Quinazoline Based HDAC Dual Inhibitors as Potential Anti-Cancer Agents.

Cancer is the most devastating disease and second leading cause of death around the world. Despite scientific advancements in the diagnosis and treatment of cancer which can include targeted therapy, chemotherapy, endocrine therapy, immunotherapy, radiotherapy and surgery in some cases, cancer cells appear to outsmart and evade almost any method of treatment by developing drug resistance. Quinazolines are the most versatile, ubiquitous and privileged nitrogen bearing heterocyclic compounds with a wide array of biological and pharmacological applications. Most of the anti-cancer agents featuring quinazoline pharmacophore have shown promising therapeutic activity. Therefore, extensive research is underway to explore the potential of these privileged scaffolds. In this context, a molecular hybridization approach to develop hybrid drugs has become a popular tool in the field of drug discovery, especially after witnessing the successful results during the past decade. Histone deacetylases (HDACs) have emerged as an important anti-cancer target in the recent years given its role in cellular growth, gene regulation, and metabolism. Dual inhibitors, especially based on HDAC in particular, have become the center stage of current cancer drug development. Given the growing significance of dual HDAC inhibitors, in this review, we intend to compile the development of quinazoline based HDAC dual inhibitors as anti-cancer agents.

Role of Indole Scaffolds as Pharmacophores in the Development of Anti-Lung Cancer Agents.

Lung cancer is the leading cause of death in men and women worldwide, affecting millions of people. Between the two types of lung cancers, non-small cell lung cancer (NSCLC) is more common than small cell lung cancer (SCLC). Besides surgery and radiotherapy, chemotherapy is the most important method of treatment for lung cancer. Indole scaffold is considered one of the most privileged scaffolds in heterocyclic chemistry. Indole may serve as an effective probe for the development of new drug candidates against challenging diseases, including lung cancer. In this review, we will focus on discussing the existing indole based pharmacophores in the clinical and pre-clinical stages of development against lung cancer, along with the synthesis of some of the selected anti-lung cancer drugs. Moreover, the basic mechanism of action underlying indole based anti-lung cancer treatment, such as protein kinase inhibition, histone deacetylase inhibition, DNA topoisomerase inhibition, and tubulin inhibition will also be discussed.

Design, synthesis and biological evaluation of piperazino-enaminones as novel suppressants of pro-Inflammatory cytokines.

Infection triggers the release of pro-inflammatory cytokines (TNF-alpha and IL-6). Over-production, however, cause tissue injury seen in severe asthma. The ability of enaminone E121 to reduce pro-inflammatory cytokines in our laboratory encouraged further examination of its structural scaffold. Piperazino-enaminones were designed by incorporating n-arylpiperazine motif into the aromatic enaminone. Four possible modifications were explored systematically. Synthesis was accomplished by amination of the corresponding methyl/ethyl 2,4-dioxo-6-(substituted)cyclohexane-carboxylate.. Sixteen novel compounds were synthesized. Biological activity was tested in J774 macrophages stimulated with lipopolysaccharides. The release of cytokines was measured via ELISA. Four compounds significantly suppressed TNF-alpha and IL-6 release in dose-dependent manner.

Emission tuning of fluorescent kinase inhibitors: conjugation length and substituent effects.

Fluorescent N-phenyl-4-aminoquinazoline probes targeting the ATP-binding pocket of the ERBB family of receptor tyrosine kinases are reported. Extension of the aromatic quinazoline core with fluorophore "arms" through substitution at the 6- position of the quinazoline core with phenyl, styryl, and phenylbutadienyl moieties was predicted by means of TD-DFT calculations to produce probes with tunable photoexcitation energies and excited states possessing charge-transfer character. Optical spectroscopy identified several synthesized probes that are nonemissive in aqueous solutions and exhibit emission enhancements in solvents of low polarity, suggesting good performance as turn-on fluorophores. Ligand-induced ERBB2 phosphorylation assays demonstrate that despite chemical modification to the quinazoline core these probes still function as ERBB2 inhibitors in MCF7 cells. Two probes were found to exhibit ERBB2-induced fluorescence, demonstrating the utility of these probes as turn-on, fluoroescent kinase inhibitors.

Defining NAD(P)(H) Catabolism.

Dietary vitamin B3 components, such as nicotinamide and nicotinic acid, are precursors to the ubiquitous redox cofactor nicotinamide adenine dinucleotide (NAD+). NAD+ levels are thought to decline with age and disease. While the drivers of this decline remain under intense investigation, strategies have emerged seeking to functionally maintain NAD+ levels through supplementation with NAD+ biosynthetic intermediates. These include marketed products, such as nicotinamide riboside (NR) and its phosphorylated form (NMN). More recent developments have shown that NRH (the reduced form of NR) and its phosphorylated form NMNH also increases NAD+ levels upon administration, although they initially generate NADH (the reduced form of NAD+). Other means to increase the combined levels of NAD+ and NADH, NAD(H), include the inhibition of NAD+-consuming enzymes or activation of biosynthetic pathways. Multiple studies have shown that supplementation with an NAD(H) precursor changes the profile of NAD(H) catabolism. Yet, the pharmacological significance of NAD(H) catabolites is rarely considered although the distribution and abundance of these catabolites differ depending on the NAD(H) precursor used, the species in which the study is conducted, and the tissues used for the quantification. Significantly, some of these metabolites have emerged as biomarkers in physiological disorders and might not be innocuous. Herein, we review the known and emerging catabolites of the NAD(H) metabolome and highlight their biochemical and physiological function as well as key chemical and biochemical reactions leading to their formation. Furthermore, we emphasize the need for analytical methods that inform on the full NAD(H) metabolome since the relative abundance of NAD(H) catabolites informs how NAD(H) precursors are used, recycled, and eliminated.

A fluorescent reporter of ATP binding-competent receptor kinases.

ERBB receptor kinases play a crucial role in normal development and cancer malignancies. A broad range of modifications creates receptor subpopulations with distinct functional properties in live cells. Their apparent activation state, typically assayed by tyrosine phosphorylation of substrates, reflects a complex equilibrium of competing reactions. With the aim of developing optical tools to investigate ERBB populations and their state of activation, we have synthesized a fluorescent 'turn-on' probe, DMAQ, targeting the ERBB ATP binding pocket. Upon binding, probe emission increases due to the hydrophobic environment and restricted geometry of the ERBB2 kinase domain, facilitating the analysis of receptor states at low occupancy and without the removal of unbound probes. Cellular ERBB2 autophosphorylation is inhibited with saturation kinetics that correlate with the increase in probe fluorescence. Thus, DMAQ is an example of a new generation of 'turn-on' probes with potential applications in querying receptor kinase populations both in vitro and in live cells.

FDA-Approved Oximes and Their Significance in Medicinal Chemistry.

Despite the scientific advancements, organophosphate (OP) poisoning continues to be a major threat to humans, accounting for nearly one million poisoning cases every year leading to at least 20,000 deaths worldwide. Oximes represent the most important class in medicinal chemistry, renowned for their widespread applications as OP antidotes, drugs and intermediates for the synthesis of several pharmacological derivatives. Common oxime based reactivators or nerve antidotes include pralidoxime, obidoxime, HI-6, trimedoxime and methoxime, among which pralidoxime is the only FDA-approved drug. Cephalosporins are ß-lactam based antibiotics and serve as widely acclaimed tools in fighting bacterial infections. Oxime based cephalosporins have emerged as an important class of drugs with improved efficacy and a broad spectrum of anti-microbial activity against Gram-positive and Gram-negative pathogens. Among the several oxime based derivatives, cefuroxime, ceftizoxime, cefpodoxime and cefmenoxime are the FDA approved oxime-based antibiotics. Given the pharmacological significance of oximes, in the present paper, we put together all the FDA-approved oximes and discuss their mechanism of action, pharmacokinetics and synthesis.

Free-fatty acid receptor-4 (FFA4) modulates ROS generation and COX-2 expression via the C-terminal ß-arrestin phosphosensor in Raw 264.7 macrophages.

Agonism of the G protein-coupled free-fatty acid receptor-4 (FFA4) has been shown to promote numerous anti-inflammatory effects in macrophages that arise due to interaction with ß-arrestin partner proteins. Humans express functionally distinct short and long FFA4 splice variants, such that FFA4-S signals through Gαq/11 and ß-arrestin, while FFA4-L is intrinsically biased solely towards ß-arrestin signaling. Recently, we and others have shown that phosphorylation of the FFA4 C-terminal tail is responsible for ß-arrestin interactability and signaling. Given the significance of ß-arrestin in the anti-inflammatory function of FFA4, the goal of this study was to examine the role of the C-terminal ß-arrestin phosphosensor in FFA4 signaling induced by PMA and LPS in murine Raw 264.7 macrophages. Our data reveal for the first time that both FFA4 isoforms modulate PMA-induced ROS generation, and that abolishment of the FFA4-S, but not FFA4-L C-terminal phosphosensor, is detrimental to this effect. Furthermore, we show that while both isoforms reduce PMA-induced expression of COX-2, removal of the FFA4-S phosphosensor significantly decreases this response, suggesting that these effects of FFA4-S are ß-arrestin mediated. On the contrary, FFA4-S, as well as the truncated C-terminal congener lacking the ß-arrestin phosphosensor were both able to reduce LPS-induced NF-κB activity and ERK1/2 phosphorylation. However, FFA4-L and its corresponding mutant were incapable of modulating either, suggesting that these responses are mediated by G protein coupling. Taken together, our data reveal important structure-function and signaling differences between the two FFA4 isoforms, and for the first time link FFA4 to modulation of ROS in macrophages.

Novel Piperazino-Enaminones Suppress Pro-Inflammatory Cytokines and Inhibit Chemokine Receptor CCR2.

Pro-inflammatory mediators including TNF-alpha, IL-6, and nitric oxide are important for the regulation of the immune response when an infection is present, but when overproduced, it can be responsible for the development of tissue and organ injury seen in sepsis, as well as severe asthma, and autoimmune diseases such as Crohn's disease and rheumatoid arthritis. Data from our lab to characterize the novel compound enaminone E121 have suggested that macrophages stimulated with lipopolysaccharide (LPS) release significantly decreased levels of TNF-alpha and IL-6 as measured by enzyme-linked immunosorbent assay as compared to the DMSO control group. Additionally, functional experiments in a mouse model of asthma have shown that E121 is efficacious in decreasing airway hyperresponsiveness. A new set of compounds synthesized in our lab (JODI) have an N-aryl piperazino motif incorporated on the aromatic side of the enaminone pharmacophore. It was hypothesized that this would enhance their immunosuppressive activity as anti-inflammatory agents by also acting as a chemokine receptor antagonist. Our studies suggest that JODI appears to suppress TNF-alpha and IL-6 in a dose-dependent manner. The JODI compounds were also more effective in reducing TNF-alpha after LPS stimulation when compared to dexamethasone. Lastly, studies using MCP-1 suggest that the JODI compounds, and not E121, are able to block CCR2 signaling as evidenced by decreased total ERK1/2. These studies indicate that E121 and its corresponding piperazino analogs could act as strong anti-inflammatory agents in asthma or other autoimmunities where efficacious therapeutic options are needed.

Highly chromic, proton-responsive phenyl pyrimidones.

Aryl pyrimidones are pharmacologically relevant compounds whose optical properties have only been partially explored. We report the synthesis and optical characterization of a series of aryl- and diaryl-2(1H)-pyrimidones. The electronic transitions of these chromophores are modulated by the extent of conjugation between the pendant phenyl ring and the pyrimidone core as well as the presence of electron-donating auxochromes. Monoprotonation of the pyrimidone ring results in large hyperchromic and bathochromic shifts as well as switching of fluorescence making these phenyl pyrimidones of interest as sensory materials.