-
Journal of Medicinal Chemistry Aug 2018SMA is an inherited disease that leads to loss of motor function and ambulation and a reduced life expectancy. We have been working to develop orally administrated,...
SMA is an inherited disease that leads to loss of motor function and ambulation and a reduced life expectancy. We have been working to develop orally administrated, systemically distributed small molecules to increase levels of functional SMN protein. Compound 2 was the first SMN2 splicing modifier tested in clinical trials in healthy volunteers and SMA patients. It was safe and well tolerated and increased SMN protein levels up to 2-fold in patients. Nevertheless, its development was stopped as a precautionary measure because retinal toxicity was observed in cynomolgus monkeys after chronic daily oral dosing (39 weeks) at exposures in excess of those investigated in patients. Herein, we describe the discovery of 1 (risdiplam, RG7916, RO7034067) that focused on thorough pharmacology, DMPK and safety characterization and optimization. This compound is undergoing pivotal clinical trials and is a promising medicine for the treatment of patients in all ages and stages with SMA.
Topics: Animals; Azo Compounds; Drug Discovery; Humans; Muscular Atrophy, Spinal; Pyrimidines; RNA Splicing; Safety; Survival of Motor Neuron 2 Protein
PubMed: 30044619
DOI: 10.1021/acs.jmedchem.8b00741 -
British Journal of Pharmacology Jul 2017Azoreductases are flavoenzymes that have been characterized in a range of prokaryotes and eukaryotes. Bacterial azoreductases are associated with the activation of two... (Review)
Review
UNLABELLED
Azoreductases are flavoenzymes that have been characterized in a range of prokaryotes and eukaryotes. Bacterial azoreductases are associated with the activation of two classes of drug, azo drugs for the treatment of inflammatory bowel disease and nitrofuran antibiotics. The mechanism of reduction of azo compounds is presented; it requires tautomerisation of the azo compound to a quinoneimine and provides a unifying mechanism for the reduction of azo and quinone substrates by azoreductases. The importance of further work in the characterization of azoreductases from enteric bacteria is highlighted to aid in the development of novel drugs for the treatment of colon related disorders. Human azoreductases are known to play a crucial role in the metabolism of a number of quinone-containing cancer chemotherapeutic drugs. The mechanism of hydride transfer to quinones, which is shared not only between eukaryotic and prokaryotic azoreductases but also the wider family of NAD(P)H quinone oxidoreductases, is outlined. The importance of common single nucleotide polymorphisms (SNPs) in human azoreductases is described not only in cancer prognosis but also with regard to their effects on the efficacy of quinone drug-based cancer chemotherapeutic regimens. This highlights the need to screen patients for azoreductase SNPs ahead of treatment with these regimens.
LINKED ARTICLES
This article is part of a themed section on Drug Metabolism and Antibiotic Resistance in Micro-organisms. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.14/issuetoc.
Topics: Anti-Bacterial Agents; Antineoplastic Agents; Azo Compounds; Bacteria; Humans; NADH, NADPH Oxidoreductases; Neoplasms; Nitrofurans; Nitroreductases; Quinones
PubMed: 27487252
DOI: 10.1111/bph.13571 -
Molecules (Basel, Switzerland) Sep 2022Azo molecules, characterized by the presence of a -N=N- double bond, are widely used in various fields due to their sensitivity to external stimuli, ch as light. The... (Review)
Review
Azo molecules, characterized by the presence of a -N=N- double bond, are widely used in various fields due to their sensitivity to external stimuli, ch as light. The emergence of bacterial resistance has pushed research towards designing new antimicrobial molecules that are more efficient than those currently in use. Many authors have attempted to exploit the antimicrobial activity of azobenzene and to utilize their photoisomerization for selective control of the bioactivities of antimicrobial molecules, which is necessary for antibacterial therapy. This review will provide a systematic and consequential approach to coupling azobenzene moiety with active antimicrobial molecules and drugs, including small and large organic molecules, such as peptides. A selection of significant cutting-edge articles collected in recent years has been discussed, based on the structural pattern and antimicrobial performance, focusing especially on the photoactivity of azobenzene and the design of smart materials as the most targeted and desirable application.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Azo Compounds
PubMed: 36080413
DOI: 10.3390/molecules27175643 -
Mini Reviews in Medicinal Chemistry 2018Azo dyes are widely used in textile, fiber, cosmetic, leather, paint and printing industries. Besides their characteristic coloring function, azo compounds are reported... (Review)
Review
Azo dyes are widely used in textile, fiber, cosmetic, leather, paint and printing industries. Besides their characteristic coloring function, azo compounds are reported as antibacterial, antiviral, antifungal and cytotoxic agents. They have the ability to be used as drug carriers, either by acting as a 'cargo' that entrap therapeutic agents or by prodrug approach. The drug is released by internal or external stimuli in the region of interest, as observed in colon-targeted drug delivery. Besides drug-like and drug carrier properties, a number of azo dyes are used in cellular staining to visualize cellular components and metabolic processes. However, the biological significance of azo compounds, especially in cancer chemotherapy, is still in its infancy. This may be linked to early findings that declared azo compounds as one of the possible causes of cancer and mutagenesis. Currently, researchers are screening the aromatic azo compounds for their potential biomedical use, including cancer diagnosis and therapy. In this review, we highlight the medical applications of azo compounds, particularly related to cancer research. The biomedical significance of cis-trans interchange and negative implications of azo compounds are also discussed in brief.
Topics: Anti-Infective Agents; Antineoplastic Agents; Azo Compounds; Carcinogens; Coloring Agents; Drug Delivery Systems; Humans; Isomerism; Mutagens; Prodrugs
PubMed: 29792144
DOI: 10.2174/1389557518666180524113111 -
Journal of Natural Products Nov 2020Azoxy compounds belong to a small yet intriguing group of natural products sharing a common functional group with the general structure RN═N(O)R. Their intriguing... (Review)
Review
Azoxy compounds belong to a small yet intriguing group of natural products sharing a common functional group with the general structure RN═N(O)R. Their intriguing chemical structures, diverse biological activities, and important industrial applications have received attention from researchers in natural product chemistry, total synthesis, and biosynthesis. This review presents current updates about the structural diversity of natural azoxy compounds isolated from different organisms and highlights the enzymes and biological logic involved in their construction. We assume that the identification of key enzymes will provide efficient tools in biocatalysis to generate new azoxy compounds, while genome mining may result in novel natural azoxy compounds of medical and industrial interest.
Topics: Azo Compounds; Biocatalysis; Biological Products
PubMed: 33197183
DOI: 10.1021/acs.jnatprod.0c00725 -
Current Topics in Medicinal Chemistry 2018The development of new antimicrobial drugs is a very challenging task owing to the rapidly developing drug resistance among the existing drugs. The hybridization of... (Review)
Review
The development of new antimicrobial drugs is a very challenging task owing to the rapidly developing drug resistance among the existing drugs. The hybridization of active and novel compounds is a commonly used approach to combat this situation. The azo linkage (N=N) is successfully used to link two bioactive moieties to enhance the therapeutic effects. The hybrid derivatives linked by azo linkage have shown their activity by acting on target proteins in microorganisms, cell wall inhibitors, DHPS inhibitors, RNA Editing Ligase 1 inhibitors, the general protein secretory (Sec) pathway inhibitors, neuraminidase inhibitors, etc. The current review covers the general enzymes and regulatory pathways in microorganisms targeted by diazenyl compounds and recent developments pertaining to diazenyl derivatives as antimicrobial agents during the last five years. This information will prove useful to the researchers for the development of novel antimicrobial agents by slight modifications in active derivatives with improved activities.
Topics: Animals; Anti-Infective Agents; Azo Compounds; Enzyme Inhibitors; Humans; Microbial Sensitivity Tests
PubMed: 29412106
DOI: 10.2174/1568026618666180206093107 -
Food and Chemical Toxicology : An... Aug 2023Azo compounds are widely distributed synthetic chemicals in the modern world. Their most important applications are as dyes, but, in addition, several azo compounds are... (Review)
Review
Azo compounds are widely distributed synthetic chemicals in the modern world. Their most important applications are as dyes, but, in addition, several azo compounds are used as pharmaceuticals. Ingested azo compounds can be reduced by the action of bacteria in the gut, where the oxygen tension is low, and the development of microbiome science has allowed more precise delineation of the roles of specific bacteria in these processes. Reduction of the azo bond of an azo compound generates two distinct classes of aromatic amine metabolites: the starting material that was used in the synthesis of the azo compound and a product which is formed de novo by metabolism. Reductive metabolism of azo compounds can have toxic consequences, because many aromatic amines are toxic/genotoxic. In this review, we discuss aspects of the development and application of azo compounds in industry and medicine. Current understanding of the toxicology of azo compounds and their metabolites is illustrated with four specific examples - Disperse Dyes used for dyeing textiles; the drugs phenazopyridine and eltrombopag; and the ubiquitous food dye, tartrazine - and knowledge gaps are identified. SUBMISSION TO: FCT VSI: Toxicology of Dyes.
Topics: Azo Compounds; Coloring Agents; Tartrazine; Bacteria; Amines
PubMed: 37451600
DOI: 10.1016/j.fct.2023.113932 -
Chemistry & Biodiversity Nov 2021Bacteria can produce nitrogenous compounds via both primary and secondary metabolic processes. Many bacterial volatile nitrogenous compounds produced during the... (Review)
Review
Bacteria can produce nitrogenous compounds via both primary and secondary metabolic processes. Many bacterial volatile nitrogenous compounds produced during the secondary metabolism have been identified and reported for their antioxidant, antibacterial, antifungal, algicidal and antitumor activities. The production of these nitrogenous compounds depends on several factors, including the composition of culture media, growth conditions, and even the organic solvent used for their extraction, thus requiring their identification in specific conditions. In this review, we describe the volatile nitrogenous compounds produced by bacteria especially focusing on their antimicrobial activity. We concentrate on azo-compounds mainly pyrazines and pyrrolo-pyridines reported for their activity against several microorganisms. Whenever significant, extraction and identification methods of these compounds are also mentioned and discussed. To the best of our knowledge, this is first review describing volatile nitrogenous compounds from bacteria focusing on their biological activity.
Topics: Anti-Bacterial Agents; Azo Compounds; Bacteria; Microbial Sensitivity Tests; Molecular Structure; Volatile Organic Compounds
PubMed: 34643327
DOI: 10.1002/cbdv.202100549 -
Critical Reviews in Biotechnology Aug 2016Azo dyes and their intermediate degradation products are common contaminants of soil and groundwater in developing countries where textile and leather dye products are... (Review)
Review
Azo dyes and their intermediate degradation products are common contaminants of soil and groundwater in developing countries where textile and leather dye products are produced. The toxicity of azo dyes is primarily associated with their molecular structure, substitution groups and reactivity. To avoid contamination of natural resources and to minimize risk to human health, this wastewater requires treatment in an environmentally safe manner. This manuscript critically reviews biological treatment systems and the role of bacterial reductive and oxidative enzymes/processes in the bioremediation of dye-polluted wastewaters. Many studies have shown that a variety of culturable bacteria have efficient enzymatic systems that can carry out complete mineralization of dye chemicals and their metabolites (aromatic compounds) over a wide range of environmental conditions. Complete mineralization of azo dyes generally involves a two-step process requiring initial anaerobic treatment for decolorization, followed by an oxidative process that results in degradation of the toxic intermediates that are formed during the first step. Molecular studies have revealed that the first reductive process can be carried out by two classes of enzymes involving flavin-dependent and flavin-free azoreductases under anaerobic or low oxygen conditions. The second step that is carried out by oxidative enzymes that primarily involves broad specificity peroxidases, laccases and tyrosinases. This review focuses, in particular, on the characterization of these enzymes with respect to their enzyme kinetics and the environmental conditions that are necessary for bioreactor systems to treat azo dyes contained in wastewater.
Topics: Animals; Azo Compounds; Bacteria; Bacterial Proteins; Biodegradation, Environmental; Coloring Agents; Humans; Oxidoreductases; Water Pollutants, Chemical
PubMed: 25665634
DOI: 10.3109/07388551.2015.1004518 -
Organic & Biomolecular Chemistry Nov 2018Molecular photoswitches are a class of chemical structures that can readily isomerize between distinct geometries upon irradiation with light. Molecular photoswitches... (Review)
Review
Molecular photoswitches are a class of chemical structures that can readily isomerize between distinct geometries upon irradiation with light. Molecular photoswitches are utilized to control protein structure and function with temporal and spatial precision. In this review, we summarize the recent progress in the development of azobenzene-based molecular photoswitches and their applications in the photocontrol of protein structure and function. For clarity of discussion, we divide the known photoswitchable proteins into different categories: protein motifs, ion channels, receptors, and enzymes. Basic approaches and considerations for the structure-guided design of photoswitchable ligands are discussed. The applications and limitations of current photoswitches are also discussed.
Topics: Azo Compounds; Humans; Light; Protein Conformation; Protein Folding; Proteins
PubMed: 30375620
DOI: 10.1039/c8ob02157k