Nanotoxicity of multifunctional stoichiometric cobalt oxide nanoparticles (SCoONPs) with repercussions toward apoptosis, necrosis, and cancer necrosis factor (TNF-α) at nano-biointerfaces.

Introduction: Apoptosis, necrosis, and cancer necrosis factor (TNF-a) are all impacted by the nanotoxicity of multifunctional stoichiometric cobalt oxide nanoparticles (SCoONPs) at nano-biointerfaces. The creation of multi-functional nanoparticles has had a considerable impact on the transport of drugs and genes, nanotheranostics (in-vivo imaging, concurrent diagnostics), interventions for external healing, the creation of nano-bio interfaces, and the instigation of desired changes in nanotherapeutics. Objectives: The quantitative structure-activity relationships, chemical transformations, biological interactions as well as toxicological analyses are considered as main objectives. Discrete dimensions of SCoNPs-cell interaction interfaces, their characteristic physical features (size, shape, shell structure, and surface chemistry), impact on cell proliferation and differentiation are the key factors responsible for nanotoxicity. Methods: The development of multi-functional nanoparticles has been significant in drug/gene delivery, nanotheranostics (in-vivo imaging, coinciding diagnostics), and external healing interventions, designing a nano-bio interface, as well as inciting desired alterations in nanotherapeutics. Every so often, the cellular uptake of multi-functional cobalt [Co, CoO, Co2(CO)8 and Co3O4] nanoparticles (SCoONPs) influences cellular mechanics and initiates numerous repercussions (oxidative stress, DNA damage, cytogenotoxicity, and chromosomal damage) in pathways, including the generation of dysregulating factors involved in biochemical transformations. Results: The concerns and influences of multifunctional SCoNPs on different cell mechanisms (mitochondria impermeability, hydrolysis of ATP, the concentration of Ca2+, impaired calcium clearance, defective autophagy, apoptosis, and necrosis), and interlinked properties (adhesion, motility, and internalization dynamics, role in toxicity, surface hydrophilic and hydrophobicity, biokinetics and biomimetic behaviors of biochemical reactions) have also been summarized. SCoONPs have received a lot of interest among the nanocarriers family because of its advantageous qualities such as biodegradability, biocompatibility, nontoxicity, and nonimmunogenicity. Conclusion: Various applications, such as bio-imaging, cell labeling, gene delivery, enhanced chemical stability, and increased biocompatibility, concerning apoptosis, necrosis, and nano-bio interfaces, along with suitable examples. In this analysis, the multi-functional cobalt [Co, CoO, Co2(CO)8 and Co3O4] nanoparticles (SCoNPs) intricacies (cytogenotoxicity, clastogenicity, and immunomodulatory), nanotoxicity, and associated repercussions have been highlighted and explained.

Reproductive toxicity of combined effects of endocrine disruptors on human reproduction.

Confluence of environmental, genetic, and lifestyle variables is responsible for deterioration of human fecundity. Endocrine disruptors or endocrine disrupting chemicals (EDCs) may be found in a variety of foods, water, air, beverages, and tobacco smoke. It has been demonstrated in experimental investigations that a wide range of endocrine disrupting chemicals have negative effects on human reproductive function. However, evidence on the reproductive consequences of human exposure to endocrine disrupting chemicals is sparse and/or conflicting in the scientific literature. The combined toxicological assessment is a practical method for assessing the hazards of cocktails of chemicals, co-existing in the environment. The current review provides a comprehensive overview of studies emphasizing the combined toxicity of endocrine disrupting chemicals on human reproduction. Endocrine disrupting chemicals interact with each other to disrupt the different endocrine axes, resulting in severe gonadal dysfunctions. Transgenerational epigenetic effects have also been induced in germ cells, mostly through DNA methylation and epimutations. Similarly, after acute or chronic exposure to endocrine disrupting chemicals combinations, increased oxidative stress (OS), elevated antioxidant enzymatic activity, disrupted reproductive cycle, and reduced steroidogenesis are often reported consequences. The article also discusses the concentration addition (CA) and independent action (IA) prediction models, which reveal the importance of various synergistic actions of endocrine disrupting chemicals mixtures. More crucially, this evidence-based study addresses the research limitations and information gaps, as well as particularly presents the future research views on combined endocrine disrupting chemicals toxicity on human reproduction.

Synthesis and Biological Evaluation of 5'-O-Fatty Acyl Ester Derivatives of 3'-Fluoro-2',3'-dideoxythymidine as Potential Anti-HIV Microbicides.

A number of 5'-O-fatty acyl derivatives of 3'-fluoro-2',3'-dideoxythymidine (FLT, 1) were synthesized. These conjugates were evaluated for their potential as topical microbicides with anti-HIV activity against cell-free (X4 and R5), cell-associated, and multidrug-resistant viruses. Compared to FLT and 3'-azido-2',3'-dideoxythymidine (AZT), 5'-O-(12-azidododecanoyl) (5), 5'-O-myristoyl (6), and 5'-O-(12-thioethyldodecanoyl) (8) derivatives of FLT were found to be more active against both cell-free viruses (lymphocytotropic and monocytotropic strains) with EC50 values of 0.4 µM, 1.1 µM, and <0.2 µM, respectively, as well as cell-associated virus with EC50 values of 12.6, 6.4, and 2.3 µM, respectively. Conjugates 5, 6, and 8 exhibited >4 and >30 times better antiviral index than FLT and AZT, respectively. Conjugates 5 and 8 were significantly more potent than FLT against many multidrug-resistant strains. A comparison of the anti-HIV activity with the corresponding non-hydrolyzable ether conjugates suggested that ester hydrolysis to FLT and fatty acids is critical to enable anti-HIV activity. Cellular uptake studies were conducted using fluorescent derivatives of FLT attached with 5(6)-carboxyfluorescein through either ß-alanine (23) or 12-aminododecanoic acid (24) spacers. The lipophilic fluorescent analog with a long chain (24) showed more than 12 times higher cellular uptake profile than the fluorescent analog with a short chain (23). These studies further confirmed that the attachment of fatty acids improved the cellular uptake of nucleoside conjugates. In addition, 5, 6, and 8 were the least cytotoxic and did not alter vaginal cell and sperm viability compared to the positive control, a commercial topical spermicide (N-9), which significantly decreased sperm and vaginal cell viability inducing the generation of proinflammatory cytokines.

Review of nanotheranostics for molecular mechanisms underlying psychiatric disorders and commensurate nanotherapeutics for neuropsychiatry: The mind knockout.

Bio-neuronal led psychiatric abnormalities transpired by the loss of neuronal structure and function (neurodegeneration), pro-inflammatory cytokines, microglial dysfunction, altered neurotransmission, toxicants, serotonin deficiency, kynurenine pathway, and excessively produced neurotoxic substances. These uncontrolled happenings in the etiology of psychiatric disorders initiate further changes in neurotransmitter metabolism, pathologic microglial, cell activation, and impaired neuroplasticity. Inflammatory cytokines, the outcome of dysfunctional mitochondria, dysregulation of the immune system, and under stress functions of the brain are leading biochemical factors for depression and anxiety. Nanoscale drug delivery platforms, inexpensive diagnostics using nanomaterials, nano-scale imaging technologies, and ligand-conjugated nanocrystals used for elucidating the molecular mechanisms and foremost cellular communications liable for such disorders are highly capable features to study for efficient diagnosis and therapy of the mental illness. These theranostic tools made up of multifunctional nanomaterials have the potential for effective and accurate diagnosis, imaging of psychiatric disorders, and are at the forefront of leading technologies in nanotheranostics openings field as they can collectively and efficiently target the stimulated territories of the cerebellum (cells and tissues) through molecular-scale interactions with higher bioavailability, and bio-accessibility. Specifically, the nanoplatforms based neurological changes are playing a significant role in the diagnosis of psychiatric disorders and portraying the routes of functional restoration of mental disorders by newer imaging tools at nano-level in all directions. Because of these nanotherapeutic platforms, the molecules of nanomedicine can penetrate the Blood-Brain Barrier with an increased half-life of drug molecules. The discoveries in nanotheranostics and nanotherapeutics inbuilt unique multi-functionalities are providing the best multiplicities of novel nanotherapeutic potentialities with no toxicity concerns at the level of nano range.

Cleaning the molecular machinery of cells via proteostasis, proteolysis and endocytosis selectively, effectively, and precisely: intracellular self-defense and cellular perturbations.

Network coordinates of cellular processes (proteostasis, proteolysis, and endocytosis), and molecular chaperones are the key complements in the cell machinery and processes. Specifically, cellular pathways are responsible for the conformational maintenance, cellular concentration, interactions, protein synthesis, disposal of misfolded proteins, localization, folding, and degradation. The failure of cellular processes and pathways disturbs structural proteins and the nucleation of amyloids. These mishaps further initiate amyloid polymorphism, transmissibility, co-aggregation of pathogenic proteins in tissues and cells, prion strains, and mechanisms and pathways for toxicity. Consequently, these conditions favor and lead to the formation of elongated amyloid fibrils consisting of many-stranded ß-sheets (N,N-terminus and C,C-terminus), and abnormal fibrous, extracellular, proteinaceous deposits. Finally, these ß-sheets deposit, and cells fail to degrade them effectively. The essential torsion angles (φ, ψ, and ω) define the conformation of proteins and their architecture. Cells initiate several transformations and pathways during the regulation of protein homeostasis based on the requirements for the functioning of the cell, which are governed by ATP-dependent proteases. In this process, the kinetics of the molding/folding phenomenon is disturbed, and subsequently, it is dominated by cross-domain misfolding intermediates; however, simultaneously, it is opposed by small stretching forces, which naturally exist in the cell. The ubiquitin/proteasome system deals with damaged proteins, which are not refolded by the chaperone-type machinery. Ubiquitin-protein ligases (E3-Ub) participate in all the cellular activity initiated and governed by molecular chaperones to stabilize the cellular proteome and participate in the degradation phenomenon implemented for damaged proteins. Optical tweezers, a single-resolution based technique, disclose the folding pathway of linear chain proteins, which is how they convert themselves into a three-dimensional architecture. Further, DNA-protein conjugation analysis is performed to obtain folding energies as single-molecule kinetic and thermodynamic data.

Experimental and Computational Studies of Microwave-Assisted, Facile Ring Opening of Epoxide with Less Reactive Aromatic Amines in Nitromethane.

Nucleophilic ring opening reactions of epoxides with aromatic amines are in the forefront of the synthetic organic chemistry research to build new bioactive scaffolds. Here, convenient, green, and highly efficient regioselective ring opening reactions of sterically hindered (2R,3S)-3-(N-Boc-amino)-1-oxirane-4-phenylbutane with various poorly reactive aromatic amines are accomplished under microwave irradiation in nitromethane. All the reactions effectively implemented for various aromatic amines involve the reuse of nitromethane that supports its dual role as a solvent and catalyst. The corresponding new ß-alcohol analogs of hydroxyethylamine (HEA) are isolated in 41-98% yields. The reactions proceed under mild conditions for a broad range of less reactive and sterically hindered aromatic amines. Proton NMR experiments suggest that the nucleophilicity of amines is influenced by nitromethane, which is substantiated by the extensive computational studies. Overall, this methodology elucidates the first-time use of nitromethane as a solvent for the ring opening reactions under microwave conditions involving an equimolar ratio of epoxide and aromatic amine without any catalyst, facile ring opening of complex epoxide by less reactive aromatic amines, low reaction time, less energy consumption, recycling of the solvent, and simple workup procedures.

Phenylpyrazalopyrimidines as Tyrosine Kinase Inhibitors: Synthesis, Antiproliferative Activity, and Molecular Simulations.

N1-(α,ß-Alkene)-substituted phenylpyrazolopyrimidine derivatives with acetyl and functionalized phenyl groups at α- and ß-positions, respectively, were synthesized by the reaction of 3-phenylpyrazolopyrimidine (PhPP) with bromoacetone, followed by a chalcone reaction with differently substituted aromatic aldehydes. The Src kinase enzyme assay revealed modest inhibitory activity (half maximal inhibitory concentration, IC50 = 21.7-192.1 µM) by a number of PhPP derivatives. Antiproliferative activity of the compounds was evaluated on human leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3), breast carcinoma (MDA-MB-231), and colon adenocarcinoma (HT-29) cells in vitro. 4-Chlorophenyl carbo-enyl substituted 3-phenylpyrazolopyrimidine (10) inhibited the cell proliferation of HT-29 and SK-OV-3 by 90% and 79%, respectively, at a concentration of 50 µM after 96 h incubation. The compound showed modest inhibitory activity against c-Src (IC50 = 60.4 µM), Btk (IC50 = 90.5 µM), and Lck (IC50 = 110 µM), while it showed no activity against Abl1, Akt1, Alk, Braf, Cdk2, and PKCa. In combination with target selection and kinase profiling assay, extensive theoretical studies were carried out to explore the selectivity behavior of compound 10. Specific interactions were also explored by examining the changing trends of interactions of tyrosine kinases with the phenylpyrazolopyrimidine derivative. The results showed good agreement with the experimental selectivity pattern among c-Src, Btk, and Lck.

Synthesis and anti-HIV activities of unsymmetrical long chain dicarboxylate esters of dinucleoside reverse transcriptase inhibitors.

A series of 11 unsymmetrical dicarboxylate conjugates of dinucleoside reverse transcriptase inhibitors were synthesized. Three dicarboxylic acids, succinic acid, suberic acid and 1,14-tetradecandioc acid, were diesterified with either 3'-azido-2',3'-dideoxythymidine (AZT), 3'-fluoro-2',3'-dideoxythymidine (FLT), 2',3'-dideoxy-3'-thiacytidine (3TC), or 5-fluoro-2',3'-dideoxy-3'-thiacytidine (FTC). The anti-HIV activity of synthesized compounds was evaluated against HIV-1 X4 (IIIB) and R5 (BaL) viral strains in single-round infection assays. Results indicated that the tetradecandioate esters of nucleosides were more active against HIV than the corresponding parent nucleosides and nucleoside conjugates. The tetradecandioate conjugate of FLT and FTC (5) was found to be the most potent compounds with EC50 values of 47 and 75nM against X4 and R5 HIV-1 strains, respectively, while the EC50 values for the parent analogs, FLT and FTC, ranged from 700 to 3300nM.

Copper triflate-mediated synthesis of 1,3,5-triarylpyrazoles in [bmim][PF6] ionic liquid and evaluation of their anticancer activities.

A simple, efficient, and environment friendly protocol for the synthesis of 1,3,5-triarylpyrazole and 1,3,5-triarylpyrazolines in [bimm][PF6] ionic liquid mediated by Cu(OTf)2 is described. The reaction protocol gave 1,3,5-triarylpyrazoles in good to high yields (71-84%) via a one-pot addition-cyclocondensation between chalcones and arylhydrazines, and oxidative aromatization without requirement for an additional oxidizing reagent. The catalyst can be reused up to four cycles without much loss in the catalytic activity. The pyrazoles (4a-o) and pyrazolines (3a-n) were evaluated for antiproliferative activity in SK-OV-3, HT-29, and HeLa human cancer cells lines. Among all compounds, 3b inhibited cell proliferation of HeLa cells by 80% at a concentration of 50 µM.

Design and biological evaluation of cell-penetrating peptide-doxorubicin conjugates as prodrugs.

Doxorubicin (Dox) is a hydrophilic anticancer drug that has short retention time due to the efficient efflux in some cancer cells (e.g., ovarian adenocarcinoma SK-OV-3). Cyclic [W(RW)(4)] and the corresponding linear peptide (RW)(4) were conjugated with Dox through an appropriate linker to afford cyclic [W(RW)(4)]-Dox and linear (RW)(4)-Dox conjugates to enhance the cellular uptake and cellular retention of the parent drug for sustained anticancer activity. Comparative antiproliferative assays between covalent (cyclic [W(RW)(4)]-Dox and linear (RW)(4)-Dox) and the corresponding noncovalent physical mixtures of the peptides and Dox were performed. Cyclic [W(RW)(4)]-Dox inhibited the cell proliferation of human leukemia (CCRF-CEM) (62-73%), ovarian adenocarcinoma (SK-OV-3) (51-74%), colorectal carcinoma (HCT-116) (50-67%), and breast carcinoma (MDA-MB-468) (60-79%) cells at a concentration of 1 µM after 72-120 h of incubation. Cyclic [W(RW)(4)]-Dox exhibited higher antiproliferative activity than linear (RW)(4)-Dox in all cancer cells with the highest activity observed after 72 h. Flow cytometry analysis showed 3.6-fold higher cellular uptake of cyclic [W(RW)(4)]-Dox than Dox alone in SK-OV-3 cells after 24 h incubation. The cellular hydrolysis study showed that 99% of cyclic [W(RW)(4)]-Dox was hydrolyzed intracellularly within 72 h and released Dox. These data suggest that cyclic [W(RW)(4)]-Dox can be used as a potential prodrug for improving the cellular delivery and retention of Dox.

Emtricitabine prodrugs with improved anti-HIV activity and cellular uptake.

Three fatty acyl conjugates of (-)-2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC, emtricitabine) were synthesized and evaluated against HIV-1 cell-free and cell-associated virus and compared with the corresponding parent nucleoside and physical mixtures of FTC and fatty acids. Among all the compounds, the myristoylated conjugate of FTC (5, EC(50) = 0.07-3.7 µM) displayed the highest potency. Compound 5 exhibited 10-24 and 3-13-times higher anti-HIV activity than FTC alone (EC(50) = 0.7-88.6 µM) and the corresponding physical mixtures of FTC and myristic acid (14, EC(50) = 0.2-20 µM), respectively. Cellular uptake studies confirmed that compound 5 accumulated intracellularly after 1 h of incubation and underwent intracellular hydrolysis in CCRF-CEM cells. Alternative studies were conducted using the carboxyfluorescein conjugated with FTC though ß-alanine (12) and 12-aminododecanoic acid (13). Acylation of FTC with a long-chain fatty acid in 13 improved its cellular uptake by 8.5-20 fold in comparison to 12 with a short-chain ß-alanine. Compound 5 (IC(90) = 15.7-16.1 nM) showed 6.6- and 35.2 times higher activity than FTC (IC(90) = 103-567 nM) against multidrug resistant viruses B-NNRTI and B-K65R, indicating that FTC conjugation with myristic acid generates a more potent analogue with a better resistance profile than its parent compound.

N-Myristoylglutamic Acid Derivative of 3'-Fluoro-3'-Deoxythymidine as an Organogel.

Designing microbicidal gels of anti-HIV drugs for local application to prevent HIV infection is a subject of major interest. 3'-Fluoro-3'-deoxythymidine (FLT), a nucleoside reverse transcriptase inhibitor (NRTI), was conjugated with a N-myristoyl glutamate scaffold. The conjugate showed gelation at 1% (w/w) in different organic solvents, such as toluene, dichloromethane, and chloroform. The gels were opaque and stable at room temperature. The results indicate that myristoyl glutamate derivative of FLT can form an organogel. The gel could have potential application as a topical anti-HIV microbicidal agent.

Synthesis and biological evaluation of fatty acyl ester derivatives of (-)-2',3'-dideoxy-3'-thiacytidine.

A number of fatty acyl derivatives of (-)-2',3'-dideoxy-3'-thiacytidine (lamivudine, 3TC, 1) were synthesized and evaluated for their anti-HIV activity. The monosubstituted 5'-O-fatty acyl derivatives of 3TC (EC(50) = 0.2-2.3 µM) were more potent than the corresponding monosubstituted N(4)-fatty acyl (EC(50) = 0.4-29.4 µM) and 5'-O-N(4)-disubstituted (EC(50) = 72.6 to >154.0 µM) derivatives of the nucleoside. 5'-O-Myristoyl (16) and 5'-O-12-azidododecanoyl derivatives (17) were found to be the most potent compounds (EC(50) = 0.2-0.9 µM) exhibiting at least 16-36-fold higher anti-HIV activity against cell-free virus than 1 (EC(50) = 11.4-32.7 µM). The EC(90) values for 16 against B-subtype and C-subtype clinical isolates were several folds lower than those of 1. The cellular uptake studies confirmed that compound 16 accumulated intracellularly after 1 h of incubation with CCRF-CEM cells and underwent intracellular hydrolysis. 5'-O-Fatty acyl derivatives of 1 showed significantly higher anti-HIV activity than the corresponding physical mixtures against the B-subtype virus.

Synthesis and anti-HIV activities of glutamate and peptide conjugates of nucleoside reverse transcriptase inhibitors.

Mono-, di-, and trinucleoside conjugates of glutamate or peptide scaffolds containing nucleoside reverse transcriptase inhibitors were synthesized. Among dinucleoside glutamate ester derivatives, N-myristoylated derivatives showed significantly higher anti-HIV activity than the corresponding N-acetylated conjugates against cell-free virus. Myristoyl-Glu(3TC)-FLT (46, EC(50) = 0.3-0.6 µM) and myristoyl-Glu(FTC)-FLT (47, EC(50) = 0.1-0.4 µM) derivatives were the most active glutamate-dinucleoside conjugates. A trinucleoside glutamate derivative containing AZT, FLT, and 3TC (34, EC(50) = 0.9-1.4 µM) exhibited higher anti-HIV activity than AZT and 3TC against cell-free virus. Compound 34 also exhibited higher anti-HIV activity against multidrug (IC(50) = 5.9 nM) and NNRTI (IC(50) = 12.9 nM) resistant viruses than parent nucleosides. The physical mixture containing FLT-succinate, AZT, 3TC, and glutamic acid exhibited 115-fold less activity against cell associated virus (EC(50) = 91.9 µM) when compared to 34 (EC(50) = 0.8 µM). Other conjugates showed less or comparable potency to that of the corresponding physical mixtures.

Synthesis, anticancer activities, and cellular uptake studies of lipophilic derivatives of doxorubicin succinate.

A number of lipophilic 14-substituted derivatives of doxorubicin were synthesized through conjugation of doxorubicin-14-hemisuccinate with different fatty amines or tetradecanol to enhance the lipophilicity, cellular uptake, and cellular retention for sustained anticancer activity. The conjugates inhibited the cell proliferation of human leukemia (CCRF-CEM, 69-76%), colon adenocarcinoma (HT-29, 60-77%), and breast adenocarcinoma (MDA-MB-361, 66-71%) cells at a concentration of 1 µM after 96-120 h of incubation. The N-tetradecylamido derivative of doxorubicin 14-succinate (10) exhibited consistently comparable antiproliferative activity to doxorubicin in a time-dependent manner (IC(50) = 77 nM in CCRF-CEM cells). Flow cytometry analysis showed a 3-fold more cellular uptake of 10 than doxorubicin in SK-OV-3 cells. Confocal microscopy revealed that the conjugate was distributed in cytoplasmic and perinuclear areas during the first 1 h of incubation and slowly relocalized in the nucleus after 24 h. The cellular hydrolysis study showed that 98% of compound 10 was hydrolyzed intracellularly within 48 h and released doxorubicin.

CNT loading into cationic cholesterol suspensions show improved DNA binding and serum stability and ability to internalize into cancer cells.

Methods which disperse single-walled carbon nanotubes (SWNTs) in water as 'debundled', while maintaining their unique physical properties are highly useful. We present here a family of cationic cholesterol compounds (Chol+) {Cholest-5en-3ß-oxyethyl pyridinium bromide (Chol-PB+), Cholest-5en-3ß-oxyethyl N-methyl pyrrolidinium bromide (Chol-MPB+), Cholest-5en-3ß-oxyethyl N-methyl morpholinium bromide (Chol-MMB+) and Cholest-5en-3ß-oxyethyl diazabicyclo octanium bromide (Chol-DOB+)}. Each of these could be easily dispersed in water. The resulting cationic cholesterol (Chol+) suspensions solubilized single-walled carbon nanotubes (SWCNTs) by the non-specific physical adsorption of Chol+ to form stable, transparent, dark aqueous suspensions at room temperature. Electron microscopy reveals the existence of highly segregated CNTs in these samples. Zeta potential measurements showed an increase in potential of cationic cholesterol aggregates on addition of CNTs. The CNT-Chol+ suspensions were capable of forming stable complexes with genes (DNA) efficiently. The release of double-helical DNA from such CNT-Chol+ complexes could be induced upon the addition of anionic micellar solution of SDS. Furthermore, the CNT-based DNA complexes containing cationic cholesterol aggregates showed higher stability in fetal bovine serum media at physiological conditions. Confocal studies confirm that CNT-Chol+ formulations adhere to HeLa cell surfaces and get internalized more efficiently than the cationic cholesterol suspensions alone (devoid of any CNTs). These cationic cholesterol-CNT suspensions therefore appear to be a promising system for further use in biological applications.

Ionic liquid-supported synthesis of sulfonamides and carboxamides.

An ionic liquid-supported aldehyde was designed and converted to ionic liquid-supported secondary aryl amines through reductive amination. The reaction of ionic liquid-supported aryl amines with sulfonyl chlorides and acid chlorides, respectively, followed by cleavage using trifluoroacetic acid (TFA) afforded sulfonamides and caboxamides. To introduce additional diversity in the synthesis of sulfonamides and caboxamides, ionic liquid-supported iodosubstituted aryl amine was synthesized using the same strategy, and underwent Suzuki coupling reaction, followed by reaction with a methanesulfonyl chloride to generate the corresponding biaryl sulfonamide. The advantages of the protocol over solid-phase synthesis are homogeneous reaction medium, high loading, easy separation of products, and characterization of intermediates.

One-pot regioselective synthesis of tetrahydroindazolones and evaluation of their antiproliferative and Src kinase inhibitory activities.

A number of 2-substituted tetrahydroindazolones were synthesized by three-component condensation reaction of 1,3-diketones, substituted hydrazines, benzaldehydes, and Yb(OTf)(3) as a catalyst in [bmim][BF(4)] ionic liquid using a simple, efficient, and economical one-pot method. The synthesized tetrahydroindazolones were evaluated for inhibition of cell proliferation of human colon carcinoma (HT-29), human ovarian adenocarcinoma (SK-OV-3), and c-Src kinase activity. 3,4-Dichlorophenyl tetrahydroindazolone derivative (15) inhibited the cell proliferation of HT-29 and SK-OV-3 cells by 62% and 58%, respectively. 2,3-Diphenylsubstituted tetrahydroindazolone derivatives, inhibited the cell proliferation of HT-29 cells by 65-72% at a concentration of 50 µM. In general, the tetrahydroindazolones showed modest inhibition of c-Src kinase where 4-tertbutylphenyl- and 3,4-dichlorophenyl- derivatives showed the inhibition of c-Src kinase with IC(50) values of 35.1 and 50.7 µM, respectively.

3-substitued indoles: one-pot synthesis and evaluation of anticancer and Src kinase inhibitory activities.

An efficient and economical method was developed for the synthesis of 3-substituted indoles by one-pot three-component coupling reaction of a substituted or unsubstituted benzaldehyde, N-methylaniline, and indole or N-methylindole using Yb(OTf)(3)-SiO(2) as a catalyst. All the synthesized compounds were evaluated for inhibition of cell proliferation of human colon carcinoma (HT-29), human ovarian adenocarcinoma (SK-OV-3), and c-Src kinase activity. The 4-methylphenyl (4o and 4p) and 4-methoxyphenyl (4q) indole derivatives inhibited the cell proliferation of SK-OV-3 and HT-29 cells by 70-77% at a concentration of 50 µM. The unsubstituted phenyl (4d) and 3-nitrophenyl (4l) derivatives showed the inhibition of c-Src kinase with IC(50) values of 50.6 and 58.3 µM, respectively.