Y. Arun

Facile one-pot synthesis of novel dispirooxindole-pyrrolidine derivatives and their antimicrobial and anticancer activity against A549 human lung adenocarcinoma cancer cell line.

Novel dispirooxindole-pyrrolidine derivatives have been synthesized through 1,3-dipolar cycloaddition of an azomethine ylide generated from isatin and sarcosine with the dipolarophile 3-(1H-indol-3-yl)-3-oxo-2-(2-oxoindolin-3-ylidene)propanenitrile, and also spiro compound of acenaphthenequinone obtained by the same optimized reaction condition. Synthesized compounds were evaluated for their antimicrobial activity and all the compounds shown significant activity. Anticancer activity was evaluated against A549 human lung adenocarcinoma cancer cell lines. Compounds 7b, 7g, 7i and 7r exhibit very good anticancer activity 62.96%, 62.03%, 67.67% and 60.22%, respectively, at the dose of 200μg/mL and compound 7i shows IC50 value in 50μg/mL.

Novel spirooxindole–pyrrolidine compounds: Synthesis, anticancer and molecular docking studies

Novel spirooxindole-pyrrolidine compounds have been synthesised through 1,3-dipolar cycloaddition of azomethine ylides generated from isatin and sarcosine or thioproline with the dipolarophile 3-(1H-imidazol-2-yl)-2-(1H-indole-3-carbonyl)acrylonitrile under the optimised reaction condition. Synthesised compounds were evaluated for their anticancer activity against A549 human lung adenocarcinoma cancer cell line. Among the 29 tested compounds 4j, 6b and 6h showed very high activity 66.3%, 64.8% and 66.3% at 25 μg/mL concentration against A549 lung adenocarcinoma cancer cell line. These spirooxindole-pyrrolidine compounds can be promising therapeutic agents for A549 lung adenocarcinoma cancer cell line.

Synthesis, DNA/protein binding, molecular docking, DNA cleavage and in vitro anticancer activity of nickel(II) bis(thiosemicarbazone) complexes

A series of N-substituted isatin thiosemicarbazone ligands (L1–L5) and their nickel(II) complexes [Ni(L)2] (1–5) were synthesized and characterized by elemental analyses and UV-Visible, FT-IR, 1H & 13C NMR, and mass spectroscopic techniques. The molecular structure of the ligands (L1 and L2) and complex 1 was confirmed by single crystal X-ray crystallography. The single crystal X-ray structure of 1 showed distorted octahedral geometry. The interaction of calf thymus (CT) DNA and bovine serum albumin (BSA) with the nickel(II) complexes was explored using absorption and emission spectral methods. A DNA cleavage study showed that the complexes cleaved DNA without any external agents. The alterations in the secondary structure of the protein by the nickel(II) complexes (1–5) were confirmed by synchronous and three dimensional fluorescence spectroscopic studies. The interaction of the complexes with DNA/protein also has been supported by molecular docking studies. An in vitro cytotoxicity study of the complexes found significant activity against human breast (MCF7) and lung (A549) cancer cell lines, with the best results for complexes 4 and 2 respectively, where the IC50 value is less than 0.1 μM concentration.

DNA/protein binding, DNA cleavage, cytotoxicity, superoxide radical scavenging and molecular docking studies of copper(II) complexes containing N-benzyl-N′-aryl-N′′-benzoylguanidine ligands

Five copper(II) complexes containing N,N′,N′′-trisubstituted guanidine ligands were synthesized and characterized by elemental analyses and UV-Visible, FT-IR, EPR and mass spectroscopic techniques. The synthesized copper(II) complexes (1–5) bear the general formula [Cu{C6H5CONC(NR)NHCH2C6H5}2] where R = phenyl (1), 4-methylphenyl (2), 4-ethoxyphenyl (3), 2-methoxyphenyl (4) or 1-naphthyl (5). The four coordinated square planar geometry of the complexes was confirmed by the single crystal X-ray diffraction study. The interaction of the Cu(II) complexes with calf thymus DNA (CT DNA) was explored using absorption and fluorescence spectroscopic methods. The results revealed that the complexes have an affinity constant for DNA in the order of 104 M−1 and the mode of interaction is non-covalent intercalation. The DNA cleavage study showed that the complexes cleaved DNA without any external agent. The interaction of Cu(II) complexes with bovine serum albumin (BSA) was also studied using absorption and fluorescence techniques. The cytotoxic activity of the Cu(II) complexes was probed in vitro against human breast (MCF7) and lung (A549) cancer cell lines. The complexes were also tested against mouse embryonic fibroblast (NIH 3T3) cell lines. Complexes 1 and 3 have good cytotoxic activity which is comparable with the cyclophosphamide drug. The complexes were less cytotoxic towards normal cell lines showing that they affect only cancer cell lines. Superoxide radical scavenging property of the complexes was assessed using the NBT assay. Copper(II) complexes showed appreciable superoxide radical scavenging activity with IC50 values ranging from 1.53 to 5.62 μM. A further molecular docking technique was employed to understand the binding of the complexes toward the molecular target DNA and human DNA topoisomerase I.

DNA binding, molecular docking and apoptotic inducing activity of nickel(II), copper(II) and zinc(II) complexes of pyridine-based tetrazolo[1,5-a]pyrimidine ligands

Six mononuclear copper(II), nickel(II) and zinc(II) complexes, [ML1Cl2] (1–3) and [M(L2)2Cl2] (4–6), of two biologically active tetrazolo[1,5-a]pyrimidine core ligands, ethyl 5-methyl-7-pyridine-2-yl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate (L1) and ethyl-5-methyl-7-pyridine-4-yl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate (L2), have been synthesized and characterized. The molecular structure of the ligands (L1&2) and complex 6 were determined by single crystal X-ray diffraction. The X-ray crystal structure of 6 confirms that it has a distorted tetrahedral structure with a ZnN2Cl2 coordination environment. All of the complexes exhibit an unusually strong luminescence at room temperature. Electroparamagnetic resonance spectra of copper(II) complexes (2 and 5) show four lines, characteristic of square planar geometry, with nuclear hyperfine spin 3/2. DNA binding studies of complexes with calf-thymus DNA suggest that complexes 2 and 5 bind in the grooves of the DNA. These results were further supported by molecular docking studies. In vitro cytotoxic activities of the ligands (L1&2) and complexes (1–6) against human cancer cell lines such as lung (A549), cervical (HeLa), colon (HCT-15) and a non-cancer human embryonic kidney cell line revealed that the complexes selectively inhibit the growth of cancer cells and are inactive against non-cancer cell lines, whereas the ligands were found to be inactive with both cancer and non-cancer cell lines. The IC50 values of the complexes revealed that the copper(II) complexes (2 and 5) exhibit high cytotoxic activity against colon (HCT-15) cells when compared to the standard drug cisplatin. Furthermore, the live cell and fluorescent imaging of cancer cells show that complexes 2 and 5 induce cell death through apoptosis.

In vitro anticancer activity of methyl caffeate isolated from Solanum torvum Swartz. fruit.

The present study was undertaken to investigate the anticancer activity of methyl caffeate isolated from Solanum torvum Swartz. fruit and to explore the molecular mechanisms of action in MCF-7 cells. Cytotoxic properties of hexane, ethyl acetate and methanol extracts were carried out against MCF-7 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Ethyl acetate extract showed good cytototoxic activities compared to hexane and methanol extracts. Methyl caffeate was isolated from the ethyl acetate extract using column chromatography. Cytotoxic properties of methyl caffeate was investigated against MCF-7, A549, COLO320, HepG-2 and Vero cells. The compound showed potent cytotoxic properties against MCF-7 cells compared to A549, COLO320 and HepG-2 cells. Methyl caffeate significantly reduced cell proliferation and increased formation of fragmented DNA and apoptotic body in MCF-7 cells. Bcl-2, Bax, Bid, p53, caspase-3, PARP and cytochrome c release were detected by western blot analysis. The activities of caspases-3 and PARP gradually increased after the addition of isolated compound. Bcl-2 protein was down regulated; Bid and Bax were up regulated after the treatment with methyl caffeate. Molecular docking studies showed that the compound bound stably to the active sites of poly (ADP-ribose) polymerase-1 (PARP1), B cell CLL/lymphoma-2 (BCL-2), E3 ubiquitin-protein ligase (MDM2) and tubulin. The results strongly suggested that methyl caffeate induced apoptosis in MCF-7 cells via caspase activation through cytochrome c release from mitochondria.

An expedient route to highly diversified [1,2,3]triazolo[1,5-a][1,4]benzodiazepines and their evaluation for antimicrobial, antiproliferative and in silico studies

An efficient diversity oriented synthesis of [1,2,3]triazolo[1,5-a][1,4]benzodiazepines has been developed by sequential diazotization, azidation and cycloaddition reactions in a one-pot fashion. This strategy allows an easy accessibility of triazole fused [1,4]benzodiazepines in good yields. The main objective of this methodology is to introduce various substituents at all possible positions under mild reaction conditions. All the synthesized compounds were evaluated for their antimicrobial, anticancer and in silico activity. Among the tested compounds (2a–n), the derivatives 2a, 2b, 2d, 2k, 2g, 2j, 2m and 2l have displayed a broad spectrum of antibacterial activity. Anticancer activity results revealed that compounds 2a, 2g and 2m exhibited potent in vitro anticancer activity against A549 lung adenocarcinoma cancer cell line. Further, molecular docking studies of all the synthesized compounds were performed to gain a comprehensive understanding of the plausible binding modes and also to compare the theoretical and experimental results of these compounds.

In vitro antiproliferative activity of 2,3-dihydroxy-9,10-anthraquinone induced apoptosis against COLO320 cells through cytochrome c release caspase mediated pathway with PI3K/AKT and COX-2 inhibition.

The present study investigated the anticancer activity of 2,3-dihydroxy-9,10-anthraquinone against different cancer cells such as MCF-7, COLO320, HepG-2, Skov-3, MOLM-14, NB-4, CEM, K562, Jurkat, HL-60, U937, IM-9 and Vero. 2,3-dihydroxy-9,10-anthraquinone showed good antiproliferative activity against COLO320 cells when compared to other tested cells. The cytotoxicity results showed 79.8% activity at the dose of 2.07 μM with IC50 value of 0.13 μM at 24 h in COLO320 cells. So we chose COLO320 cells for further anticancer studies. mRNA expression was confirmed by qPCR analysis using SYBR green method. Treatment with 2,3-dihydroxy-9,10-anthraquinone was found to trigger intrinsic apoptotic pathway as indicated by down regulation of Bcl-2, Bcl-xl; up regulation of Bim, Bax, Bad; release of cytochrome c and pro-caspases cleaving to caspases. Furthermore, 2,3-dihydroxy-9,10-anthraquinone stopped at G0/G1 phase with modulation in protein levels of cyclins. On the other hand PI3K/AKT signaling plays an important role in cell metabolism. We found that 2,3-dihydroxy-9,10-anthraquinone inhibits PI3K/AKT activity after treatment. Also, COX-2 enzyme plays a major role in colorectal cancer. Our results showed that the treatment significantly reduced COX-2 enzyme in COLO320 cells. These results indicated antiproliferative activity of 2,3-dihydroxy-9,10-anthraquinone involving apoptotic pathways, mitochondrial functions, cell cycle checkpoint and controlling the over expression genes during the colorectal cancer. Molecular docking studies showed that the compound bound stably to the active sites of Bcl-2, COX-2, PI3K and AKT. This is the first report of anticancer mechanism involving 2,3-dihydroxy-9,10-anthraquinone in COLO320 cells. The present results might provide helpful suggestions for the design of antitumor drugs toward colorectal cancer treatment.

In vitro and in vivo anticancer activity of 2-acetyl-benzylamine isolated from Adhatoda vasica L. leaves

One of the important aims of drug discovery for cancer is to find therapeutic agents from natural products that are effective and safe for cancer treatment. In the current study, an alkaloid, 2-acetyl-benzylamine, isolated from Adhatoda vasica, was screened for potent anticancer properties against leukemia cells. We used seven different types of leukemia cells such as CEM, NB-4, MOLM-14, Jurkat, IM-9, K562 and HL-60 for cytotoxic studies. 2-acetyl-benzylamine showed significant cytotoxic properties against MOLM-14 and NB-4 cells with IC50 values of 0.40 and 0.39mM at 24h when compared to other tested cells, respectively. Apoptosis was confirmed by annexin V-FITC/PI kit using flow cytometry and confocal microscope in MOLM-14 and NB-4 cells. In addition, 2-acetyl-benzylamine induced cell cycle arrest at G2/M phase in MOLM-14 cells and G0/G1 phase in NB-4 cells. Apoptosis mechanism was confirmed by RT-PCR and Western blot analysis. Treatment with 2-acetyl-benzylamine decreased the Bcl-2 activity and increased the Bax expression; cytochrome c was released and caspases-3 was activated in MOLM-14 and NB-4 cells. Besides, 2-acetyl-benzylamine inhibited the expression of JAK2/STAT3 in MOLM-14 and NB-4 cells. In vivo administration of 2-acetyl-benzylamine inhibited the growth of MOLM-14 cells in xenograft mice model. Molecular docking study has been performed to investigate the binding mode and to estimate the binding energy of 2-acetyl-benzylamine with the active site of JAK-2, AKT1, FLT3 and Bcl-2. The above findings proved that 2-acetyl-benzylamine could be developed as a potential therapeutic agent against cancer.

Ru(II)-Catalyzed Regiospecific C?H/O?H Oxidative Annulation to Access Isochromeno[8,1- ab ]phenazines: Far-Red Fluorescence and Live Cancer Cell Imaging

A facile ruthenium(II)-catalyzed regiospecific C–H/O–H oxidative annulation methodology was developed to construct isochromeno[8,1-ab]phenazines. This methodology delivers various advantages, such as scope for diverse substrates, tolerance to a range of functional groups, stability under air, and yields regioselective products. This methodology was successfully applied to synthesize far red (FR) fluorescent probes for live cancer cell imaging. The synthesized compounds displayed notable fluorescence properties in solution and thin-film. Their application in live cancer cell imaging was investigated using various cancer cell lines. The synthesized compound showed prominent FR fluorescence, with high quantum yield, and exhibited better cell-imaging properties, with excellent biocompatibility.