Nitrogen containing heterocycles are of immense research interest because they are often found as naturally occurring bioactive compounds. The prominence of N-heterocycles makes it vital to develop ...methods to increase their synthetic efficiencies and probe the effects of their modifications on biological efficacy. Medicinal chemists have exploited microwave-assisted organic synthesis (MAOS) to facilitate the development of complex heterocyclic structures. MAOS is a growing synthetic methodology among medicinal chemists and has proven to be more efficient in terms of reaction yield, reaction time, product purity and environmental friendliness for many reactions when compared to conventional thermal methods for cycloaddition and selective functionalization. The importance of nitrogen containing ring systems in medicine cannot be understated, as such ring systems have shown to be applicable in compounds such as vitamins, herbicides, anti-fungal agents, anti-bacterial agents and anti-cancer agents, among other things. The significance of these applications has created an unprecedented need for more efficient synthetic methods. This review presents an overview of MAOS and its role in recent and pressing advancements for the synthesis of small- and medium-sized nitrogen containing heterocycles, including pyrroles, indoles, pyridines, pyrrolidines, imidazoles, pyrazoles, pyrazolines, lactams, and 1,2,3-triazoles, which are significant scaffolds for compounds with medicinal uses.
Nitrogen containing heterocycles are of immense research interest because they are often found as naturally occurring bioactive compounds.
The typical method for creating targeted contrast agents requires covalent conjugation of separate targeting and fluorophore domains. In this study, we demonstrate that it is possible to create ...near-infrared (NIR) fluorophores with different tissue specificities driven by their inherent chemical structures. Thus, a single compact molecule performs both targeting and imaging. We use this strategy to solve a major problem in head and neck surgery: the identification and preservation of parathyroid and thyroid glands. We synthesized 700-nm and 800-nm halogenated fluorophores that show high uptake into these glands after a single intravenous (IV) injection of 0.06 mg kg(-1) in a pig. By using a dual-channel NIR imaging system, we observed-in real time and with high sensitivity-the unambiguous distinction of parathyroid and thyroid glands simultaneously in the context of blood and surrounding soft tissue. This novel technology lays a foundation for performing head and neck surgery with increased precision and efficiency along with potentially lower morbidity, and it provides a general strategy for developing targeted NIR fluorophores.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
NIR fluorescent small molecules for intraoperative imaging Owens, Eric A.; Lee, Stephanie; Choi, JungMun ...
Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology,
November/December 2015, Letnik:
7, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Recent advances in bioimaging and nanomedicine have permitted the exploitation of molecular optical imaging in image‐guided surgery; however, the parameters mediating optimum performance of contrast ...agents are not yet precisely determined. To develop ideal contrast agents for image‐guided surgery, we need to consider the following criteria: (1) excitation and emission wavelengths in the near‐infrared (NIR) window, (2) optimized optical characteristics for high in vivo performance, (3) overcoming or harnessing biodistribution and clearance, and (4) reducing nonspecific uptake. The design considerations should be focused on optimizing the optical and physicochemical property criteria. Biodistribution and clearance should first be considered because they mediate the fate of a contrast agent in the body such as how long after intravenous injection a contrast agent reaches the peak signal‐to‐background ratio (SBR) and how long the signal lasts (retention). WIREs Nanomed Nanobiotechnol 2015, 7:828–838. doi: 10.1002/wnan.1337
This article is categorized under:
Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
A Western-style diet, which is high in fat and sugar, can cause significant dyslipidemia and nonalcoholic fatty liver disease; the diet has an especially strong effect in women, regardless of total ...calorie intake. Dietary supplementation with beneficial microbes might reduce the detrimental effects of a Western-style diet. We assessed the effects of Lactococcus lactis subspecies (subsp) cremoris on weight gain, liver fat, serum cholesterol, and insulin resistance in female mice on a high-fat, high-carbohydrate diet.
Female C57BL/6 mice were fed either a high-fat, high-carbohydrate (Western-style) diet that contained 40% fat (mostly milk fat) and 43% carbohydrate (mostly sucrose) or a calorie-matched-per-gram control diet. The diets of mice were supplemented with 1 × 109 colony-forming units of L lactis subsp cremoris ATCC 19257 or Lactobacillus rhamnosus GG ATCC 53103 (control bacteria) 3 times per week for 16 weeks. Body weights were measured, and fecal, blood, and liver tissues were collected and analyzed. Livers were analyzed for fat accumulation and inflammation, and blood samples were analyzed for cholesterol and glucose levels. Mice were housed within Comprehensive Lab Animal Monitoring System cages, and respiratory exchange ratio and activity were measured. Hepatic lipid profiles of L lactis subsp cremoris–supplemented mice were characterized by lipidomics mass spectrometry analysis.
Mice fed L lactis subsp cremoris while on the Western-style diet gained less weight, developed less hepatic steatosis and inflammation, and had a lower mean serum level of cholesterol and body mass index than mice fed the control bacteria. Mice fed the L lactis subsp cremoris had increased glucose tolerance while on the Western-style diet compared to mice fed control bacteria and had alterations in hepatic lipids, including oxylipins.
Dietary supplementation with L lactis subsp cremoris in female mice on a high-fat, high-carbohydrate (Western-style) diet caused them to gain less weight, develop less liver fat and inflammation, reduce serum cholesterol levels, and increase glucose tolerance compared with mice on the same diet fed control bacteria. L lactis subsp cremoris is safe for oral ingestion and might be developed for persons with metabolic and liver disorders caused by a Western-style diet.
Display omitted
A novel class of near‐infrared fluorescent contrast agents was developed. These agents target cartilage with high specificity and this property is inherent to the chemical structure of the ...fluorophore. After a single low‐dose intravenous injection and a clearance time of approximately 4 h, these agents bind to all three major types of cartilage (hyaline, elastic, and fibrocartilage) and perform equally well across species. Analysis of the chemical structure similarities revealed a potential pharmacophore for cartilage targeting. Our results lay the foundation for future improvements in tissue engineering, joint surgery, and cartilage‐specific drug development.
Seeing red: Near‐infrared fluorophores specific for cartilage were synthesized and their performance tested in small and large animal models. These agents not only bind all types of cartilage in all species tested, but they can also be combined with other targeted near‐infrared fluorophores, such as those specific to bone, to provide unprecedented biomedical optical imaging.
Near-infrared (NIR) fluorescent contrast agents are emerging in optical imaging as sensitive, cost-effective, and nonharmful alternatives to current agents that emit harmful ionizing radiation. ...Developing spectrally distinct NIR fluorophores to visualize sensitive vital tissues to selectively avoid them during surgical resection of diseased tissue is of great significance. Herein, we report the synthetic variation of pentamethine cyanine fluorophores with modifications of physicochemical properties toward prompting tissue-specific uptake into sensitive tissues (i.e., endocrine glands). Tissue-specific targeting and biodistribution studies revealed localization of contrast agents in the adrenal and pituitary glands, pancreas, and lymph nodes with dependence on molecular characteristics. Incorporation of hydrophobic heterocyclic rings, alkyl groups, and halogens allowed a fine-tuning capability to the hydrophobic character and dipole moment for observing perturbation in biological activity in response to minor structural alterations. These NIR contrast agents have potential for clinical translation for intraoperative imaging in the delineation of delicate glands.
The success of near-infrared (NIR) fluorescence to be employed for intraoperative imaging relies on the ability to develop a highly stable, NIR fluorescent, nontoxic, biocompatible, and highly ...excreted compound that retains a reactive functionality for conjugation to a cancer-recognizing peptide. Herein, systematic modifications to previously detailed fluorophore ZW800-1 are explored. Specific modifications, including the isosteric replacement of the O atom of ZW800-1, include nucleophilic amine and sulfur species attached to the heptamethine core. These novel compounds have shown similar satisfactory results in biodistribution and clearance while also expressing increased stability in serum. Most importantly, all of the synthesized and evaluated compounds display a reactive functionality (either a free amino group or carboxylic acid moiety) for further bioconjugation. The results obtained from the newly prepared derivatives demonstrate that the central substitution with the studied linking agents retains the ultralow background in vivo performance of the fluorophores regardless of the total net charge.
Our initial efforts to prepare tissue-specific near-infrared (NIR) fluorescent compounds generated successful correlation between physicochemical properties and global uptake in major organs after ...systemic circulation and biodistribution. Herein, we focus on the effects on biodistribution based on modulating electronic influencing moieties from donating to withdrawing moieties at both the heterocyclic site and through meso-substitution of pentamethine cyanine fluorophores. These selected modifications harnessed innate biodistribution pathways through the structure-inherent targeting, resulting in effective imaging of the adrenal glands, pituitary gland, lymph nodes, pancreas, and thyroid and salivary glands. These native-tissue contrast agents will arm surgeons with a powerful and versatile arsenal for intraoperative NIR imaging in real time.
Protein arginine methyltransferase 1 (PRMT1) is involved in many biological activities, such as gene transcription, signal transduction, and RNA processing. Overexpression of PRMT1 is related to ...cardiovascular diseases, kidney diseases, and cancers; therefore, selective PRMT1 inhibitors serve as chemical probes to investigate the biological function of PRMT1 and drug candidates for disease treatment. Our previous work found trimethine cyanine compounds that effectively inhibit PRMT1 activity. In our present study, we systematically investigated the structure–activity relationship of cyanine structures. A pentamethine compound, E-84 (compound 50), showed inhibition on PRMT1 at the micromolar level and 6- to 25-fold selectivity over CARM1, PRMT5, and PRMT8. The cellular activity suggests that compound 50 permeated the cellular membrane, inhibited cellular PRMT1 activity, and blocked leukemia cell proliferation. Additionally, our molecular docking study suggested compound 50 might act by occupying the cofactor binding site, which provided a roadmap to guide further optimization of this lead compound.
A time-efficient and eco-conscious microwave methodology was developed and applied to synthesize a systematic library of pentamethine cyanine dyes and their corresponding precursors. The synthesis ...outlined herein drastically reduced the reaction pathway for pentamethine carbocyanine dye syntheses from days to min, as well as producing increased yields (89–98%) to the conventional heating method (18–64%). Twelve examples of pentamethine cyanine dyes were synthesized by means of microwave-assisted organic synthesis which provided excellent yield in expedited reaction time and were obtained using facile isolation methods. Furthermore, three cyanines were prepared with a novel methylene dioxy heterocyclic structure which imparted an approximately 40 nm bathochromic shift compared to unsubstituted counterparts; these results were shown to be in agreement with DFT calculations and HOMO-LUMO energy differences.
Display omitted
•The synthesis of pentamethine cyanines was developed using eco-friendly methods.•Dipole moment calculations helped determine optimum microwave reaction temperature.•Three compounds feature red-shifted optical properties arising from a methylene dioxy group.•HOMO-LUMO energy gaps agree with the observed wavelengths.
PDF
