Recent Advancements of Aptamers in Cancer Therapy.

Aptamers are chemical antibodies possessing the capability of overcoming the limitations posed by conventional antibodies, particularly for diagnostic, therapeutic, and theranostic applications in cancer. The ease of chemical modifications or functionalization, including conjugations with nucleic acids, drug molecules, and nanoparticles, has made these aptamers to gain priorities in research. In this Mini-review, various reports on therapeutics with aptamer-functionalized nanomaterials for controlled or multistep drug release, targeted delivery, stimuli-responsive drug release, etc. are discussed. In the case of nucleic-acid-conjugated aptamers, DNA nanotrains and DNA beacons are discussed in terms of the possibility of multidrug loading for chemotherapy and gene therapy. Developments with electrochemical aptasensors and signal-enhanced immune aptasensors are also discussed. Further, the future scope of aptamer technology in cancer theranostics and the prevailing limitations are discussed.

2,3-Difunctionalized Benzo[b]thiophene Scaffolds Possessing Potent Antiangiogenic Properties.

A new class of 2-anilino-3-cyanobenzo[b]thiophenes (2,3-ACBTs) was studied for its antiangiogenic activity for the first time. One of the 2,3-ACBTs inhibited tubulogenesis in a dose-dependent manner without any toxicity. The 2,3-ACBTs significantly reduced neovascularization in both ex vivo and in vivo angiogenic assays without affecting the proliferation of endothelial cells. Neovascularization was limited through reduced phosphorylation of Akt/Src and depolymerization of f-actin and ß-tubulin filaments, resulting in reduced migration of cells. In addition, the 2,3-ACBT compound disrupted the preformed angiogenic tubules, and docking/competitive binding studies showed that it binds to VEGFR2. Compound 2,3-ACBT had good stability and intramuscular profile, translating in suppressing the tumor angiogenesis induced in a xenograft model. Overall, the present study suggests that 2,3-ACBT arrests angiogenesis by regulating the Akt/Src signaling pathway and deranging cytoskeletal filaments of endothelial cells.

Antitumor Effects of Ir(III)-2H-Indazole Complexes for Triple Negative Breast Cancer.

In this work, we have synthesized a series of novel C,N-cyclometalated 2H-indazole-ruthenium(II) and -iridium(III) complexes with varying substituents (H, CH3, isopropyl, and CF3) in the R4 position of the phenyl ring of the 2H-indazole chelating ligand. All of the complexes were characterized by 1H, 13C, high-resolution mass spectrometry, and elemental analysis. The methyl-substituted 2H-indazole-Ir(III) complex was further characterized by single-crystal X-ray analysis. The cytotoxic activity of new ruthenium(II) and iridium(III) compounds has been evaluated in a panel of triple negative breast cancer (TNBC) cell lines (MDA-MB-231 and MDA-MB-468) and colon cancer cell line HCT-116 to investigate their structure-activity relationships. Most of these new complexes have shown appreciable activity, comparable to or significantly better than that of cisplatin in TNBC cell lines. R4 substitution of the phenyl ring of the 2H-indazole ligand with methyl and isopropyl substituents showed increased potency in ruthenium(II) and iridium(III) complexes compared to that of their parent compounds in all cell lines. These novel transition metal-based complexes exhibited high specificity toward cancer cells by inducing alterations in the metabolism and proliferation of cancer cells. In general, iridium complexes are more active than the corresponding ruthenium complexes. The new Ir(III)-2H-indazole complex with an isopropyl substituent induced mitochondrial damage by generating large amounts of reactive oxygen species (ROS), which triggered mitochondrion-mediated apoptosis in TNBC cell line MDA-MB-468. Moreover, this complex also induced G2/M phase cell cycle arrest and inhibited cellular migration of TNBC cells. Our findings reveal the key roles of the novel C-N-cyclometalated 2H-indazole-Ir(III) complex to specifically induce toxicity in cancer cell lines through contributing effects of ROS-induced mitochondrial disruption along with chromosomal and mitochondrial DNA target inhibition.

Hepatoprotective and Antioxidant Capacity of Clerodendrum paniculatum Flower Extracts against Carbon Tetrachloride-Induced Hepatotoxicity in Rats.

The aim of the presented work involves the isolation, characterization, and evaluation of hepatoprotective potential of Clerodendrum paniculatum flower extracts. For this purpose, petroleum ether, chloroform, ethyl acetate, alcohol, and water extracts of C. paniculatum flower were screened for the flavonoid and phenolic content and quantified. Various antioxidant activity assays including 2,2'-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO) radical scavenging, 2,2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and reducing ability were carried out. Of the above methods, the alcoholic extract exhibited high antioxidant potential and was selected further for the hepatoprotective evaluations. Hepatoprotective evaluation of the alcoholic extract was carried out for carbon tetrachloride (CCl4)-intoxicated model systems. Enzymes associated with liver functions were estimated, and histopathological evaluations were carried out to monitor the liver architecture. Prominently, reduced levels of various associated enzymes along with increased protein content were observed when the liver specimen was pretreated with the extract. Moreover, the liver architecture was almost comparable to that of the normal control group. The column chromatographic analysis of the extract revealed 13 fractions to possess high phenolics and flavonoid contents. The best two fractions were identified for in vitro hepatoprotective evaluation in the goat liver model. Furthermore, the GC-MS analyses of the fractions were carried out followed by a library search, to identify the constituents responsible for the hepatoprotective activity which revealed the presence of four major constituents-pilocarpine, glyceric acid, pangamic acid, and gallic acid. An in vitro hepatoprotective study of the isolated fractions showed better activity compared to the whole alcoholic extract, and the results were comparable to the normal group taken as a control. The investigations with an in vitro model suggest that the isolated fraction with rich flavonoid content showed better hepatoprotective activity. GC-MS analysis of the fractions that displayed good hepatoprotective activity suggested the presence of pilocarpine, glyceric acid, pangamic acid, and gallic acid, while HPTLC analysis revealed the presence of quercetin.

Overview of Pathogenesis, Diagnostics, and Therapeutics of Infectious Diseases: Dengue and Zika.

The emergence of more virulent SARS virus has made scientists look back at other so-called neglected diseases such as dengue, Zika, and chikungunya, etc. Until recently these neglected diseases have not received much attention for their control or elimination from society. Over the past decade several attempts to investigate the pathogenicity, diagnostic, and therapeutic strategies for flavivirus caused diseases have been made. Herein we have reviewed the progress made toward the detection and treatment of two diseases-dengue and Zika. The above flavivirus related pathogenesis is concerned with the host immune system and known to be mediated through various receptors along with antibody-mediated disease enhancement. Moreover, researchers have been progressing toward discovering new drugs and therapeutic methods that target various stages of the flavivirus life cycle to minimize the above caused mortality and morbidity. The available diagnostics are based on serological, small molecule detection systems and point-of-care sensing devices. In this work, we have reviewed the advancements made toward understanding the pathogenesis, diagnostics, and therapeutics of the viral diseases caused by dengue and Zika.

Synthesis and Antitumor Activity Evaluation of Cyclometalated 2H-Indazole Ruthenium(II) and Iridium(III) Complexes.

In this work, a series of novel C-N cyclometalated 2H-indazole Ru(II) and Ir(III) complexes were synthesized, wherein chelating ligands with substituents like H, and isopropyl group in the R4 position of the phenyl ring of the 2H-indazole chelating ligand are present. The cytotoxicity of Ru(II) and Ir(III) complexes has been evaluated against different human cancer cell lines (HeLa, MCF-7, and A549) in a concentration-dependent manner. The new iridium complex with isopropyl substituent in the phenyl ring of the 2H-indazole moiety showed good cytotoxic activity against MCF-7 cells with an IC50 value 3.5 µM. The complex also exhibited cytotoxicity comparable to that of cisplatin. The ability of this compound inducing apoptosis was tested by nuclear condensation, cell membrane blebbing and caspase 3/7 activation. Further, this iridium complex is capable of inhibiting cancer cell migration when tested in MCF-7 cell line. Subsequently, we have studied the DNA binding and protein binding ability of the newly synthesized iridium complex.

Diversity-Oriented Synthesis of Thiazolidine-2-imines via Microwave-Assisted One-Pot, Telescopic Approach and Its Interaction with Biomacromolecules.

In this work, a one-pot, telescopic approach is described for the combinatorial library of thiazolidine-2-imines. The synthetic manipulation proceeds smoothly via the reaction of 2-aminopyridine/pyrazine/pyrimidine with substituted isothiocyanates followed by base catalyzed ring closure with 1,2-dibromoethane to obtain thiazolidine-2-imines with broad substrate scope and high functional group tolerance. The synthetic strategy merges well with the thiourea formation followed by base catalyzed ring closure reaction for the thiazolidine-2-imine synthesis in a more modular and straightforward approach. The synthetic procedure reported herein represents a cleaner route toward thiazolidine-2-imines as compared to traditional methodologies. Moreover, the biological significance of combinatorially synthesized thiazolidin-2-imines has been investigated for their use as possible inhibitors for acetyl cholinesterase through molecular docking studies.

One-Pot, Telescopic Approach for the Chemoselective Synthesis of Substituted Benzo[e]pyrido/pyrazino/pyridazino[1,2-b][1,2,4]thiadiazine dioxides and Their Significance in Biological Systems †.

The one-pot telescopic approach has been developed for the chemoselective synthesis of substituted benzo[e]pyrido/pyrazino/pyridazino[1,2-b][1,2,4]thiadiazine dioxides using readily available 2-aminopyridines/pyrazines/pyridazine and 2-chloro benzene sulfonyl chloride. This one-pot procedure involves the chemoselective sulfonylation of 2-aminopyridines/pyrazines/pyridazine with 2-chloro benzene sulfonyl chloride followed by a Cu(I)-catalyzed Ullmann-type C-N coupling reaction to obtain benzo[e]pyrido/pyrazino/pyridazino[1,2-b][1,2,4]thiadiazine dioxides with broad substrate scope and high functional group tolerance. The synthetic sequence merges well with the nucleophilic attack on the 2-amino group of pyridines/pyrazines/pyridazines on the 2-chloro benzene sulfonyl chloride, followed by Cu(I)-catalyzed ipso chloro displacement to C-N bond formation resulting in a more modular and straightforward approach. Moreover, the biological significance of the synthesized benzothiadiazine dioxides was evaluated by following their ability to bind to protein macromolecules and their anti-inflammatory activity.