Delivery of gene editing therapeutics.

For the past decades, gene editing demonstrated the potential to attenuate each of the root causes of genetic, infectious, immune, cancerous, and degenerative disorders. More recently, Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR-associated protein 9 (CRISPR-Cas9) editing proved effective for editing genomic, cancerous, or microbial DNA to limit disease onset or spread. However, the strategies to deliver CRISPR-Cas9 cargos and elicit protective immune responses requires safe delivery to disease targeted cells and tissues.

SMALPs Are Not Simply Nanodiscs: The Polymer-to-Lipid Ratios of Fractionated SMALPs Underline Their Heterogeneous Nature.

Amphipathic styrene-maleic acid (SMA) copolymers directly solubilize biomembranes into SMA-lipid particles, or SMALPs, that are often regarded as nanodiscs and hailed as a native membrane platform. The promising outlook of SMALPs inspires the discovery of many SMA-like copolymers that also solubilize biomembranes into putative nanodiscs, but a fundamental question remains on how much the SMALPs or SMALP analogues truly resemble the bilayer structure of nanodiscs. This unfortunate ambiguity undermines the utility of SMA or SMA-like copolymers in membrane biology because the structure and function of many membrane proteins depend critically on their surrounding matrices.

pH-sensitive nanomedicine of novel tubulin polymerization inhibitor for lung metastatic melanoma.

Microtubule binding agents such as paclitaxel and vincristine have activity in metastatic melanoma. However, even responsive tumors develop resistance, highlighting the need to investigate new drug molecules. Here, we showed that a new compound, CH-2-102, developed by our group, has high anti-tumor efficacy in human and murine melanoma cells.

Nanodiscs: a versatile nanocarrier platform for cancer diagnosis and treatment.

Cancer therapy is a significant challenge due to insufficient drug delivery to the cancer cells and non-selective killing of healthy cells by most chemotherapy agents. Nano-formulations have shown great promise for targeted drug delivery with improved efficiency. The shape and size of nanocarriers significantly affect their transport inside the body and internalization into the cancer cells.

Hydrophilic nanoparticles that kill bacteria while sparing mammalian cells reveal the antibiotic role of nanostructures.

To dissect the antibiotic role of nanostructures from chemical moieties belligerent to both bacterial and mammalian cells, here we show the antimicrobial activity and cytotoxicity of nanoparticle-pinched polymer brushes (NPPBs) consisting of chemically inert silica nanospheres of systematically varied diameters covalently grafted with hydrophilic polymer brushes that are non-toxic and non-bactericidal. Assembly of the hydrophilic polymers into nanostructured NPPBs doesn't alter their amicability with mammalian cells, but it incurs a transformation of their antimicrobial potential against bacteria, including clinical multidrug-resistant strains, that depends critically on the nanoparticle sizes. The acquired antimicrobial potency intensifies with small nanoparticles but subsides quickly with large ones.

Nanoformulation design and therapeutic potential of a novel tubulin inhibitor in pancreatic cancer.

Successful treatment of pancreatic cancer remains a challenge due to desmoplasia, development of chemoresistance, and systemic toxicity. Herein, we synthesized (6-(3-hydroxy-4-methoxylphenyl)pyridin-2-yl) (3,4,5-trimethoxyphenyl)methanone (CH-3-8), a novel microtubule polymerization inhibitor with little susceptible to transporter-mediated chemoresistance. CH-3-8 binding to the colchicine-binding site in tubulin protein was confirmed by tubulin polymerization assay and molecular modeling.

Functional similarity of modified cascade impactor to deposit drug particles on cells.

Pulmonary drug delivery is a non-invasive and effective route for local or systemic drug administration. Despite several products in the market, the mechanism of drug absorption from the lungs is not well understood. An in vitro model for aerosol deposition and transport across epithelia that uses particle deposition may be a good predictor of and help understand in vivo drug disposition.

Nanoparticulate delivery of potent microtubule inhibitor for metastatic melanoma treatment.

Melanoma is the most aggressive type of skin cancer, which readily metastasizes through lymph nodes to the lungs, liver, and brain. Since the repeated administration of most chemotherapeutic drugs develops chemoresistance and severe systemic toxicities, herein we synthesized 2-(4-hydroxy-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl) methanone (abbreviated as QW-296), a novel tubulin destabilizing agent with little susceptible to transporter-mediated drug resistance. QW-296 disturbed the microtubule dynamics at the nanomolar concentration in A375 and B16F10 melanoma cells.

Post-Ugi Cyclization for the Construction of Diverse Heterocyclic Compounds: Recent Updates.

Multicomponent reactions (MCRs) have proved as a valuable tool for organic and medicinal chemist because of their ability to introduce a large degree of chemical diversity in the product in a single step and with high atom economy. One of the dominant MCRs is the Ugi reaction, which involves the condensation of an aldehyde (or ketone), an amine, an isonitrile, and a carboxylic acid to afford an α-acylamino carboxamide adduct. The desired Ugi-adducts may be constructed by careful selection of the building blocks, opening the door for desired post-Ugi modifications.

Design of Hedgehog pathway inhibitors for cancer treatment.

Hedgehog (Hh) signaling is involved in the initiation and progression of various cancers and is essential for embryonic and postnatal development. This pathway remains in the quiescent state in adult tissues but gets activated upon inflammation and injuries. Inhibition of Hh signaling pathway using natural and synthetic compounds has provided an attractive approach for treating cancer and inflammatory diseases.

Recent advances in spirocyclization of indole derivatives.

Spiroindolines and spiroindoles are an important class of spirocyclic compounds present in a wide range of pharmaceuticals and biologically important natural alkaloids. Various spiroindolines and spiroindoles possess versatile reactivity which enables them to act as precursors for other privileged heterocycles. In view of the importance of this scaffold, many researchers focused their efforts to develop facile and mild synthetic methods for spirocyclization of indoles.

Polysubstituted 2-aminoimidazoles as anti-biofilm and antiproliferative agents: Discovery of potent lead.

Most of the human bacterial infections are associated with the biofilm formation and the natural tolerance of biofilms to antibiotics challenges treatment. Because of their low immunity, cancer patients are especially susceptible to bacterial infections. Compounds with anti-biofilm activity could therefore become a useful adjunct to chemotherapy, in particular if they also show antiproliferative activities.

4-Substituted thieno[2,3-d]pyrimidines as potent antibacterial agents: Rational design, microwave-assisted synthesis, biological evaluation and molecular docking studies.

In an attempt to discover a new class of antibacterial agents with improved efficacy and to overcome the drug-resistant problems, some novel 4-substituted thieno[2,3-d]pyrimidines have been synthesized via microwave-assisted methodology and evaluated for their in vitro antibacterial activity against various pathogenic bacterial strains. Compounds 12b and 13c showed the promising inhibitory potencies against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa and Escherichia coli with MICs ranging from 2 to 10 μg/ml. Compound 13c was also found to be highly potent against methicillin-resistant S.

Development, optimization and characterization of glycyrrhetinic acid-chitosan nanoparticles of atorvastatin for liver targeting.

Glycyrrhetinic acid-modified chitosan (mGA-suc-CTS) is used as liver-targeted carrier for drug delivery. In this study, nanoparticles were prepared by ionic gelation process, and glycyrrhetinic acid act as the targeting ligand. The structure of the product was confirmed by IR and NMR techniques.

Design and Green Synthesis of Thieno[2,3-d]pyrimidine Analogues as Potential Antiproliferative Agents.

Background: Despite of significant progress achieved in the chemotherapy of cancer; it is still among the leading cause of morbidity and mortality worldwide.

Objective: Taking cognizance of the extensive biological potential of reported thieno[2,3-d]pyrimidines and inspired by the clinically available anticancer agents dasatinib and gefitinib, 4-substituted thieno[2,3-d]pyrimidines have been synthesized.

Methods: The compounds were synthesized via microwave-assisted methods and screened for their cytotoxic activity against liver HepG-2, lung NCI-H522, melanoma A-375, pancreatic MIA PaCa-2 and colon CaCo-2 human cancer cell lines using MTT assay.

Alzheimer's disease: Is this a brain specific diabetic condition?

Alzheimer's disease (AD) and type 2 diabetes (T2DM) are the two major health issues affecting millions of elderly people worldwide, with major impacts in the patient's daily life. Numerous studies have demonstrated that patients with diabetes have an increased risk of developing AD compared with healthy individuals. The principal biological mechanisms that associate with the progression of diabetes and AD are not completely understood.

Chemistry and Bioactivities of Aristeromycins: An Overview.

The majority of carbocyclic nucleosides are of synthetic origin; nature has provided two of the most interesting compounds, aristeromycin and neplanocin A. Aristeromycin and its modified derivatives are an important group of carbocyclic nucleosides that exhibits a wide range of pharmacological properties such as antiviral, anticancer and antitoxoplasma activities. Especially, aristeromycins are widely used as antiviral agents against human immunodeficiency virus, hepatitis B virus, herpes simplex virus, varicella-zoster virus, influenza virus and hepatitis C virus.

Medicinal Attributes of Imidazo[1,2-a]pyridine Derivatives: An Update.

The imidazo[1,2-a]pyridine scaffold is recognized as a privileged structure as it represents a promising area for identification of lead structures towards the discovery of new synthetic drug molecules. Several commercial drugs such as Zolpidem, Olprinone, Soraprazan and many other compounds in biological testing and preclinical evaluation, illustrate the wide therapeutic spectrum in this class of drug scaffolds. The present manuscript represents the assimilation of literature pertaining to medicinal aspects of this pharmacophore including the structure-activity relationships.

Review on EGFR Inhibitors: Critical Updates.

Epidermal Growth Factor Receptor (EGFR) is a transmembrane glycoprotein that constitutes one of the four members of ErbB family of tyrosine kinase receptors. Activation of EGFR leads to autophosphorylation of receptor tyrosine kinase that initiates a cascade of downstream signaling pathways involved in regulating cellular proliferation, differentiation, and survival. EGFR is abnormally activated by various mechanisms like receptor overexpression, mutation, ligand-dependent receptor dimerization, ligand-independent activation and is associated with the development of variety of human cancers.

New 2-Imino-2H-Chromene-3(N-aryl)carboxamides as Potential Cytotoxic Agents.

Synthesis and structure activity relationships of four series of novel 2-imino-2H-chromene-3(N-aryl) carboxamides (V-VIII) have been described by bioisosteric replacement of usually present ketone at 2nd position of coumarin with imine. Various substitutents are introduced on aryl and chromene ring of iminocoumarin to investigate the effect of lipophilicity and electronic properties of substituents on cytotoxic activity against four human cancer cell lines. Novel 2-imino-2H-chromene-3(N-aryl)carboxamides (V-VIII) were synthesized by the reaction of substituted 2- cyanoacetamides with different salicyaldehydes in the presence of sodium acetate in glacial acetic acid.

Animal models of hepatotoxicity.

Introduction: Liver is the largest and important organ in the body, involved in the metabolism of food and drugs. Liver diseases are potentially life threatening for humans. The etiology of liver disorder varied due to different reasons like autoimmune disorder, viral infection, toxic chemical, and due to changing diet style.

Herbs to curb cyclic nucleotide phosphodiesterase and their potential role in Alzheimer's disease.

Cyclic nucleotides viz., cAMP/cGMP has been well known to play important role in cellular function and deficiency in their levels has been implicated in the pathogenesis of various neurodegenerative disorders including Alzheimer's disease (AD). Phosphodiesterases (PDE) are the enzymes involved in the metabolism of cyclic nucleotides and the inhibition of phosphodiesterases is considered to be viable strategy to restore the level of cyclic nucleotides and their functions in the brain.

Recent advances in the chemistry and biology of benzothiazoles.

Benzothiazole is a privileged heterocyclic scaffold having a benzene ring fused with a five-membered thiazole ring. This moiety has attracted considerable attention because of its wide range of pharmacological activities such as antitubercular, antimicrobial, antimalarial, anticonvulsant, anthelmintic, analgesic, anti-inflammatory, antidiabetic, antitumor activity, etc. In the last few years, some novel benzothiazoles have been developed with varied biological activities.

Recent development in [1,4]benzodiazepines as potent anticancer agents: a review.

The [1,4]benzodiazepine is an important class of heterocyclic compounds and clinically used for many ailments in humans. The [1,4]benzodiazepine has unique structure that mimics the peptide linkage. This interesting observation completely shifted the interest of medicinal chemist for [1,4]benzodiazepine from CNS acting drugs to anticancer agents.