Peptidoglycan (PGN) is a major component of bacterial cell wall and is recognized as a potent immunostimulant. The PGN in the cell envelope of Mycobacterium Tuberculosis has been shown to possess ...several unique characteristics including the presence of N-glycolyl groups (in addition to N-acetyl groups) in the muramic acid residues, and amidation of the free carboxylic acid of d-Glu or of meso-DAP in the peptide chains. Using a newly developed, highly stereoselective, chemoenzymatic approach for the synthesis of meso-DAP in peptide stems, we successfully synthesized for the first time, a series of Mycobacterium PGN fragments that include both mono- and disaccharides of MurNGlyc or 1,6-anhydro-MurNGlyc, as well as peptide-amidated variants. The ability of these PGN fragments to stimulate the immune system through activation of human Nod1 and Nod2 was examined. The PGN fragments were found to modulate immune stimulation, specifically, amidation at the d-Glu and meso-DAP in the peptide stem strongly reduced hNod1 activation. This effect was dependent on modification position. Additionally, N-glycolyl (instead of acetyl) of muramic acid was associated with slightly reduced human Nod1 and Nod2 stimulatory capabilities.
Cells are covered with a thick layer of sugar molecules known as glycans. Abnormal glycosylation is a hallmark of cancer, and hypersialylation increases tumor metastasis by promoting immune evasion ...and inducing tumor cell invasion and migration. Inhibiting sialylation is thus a potential anticancer treatment strategy. However, targeting sialic acids is difficult because of the lack of selective delivery tools. Here, we present a prodrug strategy for selectively releasing the global inhibitor of sialylation peracetylated 3F
ax
-Neu5Ac (PFN) in cancer cells using the reaction between phenyl azide and endogenous acrolein, which is overproduced in most cancer cells. The prodrug significantly suppressed tumor growth in mice as effectively as PFN without causing kidney dysfunction, which is associated with PFN. The use of sialylated glycans as immune checkpoints is gaining increasing attention, and the proposed method for precisely targeting aberrant sialylation provides a novel avenue for expanding current cancer treatments.
Chemical regulation of glycan synthesis at the targeted cancer cell surface in mice leading to significant anticancer effects without side effects.
Imine is one of the most versatile functional groups in chemistry and biochemistry fields. Although many biochemical reactions involve imine formation, the inherently unstable property of ...N‐alkyl‐α,β‐unsaturated imines still hindered their utilization in organic synthesis. In this article, we described that the N‐alkyl‐α,β‐unsaturated imines, which prepared from alkylamines and acrolein, could smoothly react through 4 + 4 cycloaddition to give eight‐membered diazacyclooctane derivatives in excellent yields. Under a similar condition, in the presence of formaldehyde, the 4 + 2 and 4 + 2 + 2 cycloadditions could lead to the formation of six‐membered hexahydropyrimidine or eight‐membered triazacyclooctanes, depending on the substituent of aldehydes. Moreover, an easy functional group manipulation of the cyclic products obtained from these cycloadditions can provide variously substituted chiral linear diamines. We can utilize these novel reactivities to reveal the unknown and essential properties of many biological processes that involve N‐alkyl‐unsaturated imines.
The formal 4 + 4, 4 + 2 and 4 + 2 + 2 cycloaddition could efficiently implement the stereocontrolled synthesis of substituted chiral 1,5‐diazacyclooctanes, hexahydropyrimidines, and 1,3,5‐triazacyclooctanes through using simple substrates, namely, substituted unsaturated aldehydes, chiral phenyl glycinol, or paraformaldehyde. And, these heterocyclic products can be converted into substituted chiral cyclic and linear 1,3‐diamines derivatives via simple functional group manipulation.
Natural glycoconjugates that form glycocalyx play important roles in various biological processes based on cell surface recognition through pattern recognition mechanisms. This work represents a new ...synthesis‐based screening strategy to efficiently target the cancer cells by higher‐order glycan pattern recognition in both cells and intact animals (mice). The use of the very fast, selective, and effective RIKEN click reaction (6π‐azaelectrocyclization of unsaturated imines) allows to synthesize and screen various structurally well‐defined glycoalbumins containing two and eventually four different N‐glycan structures in a very short time. The importance of glycan pattern recognition is exemplified in both cell‐ and mouse‐based experiments. The use of pattern recognition mechanisms for cell targeting represents a novel and promising strategy for the development of diagnostic, prophylactic, and therapeutic agents for various diseases including cancers.
Very fast and selective RIKEN click reaction allows to synthesize and screen various structurally well‐defined glycoalbumins containing four different N‐glycan structures in a very short time. Pattern recognition mechanisms for cell targeting in mice represent a novel and promising strategy for diagnostic, prophylactic, and therapeutic agents for various diseases, including cancers.
Targeted α-particle therapy (TAT) is an attractive alternative to conventional therapy for cancer treatment. Among the available radionuclides considered for TAT, astatine-211 (
211
At) attached to a ...cancer-targeting molecule appears very promising. Previously, we demonstrated that aryl azide derivatives could react selectively with the endogenous acrolein generated by cancer cells to give a diazo compound, which subsequently forms a covalent bond with the organelle of cancer cells
in vivo
. Herein, we synthesized
211
At-radiolabeled 2,6-diisopropylphenyl azide (ADIPA), an α-emitting molecule that can selectively target the acrolein of cancer cells, and investigated its antitumor effect. Our results demonstrate that a single intratumor or intravenous administration of this simple α-emitting molecule to the A549 (human lung cancer) cell-bearing xenograft mouse model, at a low dose (70 kBq), could suppress tumor growth without inducing adverse effects. Furthermore, because acrolein is generally overproduced by most cancer cells, we believe ADIPA is a simple TAT compound that deserves further investigation for application in animal models and humans with various cancer types and stages.
We developed
211
At-radiolabeled 2,6-diisopropylphenyl azide (ADIPA) for targeted α-particle therapy. In the experiment using a mouse model, low-dose (70 kBq) administration of ADIPA effectively suppressed tumor growth without causing adverse effects.
Targeted α-particle therapy (TAT) is an attractive alternative to conventional therapy for cancer treatment. Among the available radionuclides considered for TAT, astatine-211 (211At) attached to a ...cancer-targeting molecule appears very promising. Previously, we demonstrated that aryl azide derivatives could react selectively with the endogenous acrolein generated by cancer cells to give a diazo compound, which subsequently forms a covalent bond with the organelle of cancer cells in vivo. Herein, we synthesized 211At-radiolabeled 2,6-diisopropylphenyl azide (ADIPA), an α-emitting molecule that can selectively target the acrolein of cancer cells, and investigated its antitumor effect. Our results demonstrate that a single intratumor or intravenous administration of this simple α-emitting molecule to the A549 (human lung cancer) cell-bearing xenograft mouse model, at a low dose (70 kBq), could suppress tumor growth without inducing adverse effects. Furthermore, because acrolein is generally overproduced by most cancer cells, we believe ADIPA is a simple TAT compound that deserves further investigation for application in animal models and humans with various cancer types and stages.
Targeted α-particle therapy (TAT) is an attractive alternative to conventional therapy for cancer treatment. Among the available radionuclides considered for TAT, astatine-211 (
At) attached to a ...cancer-targeting molecule appears very promising. Previously, we demonstrated that aryl azide derivatives could react selectively with the endogenous acrolein generated by cancer cells to give a diazo compound, which subsequently forms a covalent bond with the organelle of cancer cells
. Herein, we synthesized
At-radiolabeled 2,6-diisopropylphenyl azide (ADIPA), an α-emitting molecule that can selectively target the acrolein of cancer cells, and investigated its antitumor effect. Our results demonstrate that a single intratumor or intravenous administration of this simple α-emitting molecule to the A549 (human lung cancer) cell-bearing xenograft mouse model, at a low dose (70 kBq), could suppress tumor growth without inducing adverse effects. Furthermore, because acrolein is generally overproduced by most cancer cells, we believe ADIPA is a simple TAT compound that deserves further investigation for application in animal models and humans with various cancer types and stages.
In article number 2004831, Almira Kurbangalieva, Katsunori Tanaka, and co‐workers successfully apply the glycan pattern recognition mechanisms for developing a promising cancer targeting strategy in ...both cell‐ and mouse‐based experiments. The use of the very fast, selective and effective RIKEN click reaction allows to synthesize and screen various structurally well‐defined glycoalbumins containing four different N‐glycan structures in a very short time, as novel diagnostic, prophylactic, and therapeutic agents.
Non-enzymatic glycation between proteins and carbohydrates, such as advanced glycation end products (AGEs), are naturally occurring compounds implicated in aging and numerous degenerative diseases. ...Methyl glyoxal (MG), which is an intermediate of the AGE biosynthetic pathway, is known to react with primary amines of proteins to create a wide range of AGE modifications, such as carboxyethyl lysine (CEL) and methylglyoxal-derived lysine dimer (MOLD). As a means to investigate and probe the ROS production pathways of AGEs, low molecular weight compounds carboxyethyl spermine (CES) and methylglyoxal-derived spermine dimer (MOSD) were synthesized, which replace lysine with another highly nucleophilic biological amine, spermine (SPM). Contrary to expectations, results show CES- and MOSD-induced oxidative stress proceeds through different pathways. As such, we have developed useful probes that can be used to better understand and investigate pathways related to acrolein-based oxidative stress and/or polyamine metabolic pathways.
Cancer cells are known to over-express TRAF6 that is critical for both AKT and TAK1 activations. The Really Interesting New Gene (RING) domain of TRAF6 is believed to be responsible for the E3 ligase ...activity, ZINC fingers of TRAF6 provide critical support for the activity of the RING domain which is critical for both AKT and TAK1 activations.
We employed computational docking program to identify small molecules that could effectively and competitively bind with the RING domain of TRAF6, which is believed to be responsible for its E3 ligase activity. MTT assay and flow cytometry were employed to analyze apoptosis of cancer cells. Signaling pathways were detected using immunoprecipitation and western blotting, and immunofluorescence was pursued to assess the nature of binding of cinchonine to TRAF6. We also performed animal experiments to test effect of cinchonine in vivo.
Cinchonine, a naturally occurring Cinchona alkaloid identified from the docking study, could bind to TRAF6 in HeLa and A549 cells and induce apoptosis of these cancer cells. We found that AKT ubiquitination and phosphorylation as well as phosphorylation of TAK1 were decreased. These activities would lead to subsequent suppression anti-apoptotic protein Bcl-2, while elevating pro-apoptotic protein Bax. Immunofluorescence staining unambiguously demonstrated the binding of cinchonine specifically at the RING domain of TRAF6 in cells, thereby validating the computational modeling. Animal experiments showed that cinchonine could suppress tumor growth in mice without showing significant acute toxicity.
These investigations suggest that through competitive binding with the RING domain of TRAF6, cinchonine could induce apoptosis via inhibiting AKT and TAK1 signaling pathways.
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