7 Tetrazine-Based Cycloadditions in Click Chemistry

2022 ◽  
Author(s):  
W. Kuba ◽  
M. Wilkovitsch ◽  
J. C. T. Carlson ◽  
H. Mikula
Keyword(s):  
Reaction Mechanisms ◽  
Chemical Biology ◽  
Bond Cleavage ◽  
Therapeutic Strategies ◽  
Complex Environments ◽  
Bioorthogonal Chemistry ◽  
Bioorthogonal Reaction ◽  
Low Concentrations ◽  
Time Critical

AbstractThe spontaneous cycloaddition of tetrazines with a number of different dienophiles has become a powerful tool in chemical biology, in particular for the biocompatible conjugation and modification of (bio)molecules. The exceptional reaction kinetics made these bioorthogonal ligations the methods of choice for time-critical processes at very low concentrations, facilitating controlled molecular transformations in complex environments and even in vivo. The emerging concept of bond-cleavage reactions triggered by tetrazine-based cycloadditions enabled the design of diagnostic and therapeutic strategies. The tetrazine-triggered activation of prodrugs represents the first bioorthogonal reaction performed in humans, marking the beginning of the era of clinical translation of bioorthogonal chemistry. This chapter provides an overview of the synthesis and reactivity of tetrazines, their cycloadditions with various dienophiles, and transformations triggered by these reactions, focusing on reaction mechanisms, kinetics and efficiency, and selected applications.

scholarly journals Impact of Deoxycholic Acid on Oesophageal Adenocarcinoma Invasion: Effect on Matrix Metalloproteinases

2020 ◽  
Vol 21 (21) ◽  
pp. 8042
Author(s):  
Fran Quilty ◽  
Anne-Marie Byrne ◽  
John Aird ◽  
Sheeren El Mashad ◽  
Adolfo Parra-Blanco ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Deoxycholic Acid ◽  
Therapeutic Strategies ◽  
Oesophageal Adenocarcinoma ◽  
Low Concentrations ◽  
Cancer Invasiveness ◽  
Mrna And Protein Expression

Bile acids (BAs) have been implicated in the development of oesophagitis, Barrett’s oesophagus and oesophageal adenocarcinoma (OAC). However, whether BAs promote cancer invasiveness has not been elucidated. We evaluated the role of BAs, in particular deoxycholic acid (DCA), in OAC invasion. Migration and invasiveness in untreated and BA-treated oesophageal SKGT-4 cancer cells were evaluated. Activity and expression of different matrix metalloproteinases (MMPs) were determined by zymography, ELISA, PCR and Western blot. Finally, human OAC tissues were stained for MMP-10 by immunohistochemistry. It was found that SKGT-4 cells incubated with low concentrations of DCA had a significant increase in invasion. In addition, MMP-10 mRNA and protein expression were also increased in the presence of DCA. MMP-10 was found to be highly expressed both in-vitro and in-vivo in neoplastic OAC cells relative to non-neoplastic squamous epithelial cells. Our results show that DCA promotes OAC invasion and MMP-10 overexpression. This study will advance our understanding of the pathophysiological mechanisms involved in human OAC and shows promise for the development of new therapeutic strategies.

scholarly journals Synthetic promoter based azide biosensor toolkit to advance chemical-biology

2020 ◽  
Author(s):  
Chandra Kanth Bandi ◽  
Kyle S. Skalenko ◽  
Ayushi Agrawal ◽  
Neelan Sivaneri ◽  
Margaux Thiry ◽  
...  
Keyword(s):  
Chemical Biology ◽  
Fluorescent Protein ◽  
Low Cost ◽  
Expression System ◽  
Detection Methods ◽  
Synthetic Promoter ◽  
Bioorthogonal Reaction ◽  
Green Fluorescent

AbstractReal-time azide or azido-functionalized molecular detection inside living cells using bioorthogonal chemistry-based approaches has been revolutionary to advancing chemical-biology. These methods have enabled diverse applications ranging from understanding the role of cellular glycosylation pathways, identifying diseased cells, and targeting delivery of azido-based therapeutic drugs. However, while classical techniques were applicable only to in-vitro detection of such functional groups, even recent bioorthogonal based-detection methods require expensive sensing reagents and also cannot selectively identify inorganic azide. Here, we report an in-vivo synthetic promoter based azide biosensor toolkit to selectively detect azide anions. A promiscuous cyanate-specific promoter was engineered to detect azide and rapidly induce expression of green fluorescent protein (GFP) in Escherichia coli. Our synthetic azide operon allows highly-tunable GFP expression, outperforming the classic lac-operon, and also offers an alternative low-cost protein expression system. Finally, we showcase the utility of this toolkit for in-vivo bioorthogonal reaction biosensing and glycoengineering based applications.

Tetrazines-Mediated Bioorthogonal Removal of 3-Isocyanopropyl Groups Enables the Controlled Release of Nitric Oxide In Vivo

2021 ◽  
Author(s):  
Jianbing Wu ◽  
Tao Sun ◽  
Chenxi Yang ◽  
Tian Lv ◽  
Yu-Yang Bi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Free Radical ◽  
Controlled Release ◽  
Bond Cleavage ◽  
Bioorthogonal Chemistry

Bond cleavage bioorthogonal chemistry has been widely employed to restore or activate proteins or prodrugs. Nitric Oxide (NO), as a free radical molecule, has joined the clinical arena of cancer...

Kinetics of Various 99mTc-Sn-Pyrophosphate Compounds in the Rat

1977 ◽  
Vol 16 (04) ◽  
pp. 157-162 ◽  
Author(s):  
C. Schümichen ◽  
B. Mackenbrock ◽  
G. Hoffmann
Keyword(s):  
Normal Saline ◽  
Half Life ◽  
Compound A ◽  
Short Half Life ◽  
Low Concentrations ◽  
The Stability ◽  
Kinetics Of ◽  
In Vitro Stability

SummaryThe bone-seeking 99mTc-Sn-pyrophosphate compound (compound A) was diluted both in vitro and in vivo and proved to be unstable both in vitro and in vivo. However, stability was much better in vivo than in vitro and thus the in vitro stability of compound A after dilution in various mediums could be followed up by a consecutive evaluation of the in vivo distribution in the rat. After dilution in neutral normal saline compound A is metastable and after a short half-life it is transformed into the other 99mTc-Sn-pyrophosphate compound A is metastable and after a short half-life in bone but in the kidneys. After dilution in normal saline of low pH and in buffering solutions the stability of compound A is increased. In human plasma compound A is relatively stable but not in plasma water. When compound B is formed in a buffering solution, uptake in the kidneys and excretion in urine is lowered and blood concentration increased.It is assumed that the association of protons to compound A will increase its stability at low concentrations while that to compound B will lead to a strong protein bond in plasma. It is concluded that compound A will not be stable in vivo because of a lack of stability in the extravascular space, and that the protein bond in plasma will be a measure of its in vivo stability.

99mTc-Sn-Pyrophosphate Complexes, an Investigation of its Possible Structures

1974 ◽  
Vol 13 (03) ◽  
pp. 252-257 ◽  
Author(s):  
K. Rörvik - Schümichen ◽  
G. Hoffmann ◽  
C. Schümichen
Keyword(s):  
In Vivo Distribution ◽  
Low Concentrations ◽  
Distribution Studies

SummaryAt least two different 99mTc-Sn-pyrophosphate complexes are formed, as it is shown by comparative in vivo distribution studies: A 2 : 2 Sn : pyrophosphate complex is predominant at higher concentrations. Only this complex shows bone seeking properties. A 2 : 1 Sn : pyrophosphate complex exists only at low concentrations. This complex shows no deposition in bone but in the kidneys. Which complex is predominant depends on the pyrophosphate concentration in the equilibrium. Both complexes are rapidly excreted by the kidneys.

scholarly journals Tumor-associated macrophages: potential therapeutic strategies and future prospects in cancer

2021 ◽  
Vol 9 (1) ◽  
pp. e001341
Author(s):  
Chunxiao Li ◽  
Xiaofei Xu ◽  
Shuhua Wei ◽  
Ping Jiang ◽  
Lixiang Xue ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Poor Prognosis ◽  
Tumor Immunotherapy ◽  
Therapeutic Strategies ◽  
Preclinical Studies ◽  
Future Prospects ◽  
Tumor Associated Macrophages

Macrophages are the most important phagocytes in vivo. However, the tumor microenvironment can affect the function and polarization of macrophages and form tumor-associated macrophages (TAMs). Usually, the abundance of TAMs in tumors is closely associated with poor prognosis. Preclinical studies have identified important pathways regulating the infiltration and polarization of TAMs during tumor progression. Furthermore, potential therapeutic strategies targeting TAMs in tumors have been studied, including inhibition of macrophage recruitment to tumors, functional repolarization of TAMs toward an antitumor phenotype, and other therapeutic strategies that elicit macrophage-mediated extracellular phagocytosis and intracellular destruction of cancer cells. Therefore, with the increasing impact of tumor immunotherapy, new antitumor strategies to target TAMs are now being discussed.

scholarly journals Fighting Bisphenol A-Induced Male Infertility: The Power of Antioxidants

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 289
Author(s):  
Joana Santiago ◽  
Joana V. Silva ◽  
Manuel A. S. Santos ◽  
Margarida Fardilha
Keyword(s):  
Male Infertility ◽  
Bisphenol A ◽  
Sperm Concentration ◽  
In Vivo Studies ◽  
Sperm Dna Damage ◽  
Testicular Cells ◽  
Low Concentrations ◽  
Sperm Dna ◽  
Male Reproductive Health

Bisphenol A (BPA), a well-known endocrine disruptor present in epoxy resins and polycarbonate plastics, negatively disturbs the male reproductive system affecting male fertility. In vivo studies showed that BPA exposure has deleterious effects on spermatogenesis by disturbing the hypothalamic–pituitary–gonadal axis and inducing oxidative stress in testis. This compound seems to disrupt hormone signalling even at low concentrations, modifying the levels of inhibin B, oestradiol, and testosterone. The adverse effects on seminal parameters are mainly supported by studies based on urinary BPA concentration, showing a negative association between BPA levels and sperm concentration, motility, and sperm DNA damage. Recent studies explored potential approaches to treat or prevent BPA-induced testicular toxicity and male infertility. Since the effect of BPA on testicular cells and spermatozoa is associated with an increased production of reactive oxygen species, most of the pharmacological approaches are based on the use of natural or synthetic antioxidants. In this review, we briefly describe the effects of BPA on male reproductive health and discuss the use of antioxidants to prevent or revert the BPA-induced toxicity and infertility in men.

scholarly journals Phage-Encoded Endolysins

Antibiotics ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 124
Author(s):  
Fatma Abdelrahman ◽  
Maheswaran Easwaran ◽  
Oluwasegun I. Daramola ◽  
Samar Ragab ◽  
Stephanie Lynch ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cell Wall ◽  
Antibiotic Resistance ◽  
Bacterial Infections ◽  
Therapeutic Strategies ◽  
Therapeutic Application ◽  
Significant Evidence ◽  
Crucial Information

Due to the global emergence of antibiotic resistance, there has been an increase in research surrounding endolysins as an alternative therapeutic. Endolysins are phage-encoded enzymes, utilized by mature phage virions to hydrolyze the cell wall from within. There is significant evidence that proves the ability of endolysins to degrade the peptidoglycan externally without the assistance of phage. Thus, their incorporation in therapeutic strategies has opened new options for therapeutic application against bacterial infections in the human and veterinary sectors, as well as within the agricultural and biotechnology sectors. While endolysins show promising results within the laboratory, it is important to document their resistance, safety, and immunogenicity for in-vivo application. This review aims to provide new insights into the synergy between endolysins and antibiotics, as well as the formulation of endolysins. Thus, it provides crucial information for clinical trials involving endolysins.

scholarly journals In Bacillus subtilis, the Sirtuin Protein Deacetylase, Encoded by the srtN Gene (Formerly yhdZ), and Functions Encoded by the acuABC Genes Control the Activity of Acetyl Coenzyme A Synthetase

2009 ◽  
Vol 191 (6) ◽  
pp. 1749-1755 ◽  
Author(s):  
Jeffrey G. Gardner ◽  
Jorge C. Escalante-Semerena
Keyword(s):  
Bacillus Subtilis ◽  
Coenzyme A ◽  
Acetyl Coenzyme A ◽  
Acetyl Coenzyme ◽  
New Information ◽  
Low Concentrations ◽  
Dependent Protein ◽  
Protein Deacetylase

ABSTRACT This report provides in vivo evidence for the posttranslational control of the acetyl coenzyme A (Ac-CoA) synthetase (AcsA) enzyme of Bacillus subtilis by the acuA and acuC gene products. In addition, both in vivo and in vitro data presented support the conclusion that the yhdZ gene of B. subtilis encodes a NAD+-dependent protein deacetylase homologous to the yeast Sir2 protein (also known as sirtuin). On the basis of this new information, a change in gene nomenclature, from yhdZ to srtN (for sirtuin), is proposed to reflect the activity associated with the YdhZ protein. In vivo control of B. subtilis AcsA function required the combined activities of AcuC and SrtN. Inactivation of acuC or srtN resulted in slower growth and cell yield under low-acetate conditions than those of the wild-type strain, and the acuC srtN strain grew under low-acetate conditions as poorly as the acsA strain. Our interpretation of the latter result was that both deacetylases (AcuC and SrtN) are needed to maintain AcsA as active (i.e., deacetylated) so the cell can grow with low concentrations of acetate. Growth of an acuA acuC srtN strain on acetate was improved over that of the acuA + acuC srtN strain, indicating that the AcuA acetyltransferase enzyme modifies (i.e., inactivates) AcsA in vivo, a result consistent with previously reported in vitro evidence that AcsA is a substrate of AcuA.

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