Protein Kinase Inhibition Activity Research Articles

Polyphenolic characterization and evaluation of multimode antioxidant, cytotoxic, biocompatibility and antimicrobial potential of selected ethno-medicinal plant extracts

IntroductionScientific evidence about biological profile of natural products can support their traditional uses. The current work was aimed to assess phytochemical and biological profile of nine medicinal plants collected from Herbalists. MethodsExtracts prepared in different solvents were subjected to phytochemical, antioxidant, enzyme inhibitory, cytotoxic, and antimicrobial activities. Reverse phase-high performance liquid chromatography (RP-HPLC) analysis was performed for the quantification of polyphenols. ResultsResults showed methanol extract (M) being potent as compared to others. Gentian lutea M showed maximum extract recovery (15.00 ± 0.11 % w/w) and TFC (30.82 ± 0.21 μg QE/mg extract). Nigella sativa M displayed highest TPC (44.99 ± 0.43 μg GAE/mg extract) and TAC (334.72 ± 0.35 μg AAE/ mg extract). Results showed noteworthy quantities of vanillic acid, rutin, kaempferol, emodin in ethyl acetate (EA) and methanol (M) extracts of plants assessed by RP-HPLC. Gentisic acid was highest (11.75 µg/mg extract) in T. arjuna M extract. Similarly, maximum %FRSA (82.28 ± 0.03 %) and TRP (160.40 ± 0.38 μg AAE/ mg extract) were depicted by Terminalia chebula and Chamomilla recutita, respectively. Moreover, Mentha longifolia and G. lutea M demonstrated noteworthy (p < 0.05) antibacterial activity against Staphylococcus aureus (14 ± 0.7 mm) and Klebsiella pneumoniae (12 ± 0.3 mm), respectively. Curcuma amada, C. recutita, Murraya koenigii and G. lutea M had significant α-glucosidase activity. Another good solvent for extraction was ethyl acetate (EA), whose extracts were secondary to methanol in producing significant biological profile. For example, EA of N. sativa (TPC: 1.46 ± 0.45 µg GAE/ mg extract), G. lutea (TRP: 160.33 ± 0.52 μg AAE/mg extract: ZOI of 12 ± 0.5 mm in K. pneumoniae) and Mormodica charantia (α-amylase inhibition: 39.5 ± 0.10 %) showed significant bioactivities. All extracts displayed mild antifungal protein kinase inhibition activities and were significantly (greater than80 %: p < 0.05) cytotoxic to brine shrimps with negligible hemolytic activity. ConclusionBriefly, variable polarity solvent extracts of studied plants will be processed for isolation of antioxidant, cytotoxic, carbohydrate enzyme inhibitory and antibacterial compounds.

HPLC-DAD Based Polyphenolic Profiling and Evaluation of Pharmacological Attributes of Putranjiva roxburghii Wall.

The current study was intended to explore the phytochemical profiling and therapeutic activities of Putranjiva roxburghii Wall. Crude extracts of different plant parts were subjected to the determination of antioxidant, antimicrobial, antidiabetic, cytotoxic, and protein kinase inhibitory potential by using solvents of varying polarity ranges. Maximum phenolic content was notified in distilled water extracts of the stem (DW-S) and leaf (DW-L) while the highest flavonoid content was obtained in ethyl acetate leaf (EA-L) extract. HPLC-DAD analysis confirmed the presence of various polyphenols, quantified in the range of 0.02 ± 0.36 to 2.05 ± 0.18 μg/mg extract. Maximum DPPH scavenging activity was expressed by methanolic extract of the stem (MeOH-S). The highest antioxidant capacity and reducing power was shown by MeOH-S and leaf methanolic extract (MeOH-L), respectively. Proficient antibacterial activity was shown by EA-L extract against Bacillus subtilis and Escherichia coli. Remarkable α-amylase and α-glucosidase inhibition potential was expressed by ethyl acetate fruit (EA-F) and n-Hexane leaf (nH-L) extracts, respectively. In case of brine shrimp lethality assay, 41.67% of the extracts (LC50 < 50 µg/mL) were considered as extremely cytotoxic. The test extracts also showed mild antifungal and protein kinase inhibition activities. The present study explores the therapeutic potential of P. roxburghii and calls for subsequent studies to isolate new bioactive leads through bioactivity-guided isolation.

Bioactive heteroleptic Bismuth(V) carboxylates: Synthetic Stratagem, characterization and binding pattern validation

A series of heteroleptic triorganobismuth(V) carboxylates (1–8) of general formula Ar3Bi(COOR)2; where Ar = C6H5(1–4), p-CH3C6H4(5–8) and R = C10H7(1, 5), 2-CH3C6H4(2, 6), 3, 4- (OCH2CH3)C6H3(3, 7), 2-ClC6H4(4, 8); were synthesized by a stoichiometric reaction between the precursor, Ar3BiBr2, and the respective carboxylic acidusing triethylamine as a base in dry toluene. They were characterized by FT-IR, NMR spectroscopy and X-ray diffraction technique to get unequivocal evidence for their structural motifs. The single crystal XRD data for (2 &5) revealed the existence of five coordinated bismuth centre having distorted trigonal bipyramidal molecular geometry, whereas (6) described weakly hexacoordinated bismuth including a unique anisobidentate interaction of one carboxyl group with the resultant distorted octahedral molecular geometry. The molecular docking studies demonstrate that compounds (1, 2 and 7) give significant GOLD fitness scores of 60.09, 62.65 and 56.30 against EGFR tyrosine kinase, human pancreatic alpha amylase and H. pylori urease respectively. The synthesized compounds were also preliminary screened for their antimicrobial, α-amylase inhibition and protein kinase inhibition activities to determine their biological efficacy. The antibacterial activity profile for (2) looks good with MIC value 6.25 μg/mL against E. coli whereas, (1, 2 and 5) show significant antifungal activity against A. flavus having MIC value of 6.25 μg/mL and the values are comparable to the reference drug(s). Compound (6) displays significant % alpha amylase inhibition of 34.80, whereas (2) exhibit 30 mm bald inhibition zone for protein kinase inhibition study, thus, proving their worth as moderate enzyme inhibitors. The molecular docking studies for (1–8) demonstrate strong interactions between the receptor and the molecule and a firm protein-ligand complex formation described their effective role in enzymes’ inhibition. The bioactivity data obtained from both in silico analysis and in vitro studies are quite promising ones and the synthesized compounds may find a leading role in future drug discovery programs.

Antioxidant, Antimicrobial, Cytotoxic, and Protein Kinase Inhibition Potential in Aloe vera L.

Aloe vera is a multifunctional plant that has gained acceptance as an excellent home remedy source in Asia and the world. The present study was intended to evaluate the phytochemical contents and in vitro antioxidant, antimicrobial, antileishmanial, and protein kinase inhibition activities in different fractions of A. vera leaf. Methanolic extract of A. vera leaves was fractionated using column chromatography and ten fractions (AV1-AV10) were obtained. Phenolics composition, antioxidant, antimicrobial, antileishmanial, and protein kinase inhibition activities were evaluated using standard protocols. Well-known compounds of A. vera were used for in silico study against enzymes involved in brine shrimp and antileishmanial and hyphae formation inhibition assay on the basis of results. Five fractions (AV3 to AV7) possess potential total phenolics and flavonoids contents along with significant biological activities. AV4 fraction exhibited the highest total phenolics content 332.4 ± 32.6μg GAE/mg and total antioxidant activity 150.4 ± 25.815μg AAE/mg determined by phosphomolybdenum complex assay. Fraction AV6 showed 95% antileishmanial effect as well as the lowest LD50 value of 0.5305μg/mL in brine shrimp lethality assay. The Protein Kinase inhibition potential in A. vera leaves was determined for the first time and three fractions AV1, AV6, and AV7 depicted activity with the highest zone of inhibition up to 21±0.5mm (AV7). Docking analysis showed that A. vera contains anthraquinones, anthrones, chromones, and polysaccharides responsible for synergistic cytotoxic, antileishmanial, antibacterial, and antioxidant potential of this plant. Therefore, with more studies, A. vera could probably have the potential to be used for drug development against leishmaniasis.

Green synthesis of hematite (α-Fe2O3) nanoparticles using Rhus punjabensis extract and their biomedical prospect in pathogenic diseases and cancer

Hematite nanoparticles (NPs) are chemically and thermodynamically more stable among iron oxide NPs therefore these are considered highly suitable for biomedical applications. This work explores Rhus punjabensis extract potential as both reducing and capping agent for phytomediated synthesis of NPs from ferric chloride precursor. The structural, morphological and compositional investigations were carried out with XRD, SEM, TEM, EDS, and FFT. The synthesized NPs were hematite (Fe2O3) with rhombohedral crystal structure of an approximate size of 41.5 ± 5 nm. TEM, FTIR, and TG/DTA indicated phase-pure Fe2O3 formation with controlled size through use of capping agent. Biological activities depict that synthesized NPs had free radical scavenging, antioxidative potential and reducing power activities. These activities are due to phenolic and flavonoid like properties by attachment of different functional groups on the surface of NPs. The NPs exhibited significant Antileishmanial, antibacterial and protein kinase inhibition activities as compared with the corresponding plant extract. NPs depicted cytotoxic effect against HL-60 leukemic and DU-145 prostate cancer cell lines with ED50 values of 11.9 and 12.79 μg/ml, respectively. The inhibitory effect observed in the NF-κB assay suggested apoptotic potential of hematite NPs to cancerous cells. The green chemistry route reported in this paper for Fe2O3 NP synthesis can be safely and efficiently explored for treatment of cancer and as theranostic agent.

New 1-phthalazinone Scaffold based Compounds: Design, Synthesis, Cytotoxicity and Protein Kinase Inhibition Activity

A series of thirty-one new 1-phthalazinones was designed and synthesized based on the well-known VEGFR inhibitor vatalanib. The obtained phthalazinones were screened for their cytotoxic activity against DLD-1 and LoVo (colon), and Panc-1 and Paca-2 (pancreas) cancer cell lines using MTT assay. The tested compounds revealed exceptionally promising cytotoxic activity against LoVo cell lines with IC50 ranges 0.18-780 nM. Finally, these compounds were also found to be dual inhibitors of VEGFR-2 and EGFR in the in vitro enzyme assay with higher potency against the former (IC50 = 0.023-0.41 nM).

New ferrocenyl guanidines as potent antioxidants, protein kinase inhibitors and cytotoxic agents against human leukemia THP-1 cell line

Six new ferrocenyl guanidines were synthesized and characterized by elemental analysis, FT-IR and 1H and 13C NMR. Compounds 1–6 were screened for antioxidant, protein kinase inhibition, lethality of brine shrimp, and cytotoxicity against the human leukemia THP-1 cell line. The compounds demonstrated moderate to significant activities. Antioxidant activity of the synthesized compounds was evaluated by DPPH % inhibition with IC50 values. All compounds 1–6 showed notable antioxidant activity with DPPH having IC50 values between 23.2–15.1 and noteworthy brine shrimp lethality. Compound 6 demonstrated the highest cytotoxicity against brine shrimps with LC50 of 9.09 μg/mL. Protein kinase inhibition activity showed significant hyphea formation inhibition at 100 μg/disc with 10 to 13 mm clear zone of inhibition for the compounds 2–6. The compounds were screened for in vitro cytotoxicity using human leukemia cell line (THP-1 ATCC#TIB-202). Among all compounds, the most significant activity was demonstrated by compounds 6 and 5 with IC50 of 3.88 and 5.59 μg/mL which was comparable with the standard 5-flourouracil and vincristine drugs.

Antioxidant, Antimicrobial, Cytotoxic and Protein Kinase Inhibition Activities of Fifteen Traditional Medicinal Plants From Pakistan

Crude methanol extracts of fifteen ethnopharmacological plants were prepared by simple maceration procedure for studying their phytochemical and antimicrobial properties, cytotoxicity, and protein kinase inhibition activity. Among all, the maximum gallic acid equivalent (GAE) total phenolic content and quercetin equivalent (QE) total flavonoid content were found in Ficus carica (8.6 and 7.1 μg/mg DW, respectively). F. carica also exhibited significantly higher (P < 0.05) antiradical (DPPH) potential (IC50 = 12.6 μg/mL). Mentha piperita exhibited maximum total antioxidant capacity and reduction potential when expressed as equivalent to ascorbic acid (12.82 and 5.11 μg/mg DW, respectively). Ricinis communis was found more susceptible to Staphylococcus aureus, followed by Cannabis sativa against Salmonella typhi and Calotropis procera against Micrococcus luteus. A remarkable degree of cytotoxicity against brine shrimps was exhibited by Euphorbia helioscopia, with 50% mortality at 57.74 μg/mL. Convolvulus arvensis showed noteworthy protein kinase inhibitory activity with 20 ± 1.2 mm zone of inhibition (ZOI) analyzed by Streptomyces hyphae formation inhibition. It is concluded that methanol extracts of F. carica and M. piperita can be considered as potential sources of antioxidants, while R. communis, E. helioscopia and C. arvensis could provide potent antimicrobial and cytotoxic agent and oncogenic kinase inhibitor, respectively.

Green synthesis of silver nanoparticles from grape and tomato juices and evaluation of biological activities.

The biosynthesis of silver nanoparticles (AgNPs) is substantial for its application in lots of fields. Tomato and grape fruit juices were used as a reducing and capping agents for the biosynthesis of AgNPs. Ultraviolet spectroscopic analysis offered peaks in the range of 396‒420 nm that indicate the production of AgNPs. Fourier transform infrared spectroscopy analysis revealed attachment of different functional groups with Ag ion in both tomato and grape fruit extracts NPs. The X‒ray diffraction analysis confirmed that the synthesised AgNPs have a face centred cubic confirmation. Scanning electron microscopy confirms the size of NPs that varies from 10 to 30 nm. The DPPH free radical scavenging assay, total antioxidant capacity, reducing power assay, total flavonoid contents and total phenolic contents determination confirmed that synthesised AgNPs are potent antioxidant agents; can be used as an effective scavenger of free radicals. Biosynthesised AgNPs also showed good antibacterial activity against Pseudomonas septica, Staphylococcus aureus, Micrococcus luteus, Enterobacter aerogenes, Bacillus subtilis and Salmonella typhi. Protein kinase inhibition activity showed a clear zone which indicates anticancerous potential of biosynthesised AgNPs. The efficacious bioactivities indicate that the tomato and grape derived AgNPs can be used efficiently in pharmaceutical and medical industries.

Characterization of an Environmental DNA‐Derived Gene Cluster that Encodes the Bisindolylmaleimide Methylarcyriarubin

Bisindolylmaleimides represent a naturally occurring class of metabolites that are of interest because of their protein kinase inhibition activity. From a metagenomic library constructed with soil DNA, we identified the four gene mar cluster, a bisindolylmaleimide gene cluster that encodes for methylarcyriarubin (1) production. Heterologous expression of the mar gene cluster in E. coli revealed that the Rieske dioxygenase MarC facilitates the oxidative decarboxylation of a chromopyrrolic acid (CPA) intermediate to yield the bisindolylmaleimide core. The characterization of the mar cluster defines a new role for CPA in the biosynthesis of structurally diverse bacterial tryptophan dimers.

Structure-based design and synthesis of novel pseudosaccharine derivatives as antiproliferative agents and kinase inhibitors

This study is concerned with the implementation of structure-based techniques for the design of new heterocyclic compounds based on pseudosaccharine scaffold with protein kinase inhibition activity. This nucleus was exploited based on the well-known quinazoline core and its interactions with several protein kinases. Two series of compounds employing this new scaffold were synthesized and evaluated at enzymatic and cellular levels. Compound 9b displayed broad spectrum antiproliferative activity on NCI 60-cell lines panel with mean GI50 of 5.4 μM. Investigation of the molecular mechanism showed probable inhibitory activity against Src kinase.

Matrix Metalloproteinase–Activated Anthrax Lethal Toxin Inhibits Endothelial Invasion and Neovasculature Formation during In vitro Morphogenesis

Solid tumor growth is dependent on angiogenesis, the formation of neovasculature from existing vessels. Endothelial activation of the extracellular signal-regulated kinase 1/2, c-jun NH(2)-terminal kinase, and p38 mitogen-activated protein kinase pathways is central to this process, and thus presents an attractive target for the development of angiogenesis inhibitors. Anthrax lethal toxin (LeTx) has potent catalytic mitogen-activated protein kinase inhibition activity. Preclinical studies showed that LeTx induced potent tumor growth inhibition via the inhibition of xenograft vascularization. However, LeTx receptors and the essential furin-like activating proteases are expressed in many normal tissues, potentially limiting the specificity of LeTx as an antitumor agent. To circumvent nonspecific LeTx activation and simultaneously enhance tumor vascular targeting, a substrate preferably cleaved by the gelatinases class of matrix metalloproteinases (MMP) was substituted for the furin LeTx activation site. In vivo efficacy studies showed that this MMP-activated LeTx inhibited tumor xenografts growth via the reduced migration of endothelial cells into the tumor parenchyma. Here we have expanded on these initial findings by showing that this MMP-activated LeTx reduces endothelial proangiogenic MMP expression, thus causing a diminished proteolytic capacity for extracellular matrix remodeling and endothelial differentiation into capillary networks. Additionally, our data suggest that inhibition of the c-jun NH(2)-terminal kinase and p38, but not extracellular signal-regulated kinase-1/2, pathways is significant in the antiangiogenic activity of the MMP-activated LeTx. Collectively, these results support the clinical development of the MMP-activated LeTx for the treatment of solid tumors.

New Bromopyrrole Alkaloids from the Marine Sponges Axinella Damicornis and Stylissa Flabelliformis

Investigation of the tropical sponges Axinella damicornis and Stylissa flabelliformis, family Axinillidae, afforded five new bromopyrrole alkaloids (1–5) and thirteen known compounds (6–18). Semi synthesis of 5 was carried out in order to confirm its structure. The structures of the isolated compounds were elucidated using 1D- and 2D-NMR spectroscopy and mass spectrometry. The cytotoxicity, antimicrobial and protein-kinase inhibition activities were tested for the isolated compounds.