanoma (A-375). They have been synthesised by a number of strategies starting with isatin, anilines, nitrobenzenes and benzamides and some even with cyclohexanone and cyclohexa-1,3-diones with ammonium acetate. Many of the synthetic strategies employ the derivatisation of quinoline precursors itself. We review here the synthesis of 145 bioactive anticancer quinolines substituted at the 2-position and their anticancer activity.

Isoflavones from Calpurnia Aurea subsp. aurea and their anticancer activity.

BACKGROUND: Calpurnia aurea is an African medicinal plant used in many countries in Africa to treat a range of medical conditions or disorders. Extracts of the plant were shown to be active in antibacterial and antioxidant assays as well as against lice, ticks and maggots. The aim of the study was to isolate the phytochemical constituents from the plant and to test them in appropriate bioassays dependent on the compounds isolated in order to provide a rationale for the use of the plant in ethno-medicine or to provide some information on its constituents. MATERIALS AND METHODS: The stem and bark of the plant was extracted with organic solvents of varying polarity and the extracts separated and purified using column chromatography. The isolated compounds were identified by NMR spectroscopy and the compounds were tested for their in vitro anticancer activity against breast (MCF7), renal (TK10) and melanoma (UACC62) human cell lines using an in house method developed at the CSIR, South Africa. RESULTS: The isoflavones, 4',5,7-trihydroxyisoflavone (1), 7,3'-dihydroxy-5'-methoxyisoflavone (2), 7-hydroxy-4',8-dimethoxyisoflavone (3), 7-acetoxy-4',8-dimethoxyisoflavone (4) and 3',7-dihydroxy-4',8-dimethoxyisoflavone (5), a pterocarpan (3-acetoxy-9-methoxypterocarpan) and a quinolizidine alkaloid (calpurnine) were isolated from the stem and bark of Calpurnia aurea. The tetrasubstituted isoflavone 5 was found to be the most active in the three cell lines amongst all the compounds tested. This was followed by trisubstituted isoflavone 2. CONCLUSION: The isoflavones showed moderate activity against the renal, melanoma and breast cancer cell lines tested against, with the isoflavones 2 and 5 showing the best activity of the compounds tested. These isoflavones may have a synergistic effect with other anticancer drugs.

Structure and antioxidant activity of phenolic compounds isolated from the edible fruits and stem bark of Harpephyllum caffrum.

Antioxidant activity in edible fruits is an important characteristic in the choice of fruits for human consumption, and has profound influence on nutrition and health. Two pharmacologically active triterpenoids, ß-sitosterol and lupeol, and the powerful flavan-3-ol antioxidant, (+)-catechin, were isolated from the edible fruits of Harpephyllum caffrum while a mixture of cardanols, an alkyl p-coumaric acid ester, and (+)-catechin were isolated from the stem bark. This is the first report of these compounds being isolated from this plant. The antioxidant capacity of (+)-catechin was higher than the other isolated compounds as well as the known antioxidant, ascorbic acid.